Dubermatinib (DMB, TP-0903), a benzenesulfonamide, is an inhibitor of the tyrosine kinase AXL, which is a member of the TAM family, and can prevent GAS6-mediated activation of AXL in cancer cells. Patients with previously treated chronic lymphocytic leukemia are being studied in phase I/II clinical trials to determine its antineoplastic potential (CLL). In the current work, the reactive intermediates of DMB were studied using liquid chromatography-mass spectrometry (LC-MS). Human liver microsomes (HLMs) were exposed to dimethylbenzene in a laboratory setting, and the resulting metabolites were collected through protein precipitation. Intense reactivity toward nucleophilic macromolecules was seen in the metabolites of the piperazine and pyrimidine rings in DMB, iminium and 2,5-quinone-imine, respectively. To assess the toxicities of the possibly reactive metabolites, DMB was incubated with HLMs in the presence of 1.0 mM KCN and 1.0 mM glutathione. The DMB metabolites found by LC-MS/MS were seven in vitro phase I metabolites, three cyano adducts, and two GSH conjugates. Phase I in vitro metabolic reactions included N-demethylation, hydroxylation, and dechlorination. The in vitro metabolism of DMB and the metabolites it produces have not been studied before.

The brain's unique characteristics make it exceptionally susceptible to oxidative stress, which arises from an imbalance between reactive oxygen species (ROS) production, reactive nitrogen species (RNS) production, and antioxidant defense mechanisms. This review explores the factors contributing to the brain vascular tone vulnerability in the presence of oxidative damage, which can be of clinical interest in critically ill patients or presenting acute brain injuries. The brain's high metabolic rate and inefficient electron transport chain in mitochondria lead to significant ROS generation. Moreover, non-replicating neuronal cells and low repair capacity increase susceptibility to oxidative insult. ROS can influence cerebral vascular tone and permeability, with a potential impact on cerebral autoregulation. Different ROS species, including superoxide and hydrogen peroxide, exhibit vasodilatory or vasoconstrictive effects on cerebral blood vessels. Reactive nitrogen species (RNS), particularly NO and peroxynitrite, also exert vasoactive effects. This review further investigates the neuroprotective effects of antioxidants, including superoxide dismutase (SOD), vitamin C, vitamin E, and the glutathione redox system. Various studies suggest that these antioxidants could be used as adjunct therapies to protect the cerebral vascular tone during high oxidative stress conditions. Nevertheless, more extensive research is required to comprehensively grasp the relationship between oxidative stress and cerebrovascular tone, as well as to explore the potential benefits of antioxidants as adjunctive therapies in critical illnesses and acute brain injuries.

The Reactive Spark Plasma Sintering (R-SPS) method is compared in this work with the two-steps SHS-SPS route, based on combination of the Self-propagating High-temperature Synthesis (SHS) with the SPS process, for the fabrication of dense (Hf0.2Mo0.2Ti0.2Ta0.2Nb0.2)B2-SiC and (Hf0.2Mo0.2Ti0.2Ta0.2Zr0.2)B2-SiC ceramics. A multiphasic and inhomogeneous product, containing various borides, is obtained at 2000°C/20min by R-SPS, from transition metals, B4C and Si. In contrast, if the same precursors are first reacted by SHS, and then processed by SPS under the optimized condition of 1800°C/20min, the desired ceramics are successfully attained. Both High-Entropy-Boride/SiC products display densities > 97%, uniform microstructures and contained only small amounts of residual oxides (<2.4 wt.%). The presence of SiC makes the sintering temperature milder, i.e. 150°C below to that needed by the corresponding additive-free system. Fracture toughness is also markedly improved, particularly when considering the Nb-containing system processed at 1800°C/20min, whereas KIC progressively decreases (from 7.35 to 5.36 MPa m1/2) as the SPS conditions become more severe. SiC addition is found to inhibit the volatilization of metal oxides like MoO3 formed during oxidation experiments, thus avoiding mass loss in the ceramics. The benefits above also likely take advantage of the fact that the two composite constituents are synthesized in parallel, according to the SHS-SPS approach, rather than being produced separately and combined subsequently, so that strong interfaces between them are formed.

This study focuses on enhancing controllable fibrin-based hydrogels for tissue engineering, addressing existing weaknesses. By integrating a novel copolymer, we improve the foundation for cell-based angiogenesis with adaptable structural features. Tissue engineering often faces challenges like waste disposal and nutrient supply beyond the 200 µm diffusion limit. Angiogenesis breaks through this limitation, allowing the construction of larger constructs. Our innovative scaffold combination significantly boosts angiogenesis, resulting in longer branches and more capillary network junctions. The copolymer attached to fibrin fibers enables precise adjustment of hydrogel mechanical-dynamic properties for specific applications. Our material proves effective for angiogenesis, even under suppression factors like suramin. In our study, we prepared fibrin-based hydrogels with and without the copolymer PVP12400-co-GMA10mol%. Using a co-culture system of human umbilical vein endothelial cells (HUVEC) and mesenchymal stem cells (MSC), we analyzed angiogenetic behavior on and within the modified hydrogels. Capillary-like structures were reproducibly formed on different surfaces, demonstrating the general feasibility of three-dimensional endothelial cell networks in fibrin-based hydrogels. This highlights the biomaterial's suitability for in vitro pre-vascularization of biohybrid implants.

Cutaneous mycoses are common infections whose treatment has become more complex due to increasing antifungal resistance and the need for prolonged therapies, hindering patient adher-ence and increasing the incidence of adverse effects. Consequently, the use of physical therapies, especially photodynamic therapy (PDT), has increased for the treatment of onychomycosis due to its antimicrobial capacity mediated by the production of reactive oxygen species. This study investigates the in vitro effect of the combination of blue light (448 nm) and red light (645 nm) with terbinafine on the cell viability of human keratinocytes and the production of reactive ox-ygen species. The combination of terbinafine and blue light exhibits a synergistic effect on the production of reactive oxygen species and a significant increase in the expression of superoxide dismutase (SOD), an enzyme involved in the reduction of superoxide ions (O2-) and the genera-tion of hydrogen peroxide (H2O2). Such effect could be useful in clinical practice to improve the response of cutaneous mycoses to pharmacological treatment, reduce their toxicity, and shorten their duration.

Malaria, as a major global health problem, continues to affect a large number of people each year, especially those in the developing countries. Effective drug discovery is still one of the main efforts to control malaria. As natural products are still considered as a key source for discovery and development of therapeutic agents, we have evaluated more than 2000 plant extracts against Plasmodium falciparum. As a result, we discovered dozens of plant leads that displayed antimalarial activity. Our phytochemical study of some of these plant extracts led to identification of several potent antimalarial compounds. The prior comprehensive review article entitled “Antimalarial activity of plant metabolites” by Schwikkard and Van Heerden (2002) reported structures of plant-derived compounds with antiplasmodial activity and covered literature up to the year 2000. As a continuation of this effort, the present review covers the antimalarial compounds isolated from plants, including marine plants, reported in the literatures from 2001 to the end of 2017. During the span of the last 17 years, 175 antiplasmodial compounds were discovered from plants. These active compounds are organized in our review article according to their plant families. In addition, we also include ethnobotanical information of the antimalarial plants discussed.

This material presents the results of a comparative analysis of the fungal diversity in the world system of microbial culture collections on one side with a variety of known fungal producers on the other side. The main VKM databases used are Fungal DC and Metabolites of Fungi, the central point of analysis - the fungal ability to synthesize promising metabolites for applied use. It indicates that the option of obtaining new promising strains from the collection funds is still underestimated by the scientific community. In particular it is shown that not more than 3% of the total fungal species fund contained in culture collections are used practically. The database Fungal DC developed in VKM is available on-line in www.vkm.ru and www.mycobank.org. It is possible their use will considerably expand the range of studied strains and lead to the acquisition of new scientifically significant data.

From oxidative eustress and distress, to bioenergetic metabolism, and cell death, the reactive species interactome (RSI) and mitochondria are two connected metabolisms that require further investigation improving redox medicine. The step before, finding new clues needs a comprehensive discussion of the two metabolisms, and their relationship. Here, the review focuses on the RSI-mitochondria axis, from mitochondrial roles to crosstalk between mitochondria and other organelles, and the major implication of the RSI in mitochondrial roles. Specifically, the review discussed the apoptosis-necroptosis-ferroptosis death traingle, mitochondrial protein quality control system, calcium homeostasis, and mitochondrial metabolome. Through mitochondrial diseases, and mitochondrial dysfunction associated with diseases, the RSI-mitochondria axis is proposed as a brand-new perspective, including with the involvement of bacterial microbiota, on redox signaling, and redox medicine.

Cannabinoid metabolites have been reported to be more potent than the parent compounds. Among them, Ajulemic acid (AJA) is a synthetic analogue of Δ9-THC-11-oic which will be a good template structure for discovery of more potent analogues. Herein, we optimized the key allylic oxidation step to introduce the C-11 hydroxy group with high yield. And a series of compounds were prepared with this condition applied including HU-210, 11-Nor-Δ8-Tetrahydrocannabinol-9-carboxylic acid and Δ9-THC-COOH.

Eurotium is the teleomorph genus associated with section Aspergillus. Eurotium comprises approximately 20 species, which are widely distributed in nature and human environments. Eurotium is usually the key microorganism for the ferment ation of traditional food, such as Fuzhuan brick tea, Liupao tea, Meju, and Karebushi, thus Eurotium is an important fungus in food industry. Eurotium has been extensively studied because they contain a series of interesting, structurally diverse, and biologically important secondary metabolites, including anthraquinones, benzaldehyde derivatives, and indol diketopiperazine alkaloids. These secondary metabolites have shown multiple biological activities, including antioxidative, antimicrobial, cytotoxic, antitumor, insecticidal, antimalarial, and anti-inflammatory activities. This study presents an up-to-date review of the phytochemistry and biological activities of all Eurotium species. This review will provide the recent advances on the secondary metabolites and their bioactivities in genus Eurotium for the first time and serve as a database for future research and drug development from the genus Eurotium.

Plant secondary metabolites are organic compounds (alkaloids, flavonoids, phenolics, tannins, anthraquinones, saponins, steroids, lignins, terpenes) produced by plant for self-defense during growth and development in order to protect them from harmful agents. As population is increasing and quality of life is reducing couple with outbreak of some diseases that are posing threat on the economy, a lot of medicinal plants have attracted interest of researchers because of the usefulness of these metabolites in pharmaceuticals, food and cosmetic industries. In this review, the pharmacological activities of some medicinal plants that are rich in secondary metabolites were studied, means of identifying and quantifying using spectrophotometry and chromatography techniques were also discussed. However, this will assist to reduce the uses and dependent on the synthetic drug and the onset of the age related diseases.

Ursolic and oleanolic acids are secondary plant metabolites that are known to be involved in the plant defence system against water loss and pathogens. Nowadays these triterpenoids are also regarded as potential pharmaceutical compounds and there is mounting experimental data that either purified compounds or triterpenoid-enriched plant extracts exert various beneficial effects, including anti-oxidative, anti-inflammatory and anticancer, on model systems of both human or animal origin. Some of those effects have been linked to the ability of ursolic and oleanolic acids to modulate intracellular antioxidant systems and also inflammation- and cell death-related pathways. Therefore, our aim was to review the current knowledge about the distribution of ursolic and oleanolic acids in plants, bioavailability and pharmacokinetic properties of these triterpenoids and their derivatives, and to discuss their neuromodulatory effects in vitro and in vivo.

The gastrointestinal tract contains multiple types of immune cells that maintain the balance between tolerance and activation at the first line of host defense facing non-self antigens, including dietary antigens, commensal bacteria, and sometimes unexpected pathogens. Maintaining homeostasis at the gastrointestinal tract requires stringent regulation of the immune responses against various environmental conditions. Diet can be converted into gut metabolites which have unique functional activities through host as well as microbial enzymatic activities. Accumulating evidences demonstrate that gastrointestinal metabolites have significant impacts on the regulation of intestinal immunity and further integrate immune response of distal mucosal tissue. Metabolites, especially derived from microbiota, regulate immune cell functions by various ways including recognition and activation of cell surface receptors, controlling of gene expression by epigenetic regulation and integration of cellular metabolism. These mucosal immune regulations are key to understand underlying mechanism for the development of gastrointestinal disorders. Here, we review the recent advancement of our understanding on the role of gut metabolites in the regulation of gastrointestinal immunity with highlighting the cellular and molecular regulatory mechanisms by macronutrients-derived metabolites.

Methodologies for the synthesis and purification of metabolites, which have been developed following their discovery, analysis and structural identification, have been involved in numerous life science milestones. The renewed focus on the small molecule domain of biological cells has also created an increasing awareness of the rising gap between the metabolites identified and the metabolites which have been prepared as pure compounds. Due to the large number and molecular diversity of metabolites the design and engineering of resource-efficient and straightforward synthetic methodologies for their production have attracted much interest. The variety of metabolic pathways in biological cells provide a wonderful blueprint for designing simplified and resource-efficient synthetic routes to desired metabolites. Therefore, biocatalytic systems have become key enabling tools for the synthesis of an increasing number of metabolites, which can then be utilized as standards, enzyme substrates, inhibitors or products, or for the discovery of novel biological functions.

Resveratrol is a well-known natural polyphenol with a plethora of pharmacological activities. As a potent antioxidant, resveratrol is highly oxidizable, and readily reacts with reactive oxygen species (ROS). Such a reaction not only leads to a decrease in ROS levels in a biological environ-ment but may also generate a wide range of metabolites with altered bioactivities. Inspired by this notion, in the current study, our aim was to take a diversity-oriented chemical approach to study the chemical space of oxidized resveratrol metabolites. Chemical oxidation of resveratrol and a bioactivity-guided isolation strategy using xanthine oxidase (XO) and radical scavenging activities led to the isolation of a diverse group of compounds, including a chlorine-substituted compound (2), two iodine-substituted compounds (3 and 4), two viniferins (5 and 6), an eth-oxy-substituted compound (7) two ethoxy-substituted dimers (8 and 9). Compounds 4, 7, 8 and 9 are reported here for the first time. All compounds without ethoxy-substitution exerted stronger XO inhibition than their parent compound, resveratrol. By enzyme kinetic and in silico docking studies compounds 2, 3 and 4 were identified as potent competitive inhibitors of the enzyme while the viniferins acted as mixed-type inhibitors. Further, compounds 2 and 9 had better DPPH scavenging activity and oxygen radical absorbing capacity than resveratrol. Our results suggest that the antioxidant activity of resveratrol is modulated by the effect of a cascade of chemically stable oxidized metabolites, several of which have significantly altered target specificity as compared to their parent compound.

Polymers' controlled pyrolysis is an economical and environmentally friendly solution to prepare activated carbon. However, due to the experimental difficulty in measuring the dependence between tissues and pyrolysis parameters at high temperatures, the unknown pyrolysis mechanism hinders access to the target products with desirable morphologies and performances. In this study, we investigate the pyrolysis process of polystyrene under different heating rates and temperatures employing reactive molecular dynamics (ReaxFF-MD) simulations. A clear profile of the generation of pyrolysis products determined by the temperature and heating rate is constructed. It is found that the heating rate affects the type and amount of pyrolysis intermediates and their timing, and low-rate heating helps yield more diverse pyrolysis intermediates. While the temperature affects the pyrolytic tissues of the final equilibrium products, either too low or too high a target temperature is detrimental to generating large areas of graphitized tissue. The established theoretical evolution process matches experiments well, thus contributing to preparing target activated carbons by referring to the regulatory mechanism of pyrolytic tissues.

The study aimed to determine, through a systematic review, the relationship between Reactive Attachment Disorder (RAD) and the presence of psychopathology in children and adolescents and to determine the existence of differences about the presence of internalising and externalising psychological problems between the RAD group and groups with other disorders or with typical development. Following the PRISMA methodology, a search was carried out in the Web of Science, PubMed and Scopus databases. The search yielded 770 results, of which only 25 met the inclusion criteria. The results, indicate a relationship between the presence of RAD and/or Disinhibited social engagement disorder (DSED) with the presence of internalising and externalising problems. These difficulties are more present in children with RAD compared to children without personal difficulties, or children with DSED, children with autism, children with intellectual disabilities or children with hyperactivity. It can be concluded that the presence of RAD has negative consequences on the mental health of children and adolescents, with these being greater in the inhibited group than in the disinhibited group, and with respect to children with autism or hyperactivity.

Cutaneous lymphocytosis (CL) is an uncommon and controversial lymphoproliferative disorder described in dogs and cats. CL is generally characterized by a heterogeneous clinical presentation and histological features that may overlap with epitheliotropic lymphoma. Therefore, its neoplastic or reactive nature is still debated. Here, we describe clinicopathological, immunohistochemical and clonality features of a retrospective case series of 19 cats and 10 dogs with lesions histologically compatible with CL. In both species, alopecia, erythema and scales were the most frequent clinical signs. Histologically, a dermal infiltrate of small to medium-sized lymphocytes, occasionally extending to the subcutis, was always identified. Conversely, when present, epitheliotropism was generally mild. In cats, the infiltrate was consistently CD3+; in dogs, a mixture of CD3+ and CD20+ lymphocytes was observed only in 4 cases. The infiltrate was polyclonal in all cats, while BCR and TCR clonal rearrangements were identified in dogs. Overall, cats had a long-term survival (median overall survival=1080 days) regardless of the treatment received, while dogs showed a shorter and variable clinical course, with no evident associations with clinicopathological features. In conclusion, our results support a reactive nature of the disease in cats, associated with prolonged survival; despite a similar histological picture, canine CL was associated with a more heterogeneous lymphocytic infiltrate, clonality results, and response to treatment.

Trigonella foenum is one of the oldest medicinal plants that grow in many parts of Iran with the diverse ecological situation. Employing this plant for treating diabetes and high cholesterol has a long history, because of some metabolites. Due to the habitat of fenugreek is a wide range of climatic conditions, it may have power to cope with climate variation. The main intention of this inquiry was to understand the effect of the environmental variables on this therapeutic plant features. It was also interesting for us to understand which environment variables are more impressive for enhancing of trigonelline and 4-hydroxy isoleucine content as the most important metabolites of this plant. For achieving this goal, environmental information and vegetal data were analyzed to discover the role of nature on the seed part of fenugreek life in 50 different regions of Iran. Canonical correspondence analysis (CCA) displayed that high content of metabolites and some morphological characteristics happened in high temperature and solar irradiation. Partial least squares regression (PLSR) and path analysis used to find the best predictors and direct and indirect effect of all variables on 4-hydroxy isoleucine and trigonelline. Ecological condition were the best predictors and had the highest direct and indirect impact on 4-hydroxy isoleucine. However, for trigonelline, the environment did not play a senior role. It seems that the reaction of components of fenugreek does not follow the same way. Studying on morphological, primary and secondary metabolites, and surrounding environment of fenugreek, helped us to have a more precise judgment about the life of this plant.

The term neuroinflammation defines the reactions of astrocytes and microglia to alterations in homeostasis in the diseased central nervous system (CNS), the exacerbation of which contributes to the neurodegenerative effects of Alzheimer's disease (AD). Local environmental conditions, such as the presence of proinflammatory molecules, mechanical properties of the extracellular matrix (ECM) and local cell-cell interactions, are determinants of glial cell phenotypes. In AD, the load of the cytotoxic/proinflammatory amyloid β peptide (Aβ) is a microenvironmental component increasingly growing in the CNS, imposing time-evolving challenges on resident cells. This study aimed at investigating the temporal and spatial variations of the effects produced by this process on astrocytes and microglia, either directly or by interfering in their interactions. Ex vivo confocal analyses of hippocampal sections from the mouse model TgCRND8 at different ages have shown that overproduction of Aβ peptide induced early and time persistent disassembly of functional astroglia syncytium and promoted a senile phenotype of reactive microglia, hindering Aβ clearance. In the late stages of disease, these patterns were altered in the presence of Aβ-plaques, surrounded by typically reactive astrocytes and microglia. Morphofunctional characterization of peri-plaque gliosis revealed a direct contribution of astrocytes in plaque buildup that might result in shielding Aβ-peptide cytotoxicity and, as a side effect, in exacerbating neuroinflammation.

Microalgae are abundant components of biosphere rich in low molecular weight carbohy-drate-containing natural products (glycoconjugates). Glycoconjugates take a part in processes of photosynthesis, provide producers with important biological properties, influence other organ-isms and known by biological activities. Some of them, for example glycosylated toxins and ar-senicals, are detrimental and can be transferring via food chains into higher organisms including humans. So far, the studies on a series of particular groups of microalgal glycoconjugates were not comprehensively discussed in special reviews. In this review, a special focus was made on the isolation, structure determination, properties and approaches to the search for new bioactive metabolites. Analysis of literature data concerning structures, functions and biological activities of ribosylated arsenicals, galactosylated and sulfoquinovosylated lipids, phosphoglycolipids, gly-coside derivatives of toxins, and other groups of glycoconjugates was carried out and discussed. The discovery of a great variety of new carbohydrate-containing metabolites, important biological roles some of them, participation in regulation of microalgal blooms via viral infections as well as the detection of potent immunomodulatory activity, shown by these type metabolites could be attributed to the most interesting recent achievements. Structures, properties and biological roles of glycoconjugates from microalgae attract a great attention growing year to year.

Imidacloprid is the first-generation neonicotinoid insecticide. But, the long-term use of im-idacloprid as a pesticide has caused severe water pollution. Recently, the toxicity of imidacloprid to aquatic organisms has received increasing attention. This study aimed to investigate the ab-sorption and distribution of imidacloprid in various tissues (gills, intestine, liver, muscle, brain, and gonads) of goldfish through short-term and continuous exposure tests for 28 days. The re-sults of short-term exposure indicated that the concentration of imidacloprid and its metabolites in tissues at the transfer stage decreased steadily after 1 day of 40 mg/l imidacloprid water treatment and was below the detection limit after 3 days. Continuous exposure for 28 days at various treatment concentrations showed that the concentrations of imidacloprid and its metab-olites differed significantly among the different tissues of the goldfish. In the 20 mg/l treatment group (S1), the highest concentration of imidacloprid was found in the liver (12.04 μg /gtissue), followed by the intestine (9.91 μg /gtissue), muscle (6.20 μg /gtissue), gill (6.11 μg /gtissue), gonads (5.22 μg /gtissue), and brain (2.87 μg /gtissue). In the 40 mg/l treatment group (S2), the order of tissue concentrations was similar to that of the S1 group, with the highest concentration observed in the liver (12.04 μg/gtissue), followed by the intestine (9.91 μg/gtissue), muscle (6.20 μg/gtissue), gill (6.11 μg/gtissue), gonads (5.22 μg/gtissue), and brain (2.87 μg/gtissue). Fur-thermore, the study detected 5-hydroxyimidacloprid, imidacloprid urea, and 6-chloronicotinic acid in imidacloprid metabolites in all tissues, while imidacloprid was detected only in the intes-tine and liver. Overall, the results of this study contribute to a better understanding of the met-abolic behavior of imidacloprid in organisms and provide new data to support the assessment of imidacloprid toxicity in fish.

Native reactive electrophile species (RES) are long-recognized regulators of pathophysiology; yet, knowledge surrounding how RES regulate context-specific biology remains limited. The latest technological advances in profiling and precision decoding of RES sensing and signaling have begun to bring about improved understanding of localized RES regulatory paradigms. However, studies in purified systems—prerequisites for gaining structure/function insights—prove challenging. We here introduce emerging chemical biology tools available to probe RES signaling, and the new knowledge that these tools have brought to the field. We next discuss existing structural data of RES-sensor proteins complexed with electrophilic metabolites or small molecule drugs (limited to < 300 Da), including challenges faced in acquiring homogenous RES-bound proteins. We further offer considerations that could promote enhanced understanding of RES regulation derived from three-dimensional structures of RES-modified proteins.

Endometrial Cancer (EC) is the sixth most commonly occurring cancer in women with 380 000 cases in 2018. Sadly, EC morbidity and mortality are continuously increasing, therefore the medical society have a substantial need for an accurate and inexpensive diagnostic test for EC early detection and a prognostic tool for treatment planning and evaluation. Considering experience with different types of cancers C-reactive protein (CRP) appears to be a promising diagnostic and prognostic factor. Aiming to investigate its potential and in view of EC authors, this paper reviewed the following databases for metanalysis, randomized controlled trials and review articles published up to June 2020: Pubmed, Scopus, Google scholar and ClinicalKey. Studies indicate CRP >3.33 mg/l correlate with EC incidence with HR = 2.29 (p<0.05). Moreover, High-sensitivity CRP assay allows to detect CRP in very low concentrations and distinguish patients with endometriosis, soft tissue sarcomas and possibly EC. Preoperational and postoperational CRP, as well as its dynamic change are independent prognostic factors for EC and are more reliable if analyzed together. However, CRP-to-albumin ratio as well as Glasgow Prognostic Scale have greater prognostic value that CRP alone. Additionally, CRP is possibly a mediator of carcinogenesis and cancer progression through activation of inter alia FcgRs/MAPK/ERK, FcgRs/IL-6/AKT/STAT3 and FcgRs/NF-κB/NLRP3 pathways.

Cathinone is a natural stimulant found in Catha edulis and commonly used in new psychoactive substances. The objective of this study was to examine the disposition kinetics and metabolic profile of cathinone and its metabolite cathine through a single oral dose of cathinone administration in rats. Cathine and cathinone concentrations were identified and quantified using ion trap liquid chromatography (LC-IT/MS), while the metabolic profile was determined using the quadrupole time of flight UPLC-QTOF/MS method in the serum, brain, lung, liver, kidney, and heart over a period of 0, 0.5, 2.5, 6, 12, 24, 48, and 72 hours. The findings revealed a dynamic interplay between the pharmacokinetics of cathinone and its impact on organ-specific biomarkers. The distribution of cathinone and cathine was determined in serum, brain, heart, lung, kidney, and liver. The highest concentration of cathinone was found in the kidney at 1438.6 ug/L. It gradually decreased to 1.97 within 48 hours and disappeared after 72 hours. Within half an hour, cathinone levels in the lungs, liver, and heart were found to be 859, 798.9, and 385.8 ug/L, respectively. However, within 2.5 hours, these levels decreased to 608.1, 429.3, and 309.1 ug/L and kept decreasing until they became undetectable after 24 hours. The concentration of cathinone in the rat brain reduces quickly, dropping to undetectable levels within six hours, with levels decreasing from 712.7 ug/L after just 30 minutes. In the brain and serum, cathine reached its highest levels at 2.5 hours, while in other organs, it peaked at 0.5 hours. This indicates that the conversion of cathinone to cathine is slower in the brain and serum. The study found that cathinone's pharmacokinetics have a significant impact on organ-specific biomarkers. After administering the cathinone, there was a sharp change in biomarker levels, particularly in the liver and brain, during the initial hours. It is essential to investigate the correlation between the changes in biomarkers found in the brain and the levels of cathinone and cathine. The results have significant implications for drug development, pharmacovigilance, and clinical practices involving cathinone. In conclusion, this comprehensive analysis of cathinone's impact on organ-specific biomarkers provides a basis for informed decision-making in medical practices and further research into the cathinone's pharmacological properties.

Atmospheric turbulence, which produces chaotic motions in the planetary boundary layer, can inhibit mixing between fast-reacting species produced or released at different locations. This segregation process modifies the effective rate at which reactions occur between these species, and are not appropriately accounted for in coarse resolution models since these models assume complete mixing of tracers within each gridbox. Here we present a few examples of LES-based simulations applied to chemically reactive species in a forested area with high emissions of biogenic hydrocarbons, an urban area rich in anthropogenic emissions; and a maritime area with high emissions of reduced sulfur species.

Photoacoustic imaging is attracting a great deal of interest owing to its distinct advantages over other imaging techniques such as fluorescence or magnetic resonance image. Availability of photoacoustic probes for reactive oxygen and nitrogen species (ROS/RNS) could shed light on a plethora of biological processes mediated by these key intermediates. Tetramethylbenzidine (TMB) is a non-toxic and non-mutagenic colorless dye that develops a distinctive blue color upon oxidation. In this work we have investigated the potential of TMB as photoacoustic probe for ROS/RNS. Our results indicate that TMB reacts with hypochlorite, hydrogen peroxide, singlet oxygen and nitrogen dioxide to produce the blue oxidation product, while ROS such as the superoxide radical anion, sodium peroxide, hydroxyl radical or peroxynitrite yield a colorless oxidation product. TMB does not penetrate Escherichia coli cytoplasm but is capable of detecting singlet oxygen generated in its outer membrane.

Cellular oxidation is responsive to external and internal stimulation and is generated via signal molecules in defense mechanisms through networks of cell proliferation, differentiation, intracellular detoxification, bacterial infection, and immune reactions. Oxidative stress is not necessarily harmful per se; it depends on the balance between oxidation and antioxidation cascades, which are induced according to stimuli and can maintain oxygen homeostasis. The reactive oxygen species (ROS) that are generated during influenza virus (IV) infection have critical effects on both the virus and host cells. In this review, we outline the link between viral infection and ROS production, using IV as an example. We introduce the current state of knowledge on the molecular relationship between cellular oxidation mediated by ROS production and various effects of IV infection. We also summarize the potential anti-IV agents that act by targeting oxidative stress.

A heterobifunctional reactive oxygen species (ROS)-responsive linker for directed drug assembly onto and delivery from a quantum dot (QD) nanoparticle carrier was synthesized and coupled to doxorubicin using EDC/sulfo-NHS coupling. The doxorubicin conjugate was characterized using ¹H NMR and LC-MS and subsequently reacted under conditions of ROS formation (Cu²⁺/H₂O₂) resulting in successful and rapid thioacetal oxidative cleavage which was monitored using ¹H NMR. The deprotected amine linker is amenable to peptide or protein conjugation prior to QD assembly or to direct conjugation to cognate reactive groups on ligands that cap the QD surface.

In the current study, an ethyl acetate extract from the endophytic fungus Aspergillus ochraceus SPH2 isolated from the stem parts of the endemic plant Bethencourtia palmensis was screened for its biocontrol properties against plant pathogens (Fusarium moniliforme, Alternaria alternata and Botrytis cinerea), insect pests (Spodoptera littoralis, Myzus persicae, Rhopalosiphum padi), plant parasites (Meloidogyne javanica) and ticks (Hyalomma lusitanicum). SPH2 gave extracts with strong fungicidal and ixodicidal effects at different fermentation times. The bioguided isolation of these extracts gave compounds 1-3. Mellein (1) showed strong ixodicidal effects and was also fungicidal. This is the first report on the ixodicidal effects of 1. Neoaspergillic acid (2) showed potent antifungal effects. Compound 2 appeared during the exponential phase of the fungal growth while neohydroxyaspergillic acid (3) appeared during the stationary phase, suggesting that 2 is the biosynthetic precursor of 3. Additional molecular ions compatible with pyrazynes that were detected during the exponential phase included flavacol, and aspergilliamide while ochramide A was mostly detected during the stationary phase of the fermentation. Moreover, polyketids were also detected during the sationaty phase of the fermentation curve (dihydroaspyrone, aspyrone, asperlactone) and the alkaloid circumdatin H. Ochratoxin A was not detected. Therefore, SPH2 could be a potential biotechnological tool for the production of ixodicidal mellein.

The Cannabis plant (Cannabis sativa L.) produces an estimated 545 chemical compounds of different biogenetic classes. In addition to economic value, many of these phytochemicals have medicinal and physiological activity. The plant is most popularly known for its two most prominent and most studied secondary metabolites— Δ9-Tetrahydrocannabinol (Δ9-THC) and Cannabidiol (CBD). Both Δ9-THC and CBD have a wide therapeutic window across many ailments and form part of a class of secondary metabolites called cannabinoids—of which approximately over 104 exist. This review will focus on non-cannabinoid metabolites of Cannabis sativa that also have therapeutic potential, some of which share medicinal properties similar to those of cannabinoids. The most notable of these non-cannabinoid phytochemicals are flavonoids and terpenes. We will also discuss future directions in cannabis research and development of cannabis-based pharmaceuticals. Caflanone, a flavonoid molecule with selective activity against the human viruses including the coronavirus SARS-COV2, and certain cancers, is one of the most promising non-cannabinoid molecules that is being advanced into clinical trials. As validated by thousands of years of the use of cannabis for medicinal purposes, vast anecdotal evidence abounds on the medicinal benefits of the plant. These benefits are attributed to the many phytochemicals in this plant, including non-cannabinoids. The most promising non-cannabinoids with potential to alleviate global disease burdens are discussed.

The highly dangerous trend of escalating bacterial resistance to modern antibiotics has evolved in recent decades, with increasingly more drug-resistant strains of pathogens emerging and spreading each year. This poses a threat to not only public health, but also to entire mankind. Marine bioresources, considered as a promising alternative to traditional antibiotics and a valuable source of biologically active compounds with high pharmacological potential, now attract increasing attention of researchers. Modern biotechnology combines the genetic engineering methods and the unusual biosynthetic pathways utilized by marine microorganisms to produce natural antibiotics. The goal of this review is to summarize the latest trends in searching for new natural antimicrobial agents based on secondary metabolites of marine bacteria. The targeted control of biosynthesis mechanisms using the metabolic engineering methods in order to create hybrid peptide synthetases or to obtain hybrid peptides by disrupting the target gene of nonribosomal synthesis becomes a noteworthy trend in modern biotechnology. This pathway is not only one of the most promising approaches to the development of new antibiotics, but also a potential target for controlling the exocrine activity of pathogenic bacteria and, consequently, their viability.

Asthma is a chronic inflammatory airway disease induced by many environmental factors. The inhalation of allergens and pollutants promote the reactive oxygen species (ROS) production leading to airway inflammation, hyper-responsiveness and remodeling in allergic asthma. The effects of asthma medications on ROS production are unclear. The present study investigated the anti-ROS effects of current asthma medications including inhaled corticosteroid (ICS; budesonide and fluticasone), leukotriene receptor antagonist (LTRA; montelukast), long acting β2 agonists (LABAs; salmeterol and formoterol) and a new extra-LABA (indacaterol). The human monocyte cell line THP-1 cells were pre-treated with different concentrations of the asthma medications at different time-points after hydrogen peroxide (H₂O₂) stimulation. H₂O₂ production was measured with DCFH-DA by flow cytometry. Montelukast, fluticasone and salmeterol suppressed H₂O₂-induced ROS production. Indacaterol enhanced H₂O₂-induced ROS production. Budesonide and formoterol alone had no anti-ROS effects, but the combination of these two drugs significantly suppressed H₂O₂-induced ROS production. Different asthma medications have different anti-ROS effects on monocytes. The combination therapy with LABA and ICS seemed not be the only choice for asthma control. Montelukast may be also a good supplemental treatment for the poorly-controlled asthma because of its powerful anti-ROS effects. Our findings provide a novel therapeutic view in asthma.

Beyond their significant contribution to the dietary and industrial supplies, marine algae are considered to be a potential source of some unique metabolites with diverse health benefits. The pharmacological properties, such as antioxidant, anti-inflammatory, cholesterol homeostasis, protein clearance and anti-amyloidogenic potentials of algal metabolites endorse their protective efficacy against oxidative stress, neuroinflammation, mitochondrial dysfunction, and impaired proteostasis which are known to be implicated in the pathophysiology of neurodegenerative disorders and the associated complications after cerebral ischemia and brain injuries. As was evident in various preclinical studies, algal compounds conferred neuroprotection against a wide range of neurotoxic stressors, such as oxygen/glucose deprivation, hydrogen peroxide, glutamate, amyloid β, or 1-methyl-4-phenylpyridinium (MPP+) and, therefore, hold therapeutic promise for brain disorders. While a significant number of algal compounds with promising neuroprotective capacity have been identified over the last decades, a few of them have had access to clinical trials. However, the recent approval of an algal oligosaccharide, sodium oligomannate, for the treatment of Alzheimer's disease enlightened the future of marine algae-based drug discovery. In this review, we briefly outline the pathophysiology of neurodegenerative diseases and brain injuries for identifying the targets of pharmacological intervention, and then review the literature on the neuroprotective potentials of algal compounds along with the underlying pharmacological mechanism, and present an appraisal on the recent therapeutic advances. We also propose a rational strategy to facilitate algal metabolites-based drug development.

Nowadays a recognized need for accurate observations of atmospheric aerosols (AEs) and reactive gases (RGs) exists in the framework of regional, national and global near-surface networks based on permanent or mobile measurement stations. In this context, a paramount and not-trivial issue is related to the correct execution of continuous sampling of ambient air and its subsequent distribution to measurement analyzers hosted inside the stations. Sampling artifacts must be minimized for obtaining reliable pictures of ambient air composition. To respond to this need, a suite of novel “smart” and relatively low-cost systems for the continuous sampling of ambient air was developed in the framework of the Project I-AMICA (2012 – 2015, www.i-amica.eu). These systems were designed to execute AE and RG measurements according with WMO/GAW and ACTRIS recommendations and standard operation procedures. A particular attention was dedicated to the stabilization and control of the sampling flow rates and temperatures. The analysis of one full year of operations at the WMO/GAW regional station of Capo Granitola (GAW ID: CGR, Italy), allowed to conclude that these systems are effective in meeting the technical requirements for correct execution of AE and RG measurements

Through the ACE2, a main enzyme of the renin-angiotensin system (RAS), the SARS-CoV2 gains access into the cell, resulting in different complications which may extend beyond the RAS and impact the Arachidonic Acid (ArA) pathway. The contribution of the RAS through ArA pathways metabolites in the pathogenesis of COVID-19 is unknown. We investigated whether RAS components and ArA metabolites can be considered biomarkers of COVID-19. We measured the plasma levels of RAS and ArA metabolites using an LC-MS/MS. Results indicate that Ang1-7 levels were significantly lower, whereas Ang II levels were higher in the COVID-19 patients than healthy control individuals. The ratio of Ang1-7/Ang II as an indicator of the RAS classical and protective arms balance was dramatically lower in COVID-19 patients. There was no significant increase in inflammatory 19-HETE and 20-HETE lev-els. The concentration of EETs was significantly increased in COVID-19 patients, whereas the DHETs concentration was repressed. Their plasma levels were correlated with Ang II concentration in COVID-19 patients. In conclusion, evaluating the RAS and ArA pathway biomarkers could provide helpful information for the early detection of high-risk groups, avoid delayed medical attention, facilitate resource allocation and improve patient clinical outcomes to prevent long COVID incidence.

Aim: Exposure to polycyclic aromatic hydrocarbons (PAHs) has been in the past associated with adverse effects on human health among which belong also respiratory diseases. Our study is focused on the evaluation of PAH exposure by measuring the concentrations of their monohydroxylated metabolites (OH-PAHs) in urine and comparing their concentrations with the incidence of respiratory diseases in 2-year-old children from two locations of the Czech Republic – a control locality Ceske Budejovice and a previously highly contaminated mining district Most. Methods: The total number of 248 participants were sampled for urine samples that were analysed for the presence of 11 OH-PAHs using liquid-liquid extraction with ethyl acetate and clean-up employing dispersive solid phase extraction with a sorbent Z-Sep. Separation, identification and quantification of the target compounds was achieved by ultra-high performance liquid chromatography coupled to tandem mass spectrometry. The incidence of respiratory diseases was evaluated according to the questionnaires provided by the paediatricians. Results and discussion: The concentrations of measured OH-PAHs were higher in the urine samples collected from 2-year-old children living in Most compared to 2-year-old children from Ceske Budejovice. The same trend was observed also when the urine samples were analysed when these children were studied as newborns in our previous study. From all of the monitored respiratory diseases, only influenza due to unidentified influenza virus showed a difference between tested locations where the 2-year-old children living in Most were more frequently diagnosed with this disease. Conclusion: Even though the air pollution and lifestyle in both cities is very similar, we have observed higher incidence of respiratory diseases as well as higher concentration of OH-PAHs in urine of the 2-year-old children from Most. Therefore, we hypothesize that the population living in this previously highly contaminated location (in 1970s and 1980s) can carry some long-term health burden.

The tryptophan (TRP)-kynurenine (KYN) metabolic pathway is a main player of TRP metabolism through which more than 95% of TRP is catabolized. The pathway is activated by acute and chronic immune responses leading to a wide range of illnesses including cancer, immune diseases, neurodegenerative diseases, and psychiatric disorders. The TRP-KYN pathway synthesizes multifarious metabolites including oxidants, antioxidants, neurotoxins, neuroprotectants, and immunomodulators. The immunomodulators are known to facilitate the immune system towards a tolerogenic state, resulting in chronic low-grade inflammation (LGI) that is commonly present in obesity, poor nutrition, exposer to chemicals or allergens, prodromal stage of various illnesses, and chronic diseases. KYN, kynurenic acid, xanthurenic acid, and cinnabarinic acid are aryl hydrocarbon receptor ligands that serve as immunomodulators. Furthermore, TRP-KYN pathway enzymes are known to be activated by the stress hormone cortisol and inflammatory cytokines, and genotypic variants were observed to contribute to inflammation and thus various diseases. The tryptophan 2,3-dioxygenase, the indoleamine 2, 3-oxygenases, and the kynurenine-3-monooxygenase are main enzymes in the pathway. This review article discusses the TRP-KYN pathway with special emphasis on its interaction with the immune system and the tolerogenic shift towards chronic LGI and overviews the major symptoms, pro- and anti-inflammatory cytokines, and toxic and protective KYNs to explore the linkage between chronic LGI, KYNs, and major psychiatric, including depressive disorder, bipolar disorder, substance use disorder, post-traumatic stress disorder, schizophrenia, and autism spectrum disorder.

RANS simulations have been broadly used to investigate turbulence in the oceans and atmosphere. Within these environments there are a multitude of tracers undergoing reactions (eg. phytoplankton growth, chemical reactions). The distribution of these reactive tracers is strongly influenced by turbulent mixing. With a 50 member ensemble of two dimensional Rayleigh-Taylor induced turbulent mixing, we show that the dynamics of a reactive tracer growing according to Fisher’s equation are poorly captured by the mean. A fluctuation-dependent sink introduced by Reynolds averaging Fisher’s equation transfers concentration from the mean to the fluctuations. We compare the dynamics of the reactive tracer with those of a passive tracer. The reaction causes the concentration of reactive tracer to increase thereby increasing Fickian diffusion and allowing the reactive tracer to diffuse into turbulent structures that the passive tracer cannot reach. A positive feedback between turbulent mixing and fluctuation growth is identified. We show that eddy viscosity and diffusivity parameterizations fail to capture the bulk trends of the system and identify a need for negative eddy diffusivities. One must therefore be cautious when interpreting RANS results for reactive tracers.

Nonalcoholic fatty liver disease (NAFLD) is a liver metabolism-associated steatohepatitis caused by non-alcoholic factors. NAFLD is currently the most prevalent liver disease in the world, affecting one-fourth of the world's population, and its prevalence increases with age. There are no approved drugs specifically for the treatment of NAFLD, and one important reason hindering drug development is the lack of effective biomarkers. C-reactive protein (CRP), a marker of inflammation, has been linked to NAFLD and aging in recent studies. Coincidentally, hepatocytes are responsible for the major CRP production, and the levels of CRP increase with age. Therefore, CRP is not only a potential marker, but also acts as a key factor driving liver aging and NAFLD. Herein, we reviewed the biological function and production mechanism of CRP and the relationship between CRP and NAFLD. We also comprehensively described the potential molecular mechanisms of CRP-mediated signaling in aging-associated NAFLD. Finally, we proposed possible therapeutic approaches based on the mechanism of CRP signaling in the pathogenesis of NAFLD. We hope this study can provide new insights into the development of aging associated NAFLD biomarkers and suggest that modulation of CRP signaling is a potential therapeutic target.

The present protocol described staining protocol for Reactive Oxygen Species (ROS) in aromatic crop grown under nutrient stress through DAB and NBT histochemical method. Spearmint (Mentha spicata) were grown under manganese and salt toxicity stresses and after 10 and 20 days of the stress treatments, plants showed stunted growth. The morphological characteristics of leaves under stresses were observed. Manganese toxicity and salt stress induced the production of ROS. Accumulation of hydrogen peroxide was characterised as brown spots from the DAB polymerisation which were emerged and clearly observed in leaves from plant grown under 2.5 and 5 mM concentrations of manganese as well as 300 mM concentration of salt. Furthermore, accumulation of superoxide anion was characterised as blue pigments based upon the ability of cells to reduce NBT. Spearmint leaves showed the distribution of the blue pigment which was obviously observed under the 5 mM of manganese and 300 mM of salt. DAB and NBT staining method can be the rapid method to characterise ROS accumulation in plant cell under the abiotic stresses.

In this tutorial review, we compare and contrast the chemical mechanisms of electrophile/oxidant sensing, and the molecular mechanisms of signal propagation. We critically analyze biological systems in which these different pathways are believed to be manifest and what the data really mean. Finally, we discuss applications of this knowledge to disease treatment and drug development.

Secondary phenolic metabolites are defined as valuable natural products synthesized by different organisms that are not essential for growth and development. These compounds play an essential role in plant defense mechanisms, and an important role in the pharmaceutical, cosmetics, food, and agricultural industries. Despite the vast chemical diversity of natural compounds, their content in plants is very low, in consequence, it eliminates the possibility of the production of these interesting secondary metabolites from plants. Therefore, microorganisms are widely used as cell factories by industrial biotechnology to the production of different non-native compounds. Among microorganisms commonly used in biotechnological applications, yeasts are prominent host for the diverse secondary metabolite biosynthetic pathways. Saccharomyces cerevisiae is often regarded as the better host organism for the heterologous production of phenolics compounds, especially if the expression of different plant genes is necessary.

Naltrexone (NTX) is a potent opioid antagonist with good blood-brain barrier permeability, targeting different endogenous opioid receptors, particularly the mu-opioid receptor (MOR). Therefore, it represents a promising candidate for drug development against drug addiction. However, the details of the molecular interactions of NTX and its derivatives with MOR are not fully understood, hindering ligand-based drug discovery. In the present study, taking advantage of the high-resolution X-ray crystal structure of the murine MOR (mMOR), we constructed a homology model of the human MOR (hMOR). A solvated phospholipid bilayer was built around the hMOR and submitted to microsecond (µs) molecular dynamics (MD) simulations to obtain an optimized hMOR model. NTX and its derivatives were docked into the optimized hMOR model and submitted to µs MD simulations in an aqueous membrane system. The MD simulation results were submitted to Molecular Mechanics Generalized-Born surface area (MMGBSA) binding free energy calculations and principal component analysis. Our results revealed that NTX and its derivatives showed differences in protein-ligand interactions; however, they shared contact with residues at TM2, TM3, H6, and TM7. The binding free energy and principal component analysis revealed the structural and energetic effects responsible for the higher potency of NTX compared to its derivatives.

Volatile compounds, abundant in breath, can be used to accurately diagnose and monitor a range of medical conditions. This offers a non-invasive, low-cost approach with screening applications; however, uptake of this diagnostic approach has been limited by conflicting published outcomes. Most published reports rely on large scale screening of the public, at single time points and without reference to ambient air. Here, we present a novel approach to volatile sampling from cellular headspace and mouse breath that incorporates multi-time point analysis and ambient air subtraction revealing compound flux as an effective proxy of active metabolism. This approach to investigating breath volatiles offers a new avenue for disease biomarker discovery and diagnosis. Using gas chromatography mass spectrometry (GC/MS), we focus on low molecular weight, metabolic substrate/by-product compounds and demonstrate that this non-invasive technique is sensitive (reproducible at ~1 µg cellular protein, or ~500,000 cells) and capable of precisely determining cell type, status and treatment. Isolated cellular models represent components of larger mammalian systems and we show that stress- and pathology-indicative compounds are detectable in mice, supporting further investigation using this methodology as a tool to identify volatile targets in human patients.

Energy management systems (EMS) play a central role in improving the performance of microgrids by ensuring their efficient operation while minimizing operational costs and environmental impacts. This paper presents a comprehensive study of a MILP-based EMS developed and implemented in MATLAB using Yalmip software for the energy management of a new positive energy district in the city of Savona, Italy, as part of the Interreg Alpine Space Project ALPGRIDS. The main objective of this research is to optimize the functioning of the microgrid, focusing on cost efficiency and environmental sustainability. In pursuit of this objective, the EMS undergoes comprehensive testing and analysis, replicating actual conditions and addressing the diverse demands of end-users across typical days throughout the year considering real electricity selling and purchase price. The EMS also accounts for the reactive power capabilities of the various technologies integrated into the microgrid. The levelized cost of electricity (LCOE) serves as a metric for assessing curtailment costs, while penalties related to reactive power absorption from the distribution network are appraised in alignment with prevailing regulatory guidelines. The case study provides valuable insights into the practical implementation of EMS technology in microgrids and demonstrates its potential for sustainable energy management in complex urban energy districts. The insights and strategies developed through this research contribute to the overall goals of improving energy efficiency and reducing the environmental footprint of future energy districts.

Background: Acute viral gastroenteritis remains a leading cause of health care cost globally, prompting the need for basic diagnostic strategies. Objectives: This study aims to assess the impact of viral gastroenteritis on hemogram and C-reactive protein. Methods: By conducting a retrospective study, three groups of children diagnosed with gastroenteritis (rotavirus positive, adenovirus positive and rota/adenovirus negative group) were compared in terms of hemogram parameters and C- reactive protein. Results: Among 756 children with gastroenteritis, 7.9% of patients were rotavirus positive and 6.5% of them were adenovirus positive. Our findings disclosed a statistically significant association between low lymphocyte (2.2 ± 1.45) and MPV value (7.38 ± 0.4 fL) with rotavirus gastroenteritis. Also, the analysis revealed a high neutrophil/lymphocyte ratio (2.8± 2.1) in rotavirus group. However, our study did not reveal any prominent laboratory marker that serves as a distinctive feature of adenovirus unlike rotavirus. Conclusions: In conclusion our research highlights the potential of decreased mean platelet volume and lymphopenia as diagnostic markers for rotavirus gastroenteritis.

Marine soft corals are prolific sources of various natural products that have served as a wealthy reservoir of diverse chemical scaffolds for new drug leads. The genus Litophyton contains almost 100 species but only a small part of them had been classified and chemically investigated, which calls for more attentions from the global researchers. In the current work, 109 secondary metabolites have been discussed based on published data from 1975 to July, 2023, covering a period of near five decades. The studied species of the genus Litophyton inhabited various tropical and temperate regions and afforded a variety of biologically active natural products such as terpenes, steroids, alkaloids, and lipids. A wide spectrum of pharmacological effects of these compounds had been evaluated, including cytotoxic, anti-HIV, antibacterial, antifungal, anti-malarial, antifeedant, molluscicidal, PTP1B inhibitory, and insect growth inhibitory activities. This review aims to provide an up-to-date literature survey and comprehensive insight into chemical structures, taxonomical distributions, and biological activities of the reported metabolites from the title genus whenever available.

Studies on the neurobiological causes of anxiety disorders suggest that the GABA system in-creases synaptic concentration and enhances the affinity of GABAA (type A) receptors for ben-zo-diazepine ligands. Flumazenil antagonizes the benzodiazepine binding site of the GABA (γ-aminobutyric acid) type /benzodiazepine receptor (BZR) complex in the central nervous sys-tem (CNS). The integration of the metabolites of flumazenil by LC-tandem mass spectrometry will complete understanding of the in vivo metabolism of flumazenil and accelerate radio-pharmaceutical inspection and registration. The main goal of our study was to investigate using reversed-phase HPLC (PR-HPLC) coupled with electrospray ionization triple quadrupole tan-dem mass spectrometry (ESI-QqQ MS) for the identification of flumazenil and its metabolites in a hepatic matrix. And a carrier-free nucleophilic fluorination with automatic synthesizer for [18F]flumazenil which applied to in vivo nano-positron emission tomography (Nano-PET)/computed tomography (CT) imaging and ex vivo bio-distribution used to analyze in normal rats. The study showed that 50% of the flumazenil was bio-transformed at 60 min by the rat liver homogenate, while one metabolite (M1) was a methyl transesterification product of flumazenil. In a rat liver microsomes system, two metabolites were identified (M2 and M3) as its carboxylic acid and hydroxylated ethylester forms, respectively. [18F]flumazenil in vivo nanoPET/CT imag-ing and ex vivo bio-distribution assay also showed significant effects on GABAA receptor availa-bility in the amygdala, prefrontal cortex, cortex, and hippocampus in the rat brain, worriless about the formation of metabolites. We showed completion of the bio-transformed course of flumazenil by the hepatic system; and [18F]flumazenil can be a good ligand and serve as a PET agent for determination of GABAA/BZR complex for multiplex neurological syndromes in the clinical stage.

Ecdysterone is a phytosteroid widely discussed for its various pharmacological, growth-promoting and anabolic effects mediated by activation of estrogen receptor beta (ERbeta). Performance-enhancement in sports was demonstrated recently, and ecdysterone was consequently included in the Monitoring Program to detect potential patterns of misuse in sport. Only few studies on the pharmacokinetics of ecdysterone in humans have been reported so far. In this study, post-administration urines in twelve volunteers (single dose of 50 mg of ecdysterone) were analyzed using dilute-and-inject liquid chromatography-tandem mass spectrometry. Identification and quantitation of ecdysterone and of two metabolites, 14-deoxy ecdysterone and 14-deoxy poststerone was achieved. Ecdysterone was the most abundant analyte present in post-administration urines, detected for more than 2 days with a maximum concentration (Cmax) in the 2.8-8.5 h urines (Cmax = 4.4-30.0 µg/mL). The metabolites 14-deoxy ecdysterone and 14-deoxy poststerone were detected later reaching the maximum concentrations at 8.5-39.5 h (Cmax = 0.1-6.0 µg/mL) and 23.3-41.3 h (Cmax = 0.1-1.5 µg/mL), respectively. Cumulative urinary excretion yielded average values of 18%, 2.3% and 1.5% for ecdysterone, 14-deoxy ecdysterone and 14-deoxy poststerone, respectively. Ecdysterone and 14-deoxy ecdysterone were excreted following first order kinetics with half-lives calculated with three hours, while pharmacokinetics of 14-deoxy poststerone needs further evaluation.

Mosquitoes are a family of the order Diptera, which includes more than 3500 species. Two groups able to suck human blood and transmit diseases: the anophelines and the culicines comprise several genera such as Culex, Aedes and Aedes communis (Ac). Previous study has demonstrated a significant relationship between Ac sensitization and either extract or single bee venom components suggesting a “bee-mosquito syndrome” occurrence. It is well known that CCD can interference with the measurement of quantitative IgE results. Hence, it has been hypnotized that the presence of sIgE to CCD could have a role in the Bee-Mosquito syndrome. Method Serum from 21 different Mosquito and Ape melifera allergic individuals were combined with extracts of Mosquito (in house) and Apis melifera. SDS-PAGE and Immunoblot (IB) were carried out without and with with CCD-Inhibitor. Results The data would suggest IgE binding to common bands between Culex male, Culex female and Aedes species mosquitos of approximate molecular weight ~21kDa, ~35kDa, ~40kDa and ~55kDa. Whilst IgE binding has been observed to protein bands from the Apis melifera extract, these bands do not align with any present in the mosquito extracts. The use of a CCD-Inhibitor results in differences in IgE binding. Specifically, bands that were previously observed in the Apis melifera venom sample without use of CCD-Inhibitor at 40kDa and 90kDa are no longer observed when CCD-Inhibitor is used. Two bands of the Apis melifera venom remain present between 15-20kDa. No major differences in banding pattern were observed for the mosquito samples with or without CCD-Inhibitor, although the blot appears cleaner with less background when CCD-Inhibitor is used. Conclusion Further experiments have to be done to determine whether the reactive bands from Apis melifera are unrelated proteins or whether the proteins are related homologues of varying molecular weight.

Reactive oxygen species (ROS) play a pivotal role in cellular function, and their overproduction contributes to oxidative stress, fatigue, aging, and diseases. To counteract these effects, incorpo-rating antioxidant-rich nutrients is recommended. Functional waters, including electrolyzed hydrogen water (EHW), are gaining attention for potential antioxidant effects through daily in-take. This study employs aquaphotomics and near-infrared spectroscopy (NIRS) to elucidate the molecular mechanisms behind the antioxidant activity of EHW. Previous investigation reported a 100% loss in antioxidant functionality through autoclaving, and a 40% decrease with hydrogen gas removal, prompting the current investigation into the mechanisms of antioxidant effects and especially the role of water molecular structure in it. Aquaphotomics analysis of near infrared (NIR) spectral data revealed that the primary characteristic of EHW associated with anti-radical function is presence of water solvation shells. Autoclaving and degassing led to loss of these water molecular species and a significant increase in free water molecules. The study suggests that water shells (solvation shells) in EHW play a crucial role in neutralizing ROS, although the specific ions or nanoparticles responsible for creating these shells remain unidentified. This concept aligns well with existing proposals of the crucial role of water solvation shells in ROS neutralization.

Current microbiological methods for pneumonia diagnosis require invasive specimen collection and time-consuming analytical procedures. There is a need for less invasive and faster methods to detect lower respiratory tract infection. The analysis of volatile metabolites excreted by pathogenic microorganisms provides the basis for developing such a method. Given the synergistic role of Candida albicans in increasing the virulence of pathogenic bacteria causing pneumonia and the cross-kingdom metabolic interactions between microorganisms, we compare the emission of volatiles from Candida albicans yeasts and the bacteria Staphylococcus aureus using single and mixed co-cultures and apply that knowledge to human in vivo investigations. Gas-chromatography-mass spectrometry (GC-MS) analysis resulted in the identification of sixty-eight volatiles that were found to have significantly different levels in cultures compared to reference medium samples. Certain volatiles found in co-culture originated mainly from C. albicans metabolism (e.g., isobutyl acetate), whereas other volatiles primarily came from S. aureus (e.g., ethyl 2-methylbutyrate). Isopentyl valerate reflects synergic interactions of both microbes, as its level in co-cultures was found to be approximately three times higher than the sum of its amounts in monocultures. Hydrophilic-lipophilic balanced (HLB) coated meshes for thin-film microextraction (TFME) were used to pre-concentrate volatiles directly from bronchoalveolar lavage (BAL) specimens collected from patients suffering from ventilation-associated pneumonia (VAP) that was caused explicitly by C. albicans and S. aureus. GC-MS analyses confirmed the existence of in vitro-elucidated microbial VOCs in human specimens. Significant differences in BAL-extracted amounts respective to the pathogen causing pneumonia were found. The model in vitro experiments provided evidence that cross-kingdom interactions between pathogenic microorganisms affect the synthesis of the volatile compounds. The TFME meshes coated with HLB particles proved to be suitable for extracting VOCs from human material, enabling the translation of in vitro experiments on the microbial volatilome to the in vivo situation involving infected patients. This indicates the direction that should be taken for further clinical studies on VAP diagnosis based on volatile analysis.

Ischemic stroke is one of the leading causes of death and permanent disability in the world. Rapid diagnosis and intervention are crucial for reducing its consequences on individuals and societies. Identifying reliable biomarkers for early detection, prognostics and therapy is a criti-cal imperative for improving the stroke patient treatment. Metabolomics has been shown as a promising tool for biomarker discovery since many of the post-ischemic metabolites can found in the plasma or serum of the patient. In this research, we have performed comparative targeted metabolomic analysis of stroke thrombi, patient serums and healthy control serums in order to determine the alteration in the patients’ metabolome. The most statistically altered metabolites characterized in patient compared to control serums were glutamate and serotonin, followed by several lipid metabolites (phospholipids and triacylglycerols) and glucose. In stroke thrombi compared to patient’s serums, the most significantly altered metabolites were classified as li-pids, with choline-containing phospholipids and sphingomyelins having the highest discrimi-natory score. The results of this study could help in understanding the roles of different meta-bolic changes occurring during thrombosis and cerebral ischemia and possibly suggest new metabolic biomarkers of the ischemic stroke.

Background: The fulminant course of COVID-19, triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents with a high mortality rate and still lacks a causative treatment. C-reactive protein (CRP) has been shown to increase dramatically during the disease progression and correlates with deleterious outcomes. Selective CRP apheresis can reduce circulating CRP levels fast and effective. Methods: Seven hospitalized patients with documented severe COVID-19 progression, elevated CRP plasma levels (> 100 mg/L) and signs of respiratory failure were treated with CRP apheresis. 2-12 CRP apheresis sessions were performed generally in 24 h time intervals and depending on CRP plasma levels. Results: CRP apheresis reduced CRP plasma levels by up to 84% within a few hours, without exhibiting side effects in any patient. Despite signs of severe lung infiltration in all patients, only one patient died. The other patients showed improvements within the chest x-ray after CRP apheresis and were able to recover regardless of intubation and/or ECMO (4 patients). All remaining six patients were discharged from the hospital in good clinical condition. All patients had comorbidities. Conclusions: This case series presents a mortality rate of only 14%, which is dramatically lower than expected from the presented CRP levels as well as comorbidities and ventilation require-ments. Our clinical observations regarding the here presented seven patients support the hypoth-esis that CRP is a candidate to be therapeutically targeted in the early stage of severe COVID-19.

Studies have shown that aerosols generated from flavored e-cigarettes contain Reactive Oxygen Species (ROS), promoting oxidative stress-induced damage within pulmonary cells. Our lab investigated the ROS content of e-cigarette vapor generated from disposable vape bars, a product exempt from the Federal Drug Enforcement Agency’s (FDA) 2020 flavor ban. Specifically, we analyzed vape bars belonging to multiple flavor categories (Tobacco, Minty Fruit, Fruity, Minty/Menthol, Desserts, and Drinks), manufactured by various vendors and of various nicotine concentrations (0-6.8%). Aerosols from these flavored vape bars were generated by a single puff aerosol generator and individually bubbled through a fluorogenic solution to detect and semi-quantify ROS in H2O2 equivalents generated by the vape bars. We compared and contrasted the ROS levels generated by each flavor as an indirect determinant of oxidative stress potential by these disposable vape bars. Our results showed that ROS concentration (μM) of aerosols produced from the vape bars varied significantly between different flavors and a function of nicotine concentration. Likewise, our results suggest that flavoring chemicals and nicotine concentration play a role in alerting ROS production in e-cigarette aerosols. Our study provides insight into the differential health effects of flavored disposable vape bars and the need for their regulation.

This study investigates the role of oxygen vacancy on Fe-doped CeO₂ catalyst activity for soot oxidation. The oxygen vacancy was assessed through Ce³⁺ content. The Fe content was varied between 0 and 30% for two catalyst preparation methods, co-precipitation (CP) and solution combustion synthesis (SCS). X-ray photoelectron spectroscopy indicates that ceria exists as both Ce₄₊ and Ce₃₊, while iron is present only as Fe₃₊. The catalyst’s activity was evaluated by ignition (T10) and combustion (T50) temperatures using thermogravimetric analysis. Optimum Fe contents yielding the highest activity were found to be 10% and 5% for CP and SCS catalysts, respectively. The surface area and morphology have shown moderate effect on catalyst activity, because catalytic soot oxidation involves solid-solid contact. More importantly, regardless of the fabrication method, it was found that Ce₃₊ content, which is closely related to oxygen vacancies, plays the most important role in affecting the catalyst activity.

The present work demonstrates the new nanofiber mats prepared through co-electrospinning of two different polymers i.e. corn protein namely Zein and Nylon-6. The composite nanofiber membrane was used as an effective adsorbent material for the removal of toxic reactive dye i.e. Reactive Blue 19 (RB 19) from water solution. These co-electrospun nanofibers had good mechanical strength compared to zein nanofibers alone. Experimental results suggested that zein/nylon nanofibers have greater potential for total removal of RB19 at room temperature within 10 min of contact time from aqueous solution. The maximum capacity was found to be 70 mg/g of nanofibers. The mechanism of RB19 removal on proposed nanofibers is mainly through hydrogen bond and electrostatic means.

Understanding extremophiles and their usefulness in biotechnology involves studying their habitat, physiology and biochemical adaptations , as well as their ability to produce biocatalysts, in environments that are still poorly explored. In northwestern Peru, which saline lagoons of marine origin Pacific Ocean, the other site from the coast of Brazil of the Atlantic Ocean. Both environments are considered extreme. The objective of the present work was to compare two different strains isolated from these extreme environments at the metabolic level using molecular network methodology through the Global Natural Products Molecular Social Network (GNPS). In our study, the MS/MS spectra from the network were compared with GNPS spectral libraries, where the metabolites were annotated. Differences were observed in the molecular network presented in the two strains of Streptomyces spp. coming from these two different environments. Within the annotated compounds from marine bacteria, the metabolites characterized for Streptomyces sp. B-81 from Peruvian marshes were lobophorins A (1) and H (2), as well as divergolides A (3), B (4) and C (5). Streptomyces sp. 796.1 produced different compounds, such as glucopiericidin A (6) and dehydro-piericidin A1a (7). The search for new metabolites in underexplored environments may therefore reveal new metabolites with potential application in different areas of biotechnology.

Microalgae production is expensive and demands high volumes of water and energy to meet all market demands and yet the production of secondary metabolites using alternative media needs deeper studies. Among alternative media, the use of sugar cane vinasse has gained attention for microalgae cultivation. In this work, we’ve compared the biomass yield and secondary metabolites of Chlorella sorokiniana grown in a commercial medium (Sueoka) and in alternative medium prepared with cane vinasse (0.1%) supplemented with N, P2O5 and K2O (commercial formula 20-5-20 g.L-1). The production of microalgae biomass grown in an alternative medium was 2.2% lower, but reached its maximum growth point 14 days faster than the commercial medium. The average level of Phenolic compounds on the commercial medium were 6.02 ± 0.13 mg GAE .g-1 and increased to 15.28 ± 0.32 mg GAE.g-1when C. sorokinianawere grown in the vinasse medium. Same how, Flavonoids contents varied from 13.12 ± 1.33 to 72.30 ± 5.28 mg QE. g-1 to commercial and vinasse medium, respectively. The maximum AOA of C. sorokiniana grown in vinasse medium was 88.05% at a concentration of 1500 µg.mL-1 of extract, with IC50 at 357.7 ± 27.35 µg.mL-1. Different factors seem to induce variances on secondary metabolites synthesis, mostly stress due to QOD and ions added to the medium by vinasse. The authors recognize there are more investigations to be done, but increasing a natural and low cost pathway for flavonoids yield open up an interesting field for the bioprospection of microalgae.

The persistent issue of bacterial and fungal colonization of artificial implantable materials and decreasing efficacy of conventional systemic antibiotics used to treat implant-associated infections has led to the development of a wide range of antifouling and antibacterial strategies. This article reviews one such strategy where inherently biologically active renewable resources, i.e. secondary plant metabolites (SPMs) and their naturally occurring combinations (i.e. essential oils) are used for surface functionalization and synthesis of polymer thin films. With a distinct mode of antibacterial activity, broad spectrum of action and diversity of available chemistries, secondary plant metabolites present an attractive alternative to conventional antibiotics. However, their conversion from liquid to solid phase without significant loss of activity is not trivial. Using select examples, this article shows how plasma techniques provide a sufficiently flexible and chemically reactive environment to enable the synthesis of biologically-active polymer-coatings from volatile renewable resources.

BPA is a commonly used compound in many industries and has versatile applications in polycarbonate plastics and epoxy resins production. BPA is classified as endocrine-disrupting chemical which can hamper fetal development during pregnancy and may have long term negative health outcomes in humans. Dietary sources, main route of BPA exposure, can be contaminated by the migration of BPA into food during processing. The global regulatory framework for using this compound in food contact materials is currently not harmonized. This review aims to outline, survey, and critically evaluate BPA contamination in meat products, including level of BPA and/or metabolites present, exposure route, and recent advancements in the analytical procedures of these compounds from meat and meat products. The contribution of meat and meat products to the total dietary exposure of BPA ranges between 10 and 50% depending on the country and exposure scenario considered. From can lining materials of meat products, BPA migrates towards the solid phase resulting higher BPA concentration in solid phase than the liquid phase of the same can. The analytical procedure is comprised of meat sample pre-treatment, followed by cleaning with SPE, and chromatographic analysis. Considering several potential sources of BPA in industrial and home culinary practices, BPA can also accumulate in non-canned or raw meat products. Very few scientific studies have been conducted to identify the amount in raw meat products. Similarly, analysis of metabolites and identification of the origin of BPA contamination in meat products is still a challenge to overcome.

Polycystic ovary syndrome (PCOS) is an insulin resistant state, compensated by hyperinsulinemia. More than 50% of the women with PCOS are obese, and/or have metabolic syndrome. Weight loss improves both metabolic and reproductive outcomes. Not only the energy content, but also the nutrient composition of a diet may be important. This article will present a series of studies from our research comparing effects of dietary protein vs. simple-carbohydrates (CHO). Results of the acute challenge studies demonstrate that simple-CHO intake causes reactive hypoglycemia in one third of the women with PCOS, especially among obese and insulin resistant individuals. Symptoms of hypoglycemia are associated with secretion of cortisol and adrenal androgens. Simple-CHO suppresses the hunger signal ghrelin for a shorter period. During weight loss, women who receive protein supplementation achieve larger amounts of weight- and fat-mass losses. Amino acid compositions of the protein supplements do not affect the improvements in weight and insulin resistance. It is plausible that simple-CHO intake leads to weight gain, or interferes with weight-loss, by causing reactive hypoglycemia, triggering adrenal steroid secretion, and leading to snacking. Since obese women with PCOS are more susceptible to reactive hypoglycemia, a vicious cycle establishes. Restriction of simple-CHO may break this cycle.

Consumption of high amounts of ethanol is a risk factor for development of cardiovascular diseases such as arterial hypertension. The hypertensive state induced by ethanol is a complex multi-factorial event, and oxidative stress is a pathophysiological hallmark of vascular dysfunction associated with ethanol consumption. Increasing levels of reactive oxygen species (ROS) in the vasculature triggers important processes underlying vascular injury, including accumulation of intracellular Ca2+ ions, reduced bioavailability of nitric oxide (NO), activation of mitogen-activated protein kinases (MAPKs), endothelial dysfunction, and loss of the anticontractile effect of perivascular adipose tissue (PVAT). The enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase plays a central role in vascular ROS generation in response to ethanol. Activation of the renin-angiotensin-aldosterone system (RAAS) is an upstream mechanism which contributes to NADPH oxidase stimulation, overproduction of ROS and vascular dysfunction. This review discusses the mechanisms of vascular dysfunction induced by ethanol, detailing the contribution of ROS to these processes. Data examining the association between neuroendocrine changes and vascular oxidative stress induced by ethanol are also reviewed and discussed. These issues are of paramount interest to public health as ethanol contributes to blood pressure elevation in the general population, and it is linked to cardiovascular conditions and diseases.

A semi-analytical approach is developed for predicting pyrolysis front temperature in a solid undergoing thermal decomposition. The pre-reaction heating stage is described using an analytical formulation and invoking the concept of thermal penetration depth. The solution for the solid conversion stage accounts for decomposition enthalpy, convective flow of volatiles, and a reaction front characterized by a uniform temperature that progresses toward the inner layers. This method incorporates empirical relations into the analytical model. Two scenarios are considered. First, the solution of the pyrolysis model combined with the data of conversion time versus external heat flux leads to an algebraic expression that reveals the existence of a maximum pyrolysis-front temperature. Explicit relations are derived for both the extremum pyrolysis temperature and optimum applied heat flux. In the second case, an expression is derived for the ignition temperature of a solid fuel by incorporating ignition delay time measurements into the heating stage model. The newly derived expression allows to describe the ignition temperature as a function of the Biot number and external heat flux. The relation obtained for the ignition temperature explains the experimental trends reported in some previous studies where two local extremums were observed for the ignition temperature in the absence of volatiles reactions.

Nanoparticle-mediated radiation therapy (NPRT) is an emerging modality for radiosensitization of highly resistant cancers such as brain cancers. This is due to the ability of specific nanoparticles (NPs) to increase physical dose deposition and subsequent direct damage to cells and DNA within their local vicinity, through enhanced generation of reactive oxygen species, ROS. Here, we report the successful use of PEGylated (biocompatible) core-shell quantum dots (QDs) and carbon quantum dots (CQDs) to simultaneously enhance and assess ROS generation while radiosensitizing highly radioresistant brain cancer cell lines: T98G and U87 Glioblastoma cells. Relative peak fluorescence intensity ratio calculations and average intensity comparisons show highly significant (***p&lt;0.001) enhancement of ROS generation, for 5 Gy and 20 Gy irradiation, applied using a Faxitron Cell Irradiator. By quantifying post-radiotherapy cell attachment, proliferation, migration, cell survival and cell death using electric cell-substrate impedance sensing and clonogenic assays, we demonstrate potentially improved in vitro radiotherapeutic outcomes for brain cancer cells radiosensitized using PEGylated CdSe/ZnS QDs and CQDs.

The microbiome is capable of modulating the bioavailability of chemotherapy drugs mainly due to metabolizing these agents. Multiple cytostatic bacterial metabolites were recently identified that have cytostatic properties on cancer cells. In this study we addressed the question whether the cytostatic bacterial metabolites (cadaverine, indolepropionic acid, indoxylsulfate) can interfere with the cytostatic effects of the chemotherapy agents used in the management of breast cancer (doxorubicin, gemcitabine, irinotecan, methotrexate, rucaparib, 5-fluorouracil, paclitaxel). The chemotherapy drugs were applied in a wide concentration range to which a bacterial metabolite was added in a concentration within its serum reference range and the effects on cell proliferation were assessed. There was no interference between doxorubicin, gemcitabine, irinotecan, methotrexate, rucaparib and the bacterial metabolites. Nevertheless, cadaverine increased the Hill coefficient of the inhibitory curve of 5-fluorouracil and indolepropionic acid increased the IC50 value of 5-fluorouracil that are either disadvantageous effects or effects of unknown significance. Nevertheless, indolepropionic acid decreased the IC50 value of paclitaxel that is a potentially advantageous combination.

This mini-review examines the complex relationship between the gut microbiota and human health, with a special focus on its role in conditions such as inflammatory bowel disease (IBD) and cardiovascular disease (CVD). It explores how dietary patterns can affect the composition of the gut microbiota, thus contributing to the development of various diseases. The gut microbiota is crucial in the production of metabolites such as trimethylamine N-oxide (TMAO), which play a significant role in the development of both IBD and CVD. High levels of TMAO and other metabolites, such as phenylacetylglutamine, have been linked to an increased risk of CVD. The review highlights the potential of dietary interventions and therapies designed to modulate the gut microbiota in reducing these risks. Following a Mediterranean diet may offer cardiovascular protection, emphasizing the need for further research into the molecular mechanisms of diet-related changes in the microbiota.

Dysregulation of the arsenal of cells, growth factors, cytokines, proteases, and proteins involved in wound healing (WH), could delay the healing process. Plants and plant-derived molecules (PDMs) have been used as medicines for skin wounds. This study aimed to select and evaluate the pro-healing capacity of PMDs. Thirty-three PDMs and 10 therapeutic targets (TTs) were chosen for molecular docking and PDMs: aristolochic acid (AA), α-copaene, selinenes, β-caryophyllene (BC), and BCoxide, and TTs: metalloproteinase (MMP) 3, MMP13, and tumor necrosis factor (TNF α) for molecular dynamics. The bests inhibitor was AA, but because of its toxicity, BC and BCoxide were chosen for evaluation in HaCat cells and BALB/c mice excisional model. Both compounds were not toxic, and higher percentages of lesion area closure (LAC) were induced by BC treatment (p<0.05). All mice healed; however, an initial delay of LAC was induced by 0.05, 0.1% BCoxide, 0.1% BC, and allantoin. At the end of treatment, lower numbers of mast cells, level of cellular infiltrates (except 1% BCoxide and 0.05, 0.5%BC), epidermal thickness tendency (except 0.1, 0.5% BCoxide), and higher values of SC-thickness, and collagen fibers only by 0.5% BC treatment compared with untreated control (p<0.05) were observed. Our results show that BC is a promising multitarget candidate for wound healing treatment and optimization campaigns.

The current study aims to investigate the changes in polar metabolites, phenolic compounds, and fatty acids in the skin of Hass avocados stored under two distinct circumstances. Fruits from the Bartolillo orchard were primarily associated with linoleic and oleic acid as significant variables. Fruits were primarily associated with palmitoleic, palmitic, and oleic acids in Quilhuica. For one orchard, the phenolic content increased at the start of storage and declined at the conclusion, whereas the opposite was true for another, showing that the outcome was depending on the orchard and storage conditions. The polar metabolites that most closely connected with the fruits of the Quilhuica orchard were serine, glutaric acid, xylitol, and D-mannitol, whereas ß-sitosterol and gluconic were related to the fruits of the Bartolillo orchard.

A major challenge in the clinical management of patients with mesial temporal lobe epilepsy (MTLE) is identifying those who do not respond to antiseizure medication (ASM), allowing for the timely pursuit of alternative treatments, such as epilepsy surgery. Here, we investigated changes in plasma metabolites as biomarkers of pharmacoresistance in patients with MTLE. Furthermore, we used the metabolomics data to gain insights into the mechanisms underlying MTLE and response to ASM. We performed an untargeted metabolomic method using magnetic resonance spectroscopy and multi- and univariate statistical analyses to compare data obtained from plasma samples of 28 patients with MTLE compared to 28 controls. The patients were further divided according to response to ASM: 20 patients were refractory to treatment, and eight were responsive to ASM. We only included patients using carbamazepine in combination with clobazam. We compared the group of patients with controls and found that the profiles of glucose (p = 0.01), saturated lipids (p = 0.0002), isoleucine (p = 0.0001), β-hydroxybutyrate (p = 0.0003), and proline (p = 0.02) were different in patients compared to controls (p &lt; 0.05). In addition, lipoproteins (p = 0.05), lactate (p = 0.05), glucose (p = 0.05), unsaturated lipids (p = 0.05), isoleucine (p = 0.05), and proline (p = 0.05), could discriminate between the two groups of patients classified according to response to ASM. The identified metabolites were linked to different biological pathways related to cell energy metabolism, and pathways linked to inflammatory processes and the modulation of neurotransmitter release and activity in MTLE. In contrast, we found that pyruvate metabolism may be linked to resistance to ASM. In conclusion, in addition to insights into the mechanisms underlying MTLE and the response to treatment with ASM, our results suggest that plasma metabolites may be used as biomarkers of disease and response to ASM in patients with MTLE. These findings warrant further studies exploring the clinical use of metabolites to assist in decision-making when treating patients with MTLE.

Metabolites are essential intermediate products in metabolism, and metabolism dysregulation indicates different types of diseases. Previous studies have shown that cigarette smoke dysregulated metabolites; however, limited information is available with electronic cigarette (E-cig) vaping. We hypothesized that E-cig vaping and cigarette smoking altered systemic metabolites, and we propose to understand the specific metabolic signature between E-cig users and cigarette smokers. Plasma from non-smoker controls, cigarette smokers, and e-cig users were collected, and metabolites were identified by UPLC–MS (Ultraperformance liquid chromatography-mass spectrometer). Nicotine degradation was activated by e-cig vaping and cigarette smoking with increased concentrations of cotinine, cotinine N-oxide, (S)-nicotine, and (R)-6-hydroxynicotine. Additionly, we found significant decreased concentrations in metabolites associated with tricarboxylic acid (TCA) cycle pathways in e-cig users verses cigarette smokers, such as: D-glucose, (2R,3S)-2,3-dimethylmalate, (R)-2-hydroxyglutarate, O-phosphoethanolamine, malathion, D-threo-isocitrate, malic acid, and 4-acetamidobutanoic acid. Cigarette smoking significant up-regulated sphingolipid metabolites, such as D-sphingosine, ceramide, N-(octadecanoyl)-sphing-4-enine, N-(9Z-octadecenoyl)-sphing-4-enine, and N-[(13Z)-docosenoyl]sphingosine, verses e-cig vaping. Overall, e-cig vaping dysregulated TCA cycle realted metabolites while cigarette smoking altered sphingolipid metabolites. Both e-cig and cigarette smoke increased nicotinic metabolites. Therefore, specific metabolic signature altered by e-cig vaping and cigarette smoking could serve as potential systemic biomarkers for early cardiopulmonary diseases.

(1) Background: The severity of malaria is associated with low bioavailability of antioxidants and high concentration of free radicals that induce oxidative damage in cerebral and pulmonary microcirculation. This can be prevented by the action of consumable antioxidants present in foods. Therefore, we investigated the protective role of lycopene (LYC) on the oxidative changes induced by Plasmodium berghei (Pb); (2) Methods: Mice were infected by intraperitoneal injection of 106 parasitized red blood cells and treated via gavage with LYC (3.11 mg/kg bw/day) or NAC (62 mg/kg bw/day). They were then evaluated for 1, 4, 8 or 12 days after infection. Levels of thiobarbituric acid reactive substances (TBARS), antioxidant capacity by inhibition of ABTS radicals (AC-ABTS) and DPPH (AC-DPPH), uric acid (UA), and nitric oxide (NO) were measured in brain and lung tissues; (3) Results: The infection caused oxidative stress confirmed by increased levels of TBARS, AC-ABTS, AC-DPPH, UA, and NO in the tissues leading to the death of the animals. LYC prevented the increase in TBARS, AU, and NO levels compared to Pb (p&lt; 0.0001) and NAC+Pb groups (p&lt;0.0001), reaching values similar to those of Sham animals; (4) Conclusions: These results are striking evidence of the beneficial effect of lycopene supplementation on oxidative stress in experimental malaria in vivo and emphasize the importance of antioxidant supplementation in the treatment of the disease.

Emerging data have demonstrated a strong association between the gut microbiota and the development of cardiovascular disease (CVD) risk factors such as atherosclerosis, inflammation, obesity, insulin resistance, platelet hyperactivity, and plasma lipid abnormalities. Several studies in humans and animal models have demonstrated an association between gut microbial metabolites, such as trimethylamine-N-oxide (TMAO), short-chain fatty acids, and bile acid metabolites, amino acid breakdown products, with CVD. Human blood platelets are a critical contributor to the hemostatic process. Besides, these blood cells play a crucial role in developing atherosclerosis and, finally, contribute to cardiac events. Since the TMAO, and other metabolites of the gut microbiota, are associated with platelet hyperactivity, lipid disorders, and oxidative stress, the diet-gut microbiota interactions have become an important research area in the cardiovascular field. Platelets became hyperactive in people with diabetes mellitus, sedentary lifestyle, obesity, and insulin resistance and exhibited increased sensitivity at a baseline level and in response to agonists, ultimately contributing to increased aggregation plaque development. In addition to these factors, TMAO also contributes to platelet hyperactivity. Several approaches are now suggested to reduce plasma TMAO levels, such as microbiota modulation using probiotics, prebiotics, and oral broad-spectrum antibiotics. This review describes the association between microbiota-derived metabolites and CVD development.

The human gastrointestinal tract is inhabited by trillions of commensal bacteria collectively known as the gut microbiota. Our recognition of the significance of the complex interaction between the microbiota, and its host has grown dramatically over the past years. A balanced microbial community is a key regulator of the immune response, and metabolism of dietary components, which in turn, modulates several brain processes impacting mood and behavior. Consequently, it is likely that disruptions within the composition of the microbiota would remotely affect the mental state of the host. Here, we discuss how intestinal bacteria and their metabolites can orchestrate gut-associated neuroimmune mechanisms that influence mood and behavior leading to depression. In particular, we focus on microbiota-triggered gut inflammation and its implications in shifting the tryptophan metabolism towards kynurenine biosynthesis while disrupting the serotonergic signaling. We further investigate the gaps to be bridged in this exciting field of research in order to clarify our understanding of the multifaceted crosstalk in the microbiota-gut-brain interphase, bringing about a novel microbiota-targeted therapeutics for mental illnesses.

Immune-cell reprogramming driven by mitochondria-derived reactive electrophilic immunometabolites (mt-REMs—e.g., fumarate, itaconate) is an emerging phenomenon of major biomedical importance. Despite their localized production, mt-REMs elicit significantly-large local and global footprints within and across cells, through mechanisms involving electrophile signaling. Burgeoning efforts are being put into profiling mt-REMs’ potential protein-targets and phenotypic mapping of their multifaceted inflammatory behaviors. Yet, precision indexing of mt-REMs’ first-responders with spatiotemporal intelligence and locale-specific function assignments remains elusive. Highlighting the latest advances and overarching challenges, this perspective aims to stimulate thoughts and spur interdisciplinary innovations to address these unmet chemical-biotechnological needs at therapeutic immuno-signaling frontiers.

Phosphatase and tensin homolog (PTEN) is a tumor suppressor due to its ability to regulate cell survival, growth and proliferation by down-regulating PI3K/AKT signaling pathway. In addition, PTEN plays an essential role in other physiological events associated with cell growth demands, such as ischemia-reperfusion, nerve injury and immune response. Therefore, recently PTEN inhibition has emerged as a potential therapeutic intervention in these situations. Increasing evidence demonstrates that reactive oxygen species (ROS), especially hydrogen peroxide (H2O2), are produced and required for the signaling in many important cellular processes under such physiological conditions. ROS have been shown to oxidize PTEN at the cysteine residue of its active site, consequently inhibiting its function. Here we provide an overview of studies that highlight the role of oxidative inhibition of PTEN in physiological processes.

Reactive transport (RT) couples bio-geo-chemical reactions and transport. RT is important to understand numerous scientific questions and solve some engineering problems. RT is highly multidisciplinary, which hinders the development of a body of knowledge shared by RT modelers and developers. The goal of this paper is to review the basic conceptual issues shared by all RT problems, so as to facilitate advance along the current frontier: biochemical reactions. To this end, we review the basic equations to point that chemical systems are controlled by the set of equilibrium reactions, which are easy to model, but whose rate is controlled by mixing. Since mixing is not properly represented by the standard advection-dispersion equation (ADE), we conclude that this equation is poor for RT. This leads us to review alternative transport formulations, and the methods to solve RT problems using both the ADE and alternative equations. Since equilibrium is easy, difficulties arise for kinetic reactions, which is especially true for biochemistry, where numerous frontiers are open (how to represent microbial communities, impact of genomics, effect of biofilms on flow and transport, etc.). We conclude with the basic 10 issues that we consider fundamental for any conceptually sound RT effort.

Naive CD4+ T cells engage cognate peptide MHC-II complexes (pMHC-IIs) to differentiate and acquire one of several T helper (Th) fates whose specific trajectories are guided by a dynamic cytokine milieu that develops in response to antigenic entity. This physiological process is often erroneously conflated with a pathological one termed Th polarization. Using the SPIRAL model, we argue here that unlike Th fate choice, innate signaling alone is insufficient to initiate Th polarization in naive CD4+ T cells, that it instead develops from pre-existing memory CD4+ T cells that express cross-reactive TCRs, and that it inevitably leads to immunopathology.

Obstacle-avoidance robots have become an essential field of study in recent years. This paper analyzes two cases that extend reactive systems focused on obstacle detection and its avoidance. The scenarios explored get data from their environments through sensors and generate information for the models based on artificial intelligence to obtain a reactive decision. The main contribution is focused on the discussion of aspects that allow comparing both approaches, such as the heuristic approach implemented, requirements, restrictions, response time, and performance. The first case presents a mobile robot that applies fuzzy logic to achieve soft turning basing its decision on depth image information. The second case introduces a mobile robot based on multi-layer perceptron and ultrasonic sensors to decide how to move in an uncontrolled environment. The analysis of both options offers perspectives to choose between reactive obstacle-avoidance systems based on ultrasonic or Kinect sensors, models that infer optimal decisions applying fuzzy logic or artificial neural networks, with key elements and methods to design mobile robots with wheels. Therefore, we show how AI or Fuzzy Logic techniques allow us to design mobile robots that learn from their “ experience ” by making them safe and adjustable for new tasks, unlike traditional robots that use large programs to perform a specific task.

This paper updates earlier thoughts by the author on a putative propulsion system. The concept was based around static electromagnetic momentum, as expounded in the “Feynman Disk” and experimentally verified by Graham and Lahoz. That said, naïve static electromagnetic momentum schemes to achieve linear translation are defeated by “hidden momentum” mechanisms, so too are simple arrangements just cycling the fields; we shall survey the flaws in their arguments. It may however be possible to achieve linear translation by means of arrangements of torques with a novel mechanism to break the symmetry of forces (or torques) on the second half of the cycle as the field is switched off. At the time of earlier presentation no mechanism could be found to explain the momentum balance for the process but it was believed that momentum was being given to the zero-point of the field. We show that it is possible to dump angular momentum and thence linear momentum to the ground state by standard quantum analysis of the EM field. None of this violates the conservation of momenergy.

This paper presents an alternative constraint handling approach within a specialized genetic algorithm (SGA) for the optimal reactive power dispatch (ORPD) problem. The ORPD is formulated as a nonlinear single-objective optimization problem aiming to minimize power losses while keeping network constraints. The proposed constraint handling approach is based on a product of sub-functions that represents permissible limits on system variables and that includes a specific goal on power loss reduction. The main advantage of this approach is the fact that it allows a straightforward verification of both feasibility and optimality. The SGA is examined and tested with the proposed constraint handling approach and the traditional penalization of deviations from feasible solutions. Several tests are run in the IEEE 30, 57, 118 and 300 bus test power systems. The results obtained with the proposed approach are compared to those offered by other metaheuristic techniques reported in the specialized literature. Simulation results indicate that the proposed genetic algorithm with the alternative constraint handling approach yields superior solutions when compared to other recently reported techniques.

Uncoupling protein 3 (UCP3) belongs to the mitochondrial carrier protein superfamily SLC25 and is abundant in brown adipose tissue (BAT), heart and muscles. Unlike UCP1, which is localized in BAT and involved in non-shievering thermogenesis, its biological function is under dispute. The expression of UCP3 in tissues mainly dependent on fatty acid oxidation suggests its involvement in cellular metabolism and has drawn attention to its possible transport function beyond the transport of protons in the presence of fatty acids. Based on the high homology between UCP2 and UCP3, we hypothesized that UCP3 transports C4 metabolites similar to UCP2. To test this, we measured the transport of substrates against phosphate (32Pi) in proteoliposomes reconstituted with recombinant murine UCP3. We found that UCP3 mainly transports aspartate and sulfate but also malate, malonate, oxaloacetate and succinate. The transport rates calculated from the exchange of 32Pi against extraliposomal aspartate and sulfate were 23.9 ± 5.8 and 17.5 ± 5.1 µmol/min/mg, respectively. Using site-directed mutagenesis we revealed that mutation of R84 resulted in impaired aspartate/phosphate exchange, demonstrating its critical role in substrate transport. Difference in substrate preference between UCP2 and UCP3 may be explained by their different tissue expression pattern and biological function in these tissues.

This study aimed to select the most effective metabolites for controlling honey bee nosemosis using culture extracts from 342 entomopathogenic fungi of 24 species from 18 genera. The germination inhibitory activity of the fungal culture extract against Nosema ceranae spores was evaluated using an in vitro germination assay method. Among 89 fungal culture extracts showing germination inhibitory activity of approximately 80% or more, 44 culture extracts that maintained their inhibitory activity even at a concentration of 1% were selected. Finally, the honey bee nosemosis inhibitory activity was evaluated using the cultured extracts of 5 fungal isolates having a Nosema inhibitory activity of approximately 60% or more even when the extract was removed after treatment. As a result, the proliferation of Nosema spores was reduced by all fungal culture extract treatments. However, only the treatment of the culture extracts from Paecilomyces marquandii 364 and Pochonia bulbillosa 60 showed a reduction in honey bee mortality due to nosemosis. In particular, the extracts of these two fungal isolates also increased the survival of honey bees.

Lichen secondary metabolites are generally considered as repellent compounds for lichen feeders. Nevertheless, if the only food available consists in lichens rich in secondary metabolites, lichenophages such as Notodiscus hookeri, a gastropod native from the Possession Island, seem able to implement strategies to overcome the toxicity of these metabolites. Thus, the balance between phagostimulant nutrients and deterrent metabolites appears to play a key role in their feeding preferences. To further understand lichen-gastropod interactions, we studied the feeding behavior of Notodiscus hookeri fed exclusively with Usnea taylori, a lichen rich in usnic acid and arabitol. Snail feeding choice experiments with intact lichens vs acetone-rinsed lichens were carried out to study the influence of secondary metabolites. Simultaneously, usnic acid and arabitol were quantified and localized within the lichen thallus using HPLC-DAD-MS and in situ imaging by mass spectrometry to assess whether their spatial distribution induce preferential snail grazing. Then, no-choice feeding experiments were devised using usnic acid and arabitol embedded in artificial diet, separately or together. This case study demonstrated that the nutritional activity of N. hookerii was governed by the chemical quality of the food and primarily by nutrient availability (arabitol), despite the presence of deterrent metabolites (usnic acid).

Background: Inflammation is an important mechanism in atherosclerosis and plaque formation. C-reactive protein (CRP) is a common inflammatory biomarker associated with the risk of coro-nary heart disease. We investigated the relationship of CRP with findings from myocardial per-fusion imaging (MPI). Methods: In this retrospective study, 102 consecutive patients (mean age 71 years, 68% males) that underwent MPI (for diagnostic reasons or quantification of myocardial ischemia) and CRP determination (upper limit: 6mg/L) within 1 month from MPI, were included. Patients had no infection or recent acute coronary syndrome. Results: the median CRP level was 4mg/L (2,10) among the study population. Patients with raised CRP had higher summed stress score (SSS) (P = 0.006) and summed rest score (SRS) (P = 0.001) and higher risk for SSS > 3 (OR 9.25, 95% CI 2.03-42.13, P = 0.001) compared to those with low CRP. The association of SSS and SRS with CRP levels was more evident in patients over 70 years (P = 0.027 and P = 0.005 respectively). No significant difference in summed difference score was shown. The two groups had no difference in other risk factors (p > 0.05 for all comparisons). Conclusion: A high level of CRP was associated with the presence and extent of stress-induced myocardial ischemia in MPI.

Titanium oxynitride thin films are deposited by DC reactive magnetron sputtering. A pure titanium target is sputtered in a reactive atmosphere composed of argon, oxygen and nitrogen gases. The oxygen mass flow rate as well as that of the nitrogen gas are both pulsed during the deposition time using an independent and rectangular signal for each reactive gas. A constant pulsing period T = 45 s is applied for both reactive gases and a delay time  of 34 s between N2 and O2 injection times is set for all depositions. Oxygen and nitrogen duty cycles are systematically and independently changed from 0 to 100% of their pulsing period. From real time measurements of the Ti target potential and total sputtering pressure, it is shown that the reactive process alternates between oxidized, nitrided and elemental sputtering modes as a function of the oxygen and nitrogen injection times. The full poisoning of the Ti target surface by oxygen and/or nitrogen can be avoided for some given ranges of O2 and N2 duty cycles. Deposition rates of titanium oxynitride films are substantially enhanced and can be adjusted between that of pure Ti and TiN films with a gradual transition of their optical transmittance in the visible range. These results support that titanium oxynitride compounds exhibiting absorbent to transparent behaviors can be precisely sputter-deposited by means of a two reactive gases pulsing process.

β-apopicropodophyllin (APP), a derivative of podophyllotoxin (PPT), has been identified as a potential anti-cancer drug. This study tested whether APP acts as an an-ti-cancer drug and can sensitize colorectal cancer (CRC) cells to radiation treatment. APP had an anti-cancer effect against the CRC cell lines HCT116, and DLD-1, SW480 and COLO320DM with IC50 values of 7.88 nM, and 8.22 nM, 9.84 nM and 7.757 nM, respec-tively induction of DNA damage. Colonogenic and cell counting assays indicated that the combined treatment of APP and γ-ionizing radiation (IR) showed greater retardation of cell growth than either alone, suggesting that APP sensitizes CRC cells to IR. Annexin V-propidium iodide (PI) assays and immunoblot analysis showed that the combined treatment of APP and IR increased apoptosis in CRC cells compared with either APP or IR alone. Results obtained from the xenograft experiments also indicated that the combination of APP and IR enhanced apoptosis in in vivo animal model. Apoptosis induction by the combined treatment of APP and IR resulted from reactive oxygen species (ROS). Inhibition of ROS by N-acetylcysteine (NAC) restored cell viability and decreased the induction of apoptosis by APP and IR in CRC cells. Taken together, these results indicate that a combined treatment of APP and IR might promote apoptosis by inducing ROS in CRC cells.

Limited research has been conducted on the metabolites present in the essential oils (EOs) of Phlomoides rotata (Benth. ex Hook. f.) Mathiesen (PR, syn. Lamiophlomis rotata (Benth.) Kudô), and their potential pharmacological activities, such as antioxidant properties, are often overlooked. We conducted a metabolomics-based screening to identify the characteristic metabolites (CMs) in the EOs extracted from PR. Meanwhile, we evaluated their in vitro antioxidant activities (AOAs). The EOs obtained through hydro-distillation are characterized by a light yellow color and a fresh, elegant fragrance. Cryoprecipitation was used to separate the crystals (Crs) from the EOs, resulting in the crystal-free EOs (CFs). A total of 121 components are identified and quantified in the EOs, Crs, and CFs. Among them, 84 were reported for the first time from such EOs. The major compounds include long-chain fatty acids (LCFAs) and their esters, such as palmitic acid (PA), myristic acid (MA), linoleic acid (LA), oleic acid (OA), stearic acid, and methyl palmitate (MP). Furthermore, 11 kinds of apocarotenoids (also called norisoprenoids) were first systematically investigated. Among them, eight C13-norisoprenoids, with trans-β-damascenone (DN) being particularly notable for its flavor, were identified. A sum of 11 CMs are screened , including PA, MA, LA, OA, MP, hexahydrofarnesyl acetone, phytol (PT), DN, stearic acid, linalool, and hexanal. These CMs are biosynthesized through FAs and 2-C-Methyl-D-erythritol 4-phosphate/1-Deoxy-D-xylulose 5-phosphate pathways. The in vitro AOAs of EOs, Crs, CFs, and seven selected CMs (PA, MA, LA, OA, MP, PT, and DN) were evaluated. Generally, PA and MA exhibited pro-oxidant activities (POAs) or weak AOAs. LA and OA demonstrated POAs or weak AOAs at lower concentrations, but at higher concentrations, they displayed medium to strong AOAs. Importantly, the CFs typically exhibited stronger AOAs compared to the corresponding EOs and Crs, potentially due to variations in their PA content. Overall, this study provides valuable insights into the potential utilization of EOs from PR.

The wound management sector has attracted considerable attention due to the increasing challenge posed by antimicrobial resistance (AMR) and the specialized care required for chronic wounds. Effective wound care involves selecting appropriate dressings tailored with antimicrobial agents to prevent bacterial infection. Among various types of wound dressings, fibers and electrospun fibers, with their unique characteristics, have emerged as innovative new materials. However, the rise of AMR necessitates the exploration of new antimicrobial agents for wound dressings, particularly for addressing bacterial pathogens like methicillin-resistant Staphylococcus aureus (MRSA). Endophytic fungi, known for producing diverse bioactive compounds, including novel antibacterial agents, represent a promising source of such new agents. This study tested thirty-two endophytic fungi from thirteen distinct Australian native plants for their antibacterial activity against S. aureus, the most common wound-associated bacteria. Ethyl acetate (EtOAc) extracts from fungal culture filtrates exhibited inhibitory effects against both methicillin-sensitive S. aureus ATCC 25923 and MRSA strains M173525 and M180920. DNA sequence analysis was employed for fungal identification, with EtOAc extracts from the most active sample, EL 19 (Chaetomium globosum), selected for further bactericidal and antibiofilm testing against the chosen bacteria. Biofilm of S. aureus ATCC 25923 was reduced by 55% by EtOAc extracts of EL 19 at 1/2 × MIC. To demonstrate the potential application in wound dressing materials, three different concentrations of the extract were incorporated into Polycaprolactone fiber mats through electrospinning, with resultant inhibition of S. aureus ATCC 25923 being observed. This research underscores the potential of endophytic fungi from Australian plants as sources of substances effective against common wound pathogens. Further exploration of the responsible compounds and their mechanisms could facilitate the development of wound dressings effective against MRSA and innovative biofilm-resistant electrospun fibers, contributing to the global efforts to combat AMR.

The recently reported microbial natural product N-benzoyl-tryptophane (1) along with twenty-two diverse known bioactive compounds were isolated from the marine Aspergillus terreus LGO13 after its re-cultivation using liquid culture fermentation. Structures of the isolated compounds were established on the basis of HR-ESIMS 1D/2D NMR spectroscopy, and comparison with literature data. The antimicrobial, cytotoxicity, and antiviral activities of the microbial extract and the obtained compounds were investigated using a set of microorganisms, cervix carcinoma KB-3-1, non-small cell lung cancer (NSCLC) A549, and coronavirus (SARS-CoV-2), respectively. Molecular docking (MD) simulation was employed to explore the theoretical targets of the isolated metabolites as anti-SARS-CoV-2 agents. Chaetominine (2) seemed to be a potential candidate against papain-like protease (PLpro), one of the viral proteins being aimed by recent research as a possible target of anti-covid agents. Inspired by the MD results, we accordingly assessed the antiviral efficacy of chaetominine (2), fumitremorgin C (6), and azaspirofuran A (9) against SARS-CoV-2. Fumitremorgin C (6) showed a high selectivity index (SI = 20.3), while chaetominine (2) and azaspirofuran A (9) showed moderate selectivity index (SI = 6.6 and 3.2, respectively). These results showed a promising antiviral activity of Fumitremorgin C against SARS-CoV-2 virus.

Lactobacillus plantarum has been observed to play a crucial role in shaping the sensory properties of chili sauce. However, the specific taste-active metabolites responsible for the desirable flavor profile of chili sauce remain inadequately characterized. This study employed a combination of metabolomics and web-based computational tools analysis to investigate the dynamic changes in taste-active metabolites during chili sauce fermentation. Initially, metabolites were rapidly annotated using a feature-based molecular network, leading to the tentative annotation of 206 metabolites, of which a significant proportion had not been previously reported. Subsequently, the VirtualTaste tool identified dihydrosphingosine, lactic acid, isoleucine, phytosphingosine, and gluconic acid as potential taste markers for quality control. Finally, pathway enrichment analysis revealed that these components were primarily associated with amino acid tRNA, phenylalanine, tyrosine, and tryptophan biosynthesis, as well as sphingolipid metabolism. This study provides valuable insights into the mechanisms underlying the formation of the distinctive flavor of chili sauce.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have triggered a recent pandemic of respiratory disease and affected almost every country all over the world. A large amount of natural bioactive compounds is under clinical investigation for various diseas-es. Especially, marine natural compounds are gaining more attention in the new drug develop-ment process. The present study has aimed to identify potential marine-derived inhibitors against the target proteins of COVID-19 using a computational approach. Currently, 16 marine clinical-level compounds were selected for computational screening against the four SARS-CoV-2 main proteases. Computational screening resulted from the best drug candidates for each target based on the binding affinity scores and amino acid interactions. Among these, five marine-derived compounds namely Chrysophaentin A (-6.6 kcal/mol), Geodisterol sulfates (-6.6 kcal/mol), Hymenidin (-6.4 kcal/mol), Plinabulin (-6.4 kcal/mol) and Tetrodotoxin (-6.3 kcal/mol) expressed the minimized binding energy and molecular interactions such as covalent and hydrophobic interactions to the SARS CoV-2 Main Protease. Using Molecular dynamic stud-ies, the Root-Mean-Square Deviation (RMSD), Root-Mean-Square Fluctuation (RMSF), Radius of Gyration (ROG), and Hydrogen bonds (H-Bonds) values were calculated for SARS-CoV-2 Main Protease with Hymenidin docked complex. Additionally, in silico Druglikeness and pharmaco-kinetic property assessments of the compounds demonstrated favorable druggability. These re-sults suggested that marine natural compounds are capable of fighting SARS-CoV-2. Further, in vitro and in vivo studies need to be carried out to confirm their inhibitory potential.

Metandienone and methyltestosterone are orally active anabolic-androgenic steroids with a 17α-methyl structure that are prohibited in sports but are frequently detected in anti-doping analysis. After the previously reported detection of long-term metabolites with a 17ξ-hydroxymethyl-17ξ-methyl-18-nor-5ξ-androst-13-en-3ξ-ol structure in the chlorinated metandienone analog dehydrochloromethyltestosterone (“Oral Turinabol”), in this study we investigated the formation of similar metabolites of metandienone and 17α-methyltestosterone with a rearranged D-ring and a fully reduced A-ring. Using a semi-targeted approach including synthesis of reference compounds, two diastereomeric substances, viz. 17α-hydroxymethyl-17β-methyl-18-nor-5β-androst-13-en-3α-ol and its 5α-analog, were identified following an administration of methyltestosterone. In post-administration urines of metandienone, only the 5β-metabolite was detected. Additionally, 3α,5β-tetrahydro-epi-methyltestosterone was identified in the urines of both administrations besides the classical metabolites included in the screening procedures. Besides their applicability for anti-doping analysis, the results provide new insights on the metabolism of 17α-methyl steroids with respect to the order of reductions in the A-ring, the participation of different enzymes, and alterations of the D-ring.

Plants, including Cannabis (Cannabis sativa subsp. sativa) host distinct beneficial microbial communities on and inside their tissues, designated the plant microbiota from the moment that they are planted into the soil as seed. They contribute to plant growth promotion, facilitating mineral nutrient uptake, inducing defense resistance against pathogens, higher yield and modulating plant secondary metabolites. Understanding the microbial partnerships with Cannabis has the potential to affect agricultural practices by improving plant fitness and the production yield of cannabinoids. Much less is known about this beneficial Cannabis-microbe partnership, and the complex relationship between the endogenous microbes associated with various tissues of the plant, particularly, the role that cannabis may play in supporting or enhancing them. This review will focus on Cannabis microbiota studies and the effect of endophytes on the elicitation of secondary metabolites production in Cannabis plants. The aim of this review is to shed light on the importance of Cannabis microbiome and how cannabinoid compounds concentration can be stimulated through symbiotic and or mutualistic relationships with endophytes.

Biodegradable and renewable plastic films have been regarded as promising alternative green materials to achieve the substitution polythene (PE)films to reduce plastic pollution. Poly (butylene adipate-co-terephthalate) (PBAT) is a kind of biodegradable polyester, which is widely used in the production of biodegradable mulching films. However, the high cost of PBAT limited it applications. Thus, lignin, one of the most abundant biomass resources was incorporated into PBAT matrix in the present work. A series of Lignin/PBAT biodegradable plastics films with different Lignin/PBAT weight ratios (0.00 %-5.00 %) were successfully fabricated using twin screw and twin roll extruders. The chemical compositions, morphologies, thermal stabilities, mechanical properties, and barrier properties of samples were characterized by XRD, FTIR, TG/DSC, mechanical testing machine, and WVTR, respectively. Results show that the corporation of lignin into PBAT matrix could lead to improved thermal stabilities, mechanical properties and barrier properties of films even after Xenon lamp aging process, especially when Lignin/PBAT weight ratio is 1.00 % in the present work. This work provides a very promising approach for fabrication of biodegradable plastics films with low cost, enhanced mechanical properties and barrier properties, the as-prepared samples may have potential applications in agricultural or food packaging materials.

The article concerns problems related to the assessment of reactive power in power networks with non-linear, fast-varying loads, such as electric arc furnaces, rolling mill drives, etc. The operation of this type of loads is characterized by the introduction of interharmonic currents (including higher harmonics) into the power supply network and a relatively low power factor. Rapid changes in the RMS value of the current also cause voltage fluctuations and the related phenomenon - flicker. Therefore, there is a need to evaluate the selection of power of compensating devices taking into account the random nature of load changes and the distortion of current and voltage waveforms, in particular interharmonic components, the impact of which has not been fully investigated so far. To analyze the random nature of load changes, autocorrelation functions were used, which allowed for the estimation of the expected values of the arc furnace current distortion coefficient (based on the recorded waveforms). In order to determine the parameters of reactive power compensating devices, and in particular capacitor banks, an autocorrelation function in the exponential-cosine-sine form was used, which meets the conditions of differentiation. The article contains comparative results of calculations of the reactive power of capacitor banks determined using different methods.

Anion doping of tungsten trioxide by nitrogen is used to obtain electrochrome cathode material, the spectral transmittance of which can be controlled by the doping level. A series of samples was synthesized by reactive magnetron sputtering of a metal tungsten target in a mixture of argon, nitrogen and oxygen gases. Warm-colored tungsten oxynitride films were prepared at higher doping levels and characterized using scanning electron microscopy, X-ray diffraction and X-ray photoelectron spectroscopy techniques. Optical properties were measured making use of transmission spectrophotometry and spectroscopic ellipsometry. These extensive experimental studies revealed an increase in absorption towards shorter wavelengths with increasing the doping level. At the same time, it was found that with increasing the doping level, the fraction of non-stoichiometric oxygen also steadily increases to half the total oxygen content. The imperfection of the doped material can stimulate its intercalation with electrolyte ions, accelerating the coloring/bleaching process and increasing the dynamical range between the dark and clear states, thus improving the consumer qualities of electrochemical materials and devices.

It remains unclear in the literature what is the cause of the so-called alkali-carbonate reaction (ACR) damage to concrete yet, a consensus is reached when considering dedolimitization as non-expansive. However, expansion and cracks as distress features are often attributed to alkali-silica reaction (ASR) when evidence of a reactive mineral is found in the aggregate. Evidently, different types of aggregates may produce different types and degrees of damage. Therefore, this work aims to assess the damage to concrete generated and propagated by the so-called ACR susceptible reactive Kingston coarse aggregate through mechanical testing (i.e., direct shear test), microscopy (the damage rating index – DRI), and other techniques. Distinct induced expansion levels (i.e., 0%, 0.05%, 0.12%, and 0.20%) were selected to compare the distress caused by ACR to concrete affected by ASR. Result show that the behaviour of ACR, namely as captured through the DRI, is inconsistent with that of ASR thus attesting to ACR being a distinct distress mechanism.

Viral infections induce exosomes containing viral material and inflammatory factors. During respiratory tract infection, exosomes can easily cross the blood-brain barrier and transmit the inflammatory signal to the brain; however, such a hypothesis has no experimental evidence. The study investigated whether exosomes from virus mimetic poly (I:C)-primed airway cells enter the brain and interact with brain immune cells microglia. Airway cells were isolated from Wistar rats and BALB/c mice; microglial cell cultures - from Wistar rats. Exosomes from poly (I:C)-stimulated airway cell culture medium were isolated by precipitation, visualised by transmission electron microscopy, and evaluated by nanoparticle analyser; exosomal markers CD81 and CD9 were determined by ELISA. For in vitro and in vivo tracking, exosomes were loaded with Alexa Fluor 555-labelled RNA. Intracellular reactive oxygen species (ROS) were evaluated by DCFDA fluo-rescence and mitochondrial superoxide - by MitoSOX. The exosomes from poly (I:C)-primed airway cells entered the brain within an hour after intranasal introduction, were internalised by microglia, and induced intracellular and intramitochondrial ROS production. There was no ROS increase in microglial cells was after treatment with exosomes from airway cells untreated with poly (I:C). The data indicate that virus-primed airway cell exosomes might enter the brain and induce the activation of microglial cells.