A derivative series of 3,4-dimethoxy-β-nitrostyrene were synthesized and identified including new compound 6. The effect of antimicrobial activity of 3,4-alkyloxy modification of β-nitrostyrene was investigated. A molecular docking was also performed to obtain information about their interactions with Protein Tyrosine Phosphatase 1B (PTP1B). PTP1B containing cysteine 215 and arginine 221 as essential active residues plays a key role in signaling pathways that regulate various cell functions of microorganisms, which also act as negative regulator in signaling pathways of insulin that are involved in type 2 diabetes and other metabolic diseases. Compound 5 and 6 were the most potent as fragment of PTP1B inhibitor based on molecular docking, but compound 5 was more effective against Candida albicans. These compounds interact with serine 216 and arginine 221 residues. However, further research is needed to investigate their potential medicinal use.

Treatment of the non-purified mixture of dinitro isomers obtained from the nitration of 1,4-dimethoxybenzene with piperidine, led to the isolation of novel but minor adduct, 1-(2,5-dimethoxy-4-nitrophenyl)piperidine (2b) in 15% yield. Yields of nucleophilic aromatic substitution adducts are high when using purified 1,4-dimethoxy-2,5-dinitrobenzene (1b) with piperidine and pyrrolidine to give 2b and 1-(2,5-dimethoxy-4-nitrophenyl)pyrrolidine (3b) in 76% and 82%, respectively.

β-Lactams are pharmacologically important compounds because of their various biological uses, including antibiotic and so on. β-Lactams were synthesized from benzylidene-inden derivatives and acetoxyacetyl chloride. The inhibitory effect of these compounds was also examined for human carbonic anhydrase I and II (hCA I, and II) and acetylcholinesterase (AChE). The results reveal that β-lactams are inhibitors of hCA I, II and AChE. The K_i values of β-lactams (2a-k) were 0.44-6.29 nM against hCA I, 0.93-8.34 nM against hCA II, and 0.25-1.13 nM against AChE. Our findings indicate that β-lactams (2a-k) inhibit both CA isoenzymes and AChE at low nanomolar concentrations.

The three-component reaction of enaminones, benzaldehyde and hydrazine-HCl or four-component reaction of enaminones, benzaldehyde, hydrazine–HCl and ethyl cyanoacetate in water in the presence of catalytic amount of ammonium acetate has been devised as a straightforward , sustainable approach for the synthesis of 1-H-pyrazole, N-aminopyridine and pyrazol[3,4-b]pyridine derivatives . The key benefits of this approach is simple experimental procedure associated with cost effective and environmentally friendly techniques.

The -blocker (S)-practolol ((S)-N-(4-(2-hydroxy (isopropylamino)propoxy)phenyl)acetamide) was synthesized with 96% enantiomeric excess (ee) from the chlorohydrin (R)-N-(4-(3-chloro-2 hydroxypropoxy)phenyl)acetamide, which was produced in 97% ee and with 27% yield. Racemic building block 1-((1H-indol-4-yl)oxy)-3-chloropropan-2-ol for the -blocker pindolol was produced in 53% yield and (R)-1-((1H-indol-4-yl)oxy)-3-chloropropan-2-ol was produced in 92% ee. The chlorohydrin 7-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one, a building block for a derivative of carteolol was produced in 77% yield. (R)-7-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one was obtained in 96% ee. The S-enantiomer of this carteolol derivative was produced in 97% ee in 87% yield. Racemic building block 5-(3-chloro-2-hydroxypropoxy)- 3,4-dihydroquinolin-2(1H)-one, building block for the drug carteolol was also produced in 53% yield, with 99% ee of the R-chlorohydrin (R)-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one. The yield of all four chlorohydrins increased by use of catalytic amounts of base. The reason for this was found to be less formation of the dimeric by-products compared to use of higher concentration of the base. An overall reduction of reagents and reaction time was also obtained compared to our previous reported data of similar compounds. The enantiomers of the chlorohydrin building blocks were obtained by kinetic resolution of the racemate in transesterification reactions catalyzed by Candida antarctica Lipase B (CALB) from SyncoZymes Co, Shanghai, China. Optical rotations confirmed the absolute configuration of the enantiopure drugs.

This paper aims to demonstrate that, beyond the small world of Riemann-Liouville and Caputo derivatives, there is a vast and rich world with many derivatives suitable for specific problems and various theoretical frameworks to develop, corresponding to the different paths taken. Notions of time and scale sequences are introduced and general associated basic derivatives, namely right/stretching and left/shrinking, are defined. A general framework for fractional derivative definitions is reviewed and applied to get both known and new fractional order derivatives. Several fractional derivatives are considered, mainly: Liouville, Hadamard, Euler, bilinear, tempered, q-derivative, and Hahn.

Isoamyl (E)-3-(3,4-dimethoxyphenyl)acrylate (1) was obtained 95% yield by 2-methyl-6-nitrobenzoic anhydride (MNBA)/4-dimethylaminopyridine (DMAP)-catalyzed reaction at room temperature for 190 minutes in dichloromethane. The structure of isoamyl (E)-3-(3,4-dimethoxyphenyl)acrylate (1) was established by NMR, FTIR, and the high resolution of mass spectroscopies. In vitro sun protection factor evaluation exhibited value of 37.10 ± 0.03 which indicates that isoamyl (E)-3-(3,4-dimethoxyphenyl)acrylate (1) as a sunscreen agent with high protection.

Metallo-β-lactamases (MBLs) are members of the structurally conserved but functionally diverse MBL-fold superfamily of metallohydrolases. MBLs are a major concern for global health care as they efficiently inactivate β-lactam antibiotics, including the “last-resort” carbapenems, and no clinically suitable inhibitors are currently available. Increasingly, promiscuous β-lactamase activity is also observed in other members of the superfamily, including from viruses, which represents an underexplored reservoir for future pathways to antibiotic resistance. Here, two such MBL-fold enzymes from Bacillus phages, the cyclic mononucleotide-degrading proteins ApycGoe3 and ApycGrass, are shown to efficiently degrade β-lactam substrates in vitro. In particular, ApycGrass displays a distinct preference for carbapenem substrates with a catalytic efficiency that is within one order of magnitude of that of the clinically relevant MBL NDM-1. Mutagenesis experiments also demonstrate that the loss of a metal-bridging aspartate residue reduces nuclease activity up to 35-fold, but improves carbapenemase activity. In addition, we propose that the oligomeric state significantly influences β-lactamase activity by modifying access to the active site pocket. Together, these observations hint at a possible new avenue of resistance via the spread of phage-borne MBL-fold enzymes with β-lactamase activity.

A useful perioperative nutritional therapy for highly invasive esophageal cancer surgical cases needs to be developed. We clarified the usefulness of amino acid-enriched nutritional therapy using glutamine (Gln)/arginine (Arg)/calcium β-hydroxy-β-methylbutyrate (HMB) products on the short-term postoperative outcomes of minimally invasive esophagectomy for esophageal cancer. Altogether, 114 patients (Gln/Arg/HMB group) received perioperative nutritional therapy with Gln/Arg/HMB products, and we retrospectively investigated the change in nutritional parameters including skeletal muscle mass, occurrence of postoperative complications, and short-term postoperative outcomes in this group. The results were compared between the Gln/Arg/HMB and control groups (79 patients not receiving the Gln/Arg/HMB products). The incidence of all postoperative complications, sputum expectoration disorder, and pleural effusion of grade ≥III was significantly lower in the Gln/Arg/HMB group (62.0% vs. 38.6%, p = 0.001; 44.3% vs. 28.1%, p = 0.020; 27.8% vs. 13.2%, p = 0.011, respectively). The psoas muscle area and postoperative body weight was significantly higher at 1 month and 1 year after surgery in the Gln/Arg/HMB group than in the control group (93.5% vs. 99.9%, p < 0.001; 92.0% vs. 95.4%, p = 0.006). Perioperative amino acid-enriched nutritional therapy may improve the short-term postoperative outcomes, nutritional status, and skeletal muscle mass of esophageal cancer surgical patients.

(S)-Atenolol ((S)-2-(4-(2-Hydroxy-3-(isopropylamino)propoxy)phenyl)acetamide) has been synthesized in >99% ee with use of Candida antarctica lipase B from Syncozymes (Shanghai, China), in a kinetic resolution of the corresponding racemic chlorohydrin. Deprotonation of the starting phenol building block was base catalyzed. The enantiopurity of the chlorohydrin building block remained unchanged upon subsequent amination. All four steps in the synthesis protocol have been optimized compared to previously reported methods, which makes this new protocol more sustainable and in accordance with green chemistry principles compared to previously reported protocols.

The aim of this work is research dedicated to the search for new bactericidal systems for use in cosmetic formulations, dermocosmetics, or the production of wound dressings. Over the last two decades chitosan due to its special biological activity, has become a highly indispensable biopolymer with very wide application possibilities. Literature reports on the antibacterial effects of chitosan are very diverse, but our research has shown that they can be successfully improved through chemical modification. Therefore, in this study, results on the synthesis of new Schiff bases chitosan – dCsSB-SFD and dCsSB-PCA obtained using two aldehydes: sodium 4-formylbenzene-1,3-disulfonate (SFD) and 2-pyridine carboxaldehyde (PCA) respectively. Chitosan derivatives synthesized in this way demonstrate stronger antimicrobial activity. Carrying out the procedure of grafting chitosan with a caproyl chain allowed obtaining compatible blends of chitosan derivatives with κ-carrageenan, which are stable hydrogels with a high swelling coefficient. Furthermore, covalently bounded PCL improved the solubility of obtained polymers in organic solvents. With this respect, the Schiff base-containing polymers obtained in this study, with special hydrogel and antimicrobial properties are very promising materials for the potential use as a controlled-release formulation of both, hydrophilic and hydrophobic drugs in cosmetic products for skin health.

In this study, a novel oral formulation of berberine hydrochloride (BBH) hydrogel was successfully synthesized through physical cross-linking using chitosan (CS) and carboxymethyl-β-cyclodextrin (CMCD). The characterization results confirmed the successful synthesis of CS/CMCD hydrogel and the subsequent loading of BBH into this composite (CS/CMCD/BBH) was effectively accomplished. BBH was used as a model drug and the resulting hydrogel demonstrated a sustained drug release profile. In addition to its improved solubility and sustained release characteristics, the hydrogel exhibited excellent antibacterial activity against common pathogens such as Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Candida albicans (C. albicans). Additionally, in vitro studies indicated that the hydrogel was not cytotoxic to NIH3T3 and HaCaT cells, suggesting its safety for biomedical applications. This lack of cytotoxic effects, combined with the mechanical strength, solubility improvements, and antibacterial properties of the hydrogel, positions the CS/CMCD/BBH hydrogel as a promising candidate for effective oral delivery of BBH. By addressing the solubility and delivery challenges of BBH, this hydrogel offers a viable solution for the oral administration of berberine hydrochloride, with potential applications in various biomedical fields.

Fractional calculus gained a lot of attention in the last couple of years. Researchers discovered that processes in various fields follow rather fractional dynamics than ordinary integer-ordered dynamics, meaning the corresponding differential equations feature non-integer valued derivatives. There are several arguments for why this is the case, one of them being that fractional derivatives’ inherit spatiotemporal memory and/or the ability to express complex naturally occurring phenomena. Another popular topic nowadays is machine learning, i.e., learning behavior and patterns from historical data. In our ever-changing world with ever-increasing amounts of data, machine learning is a powerful tool for data analysis, problem-solving, modeling, and prediction. It further provides many insights and discoveries in various scientific disciplines. As these two modern-day topics provide a lot of potential for combined approaches to describe complex dynamics, this article reviews combined approaches of fractional derivatives and machine learning from the past, puts them into context, and thus provides a list of possible combined approaches and the corresponding techniques. Note, however, that this article does not deal with neural networks, as there already is profound literature on neural networks and fractional calculus. We sorted past combined approaches from the literature into three categories, i.e., preprocessing, machine learning & fractional dynamics, and optimization. The contributions of fractional derivatives to machine learning are manifold as they provide powerful preprocessing and feature augmentation techniques, can improve physically informed machine learning, and are capable of improving hyperparameter optimization. Thus, this article serves to motivate researchers dealing with data-based problems, to be specific machine learning practitioners, to adopt new tools and enhance their existing approaches.

The general synthesis of boron-containing cyclic compounds (boracycles) necessitates toxic organotin precursors or highly reactive boron halides. Here we report the synthesis of seven- and five-membered boracycles utilizing arylboronic acid pinacol esters (ArBpins) as stable boron sources. Grignard reagents generated from 2,2′-dibromodibenzyl or 2,2′-dibromobiphenyl reacted with ArBpins, where Ar = 9-anthryl (Anth), 2,4,6-trimethylphenyl (Mes), 2,4,6-triisopropylphenyl (Tip), to give 10,11-dihydro-5H-dibenzo[b,f]borepins or dibenzoborole derivatives. This Bpin-based method was successfully applied to a one-shot double boracycle formation, providing a dihydrodibenzoborepin–anthracene–dihydrodibenzoborepin triad molecule in a good yield. The dihydrodibenzoborepin bearing the Anth group was directly converted to the unsaturated borepin by NBS/AIBN. All products were characterized by NMR, HRMS, and in some cases, single-crystal X-ray diffraction analysis. Additionally, the photophysical properties of the products are also reported.

DFT calculations on the photoisomerization reactions of pyridazine N-oxide derivatives are presented. The irradiation of 3,6-diphenylpyridazine N-oxide allowed to obtain the first excited singlet state that underwent to a ring opening reaction induced to the oxygen migration to the adjacent carbon atom, with the formation of a diazo derivative. This intermediate can give a ring closure reaction to give a pyrazole derivative, or, with a higher transition energy, it can lose nitrogen allowing the formation of 2,5-diphenylfuran. The irradiation of 3-phenylpyridazine N-oxide allowed the formation only of 2-phenylfuran. In this case, calculations allowed to explain this behavior. The first excited singlet state gave a photoisomerization reaction with the formation of the corresponding diazo intermediate. This intermediate could not be converted into the corresponding pyrazole derivative because it was converted into a N-formyl pyrazole never reported in literature. The only possible reaction is the loss of nitrogen and the formation of 2-phenylfuran.

Reactions of quinones with compounds containing an amino group can produce a wide variety of addition or substitution products that depend on reactivity of both quinone and amino derivative. 6,7-Dichloropyrido[1,2-a]benzimidazole-8,9-diones undergo selective nucleophilic substitution reaction with different benzohydrazides and α-hydroxy-p-quinone imine derivatives stabilized by strong intramolecular hydrogen bond were isolated. Synthesized compounds represent a combination of several structural motifs: benzimidazole core fused with α-hydroxy-p-quinone imine which contains a benzamido fragment. The protonation/deprotonation processes were investigated in a solution using UV-Vis spectroscopy and 1H NMR titration experiment. X-ray crystallography analysis revealed a set of weak non-covalent interactions such as intra- and intermolecular hydrogen bonds and π-π stacking. Additionally, the redox behavior of 6,7-dichloropyrido[1,2-a]benzimidazole-8,9-dione and its p-imino derivative was investigated in acidic and neutral environment using cyclic voltammetry measurements. Cathode material based on 6,7-dichloropyrido[1,2-a]benzimidazole-8,9-dione could act as potential effective active electrode in aqueous electrolyte batteries, however further optimization is required.

Recent interest in intestinal hormones has risen with the idea that they modulate glucose tolerance and food intake through a variety of mechanisms, and such hormones like peptide YY (PYY), ghrelin, glucagon-like peptide (GLP)-1 and 2, and cholecystokinin (CKK) are therefore excellent therapeutic candidates for the treatment of diabetes and obesity. Furthermore, in the recent years, multiple studies suggest that the microbiota is critically important for normal host functions, while impaired host microbiota interactions contribute to the pathogenesis of numerous common metabolic disorders. In this study, we considered the nutraceutical effects of β-glucans added to pasta at the concentration of 6g\100g. Ten participants have been recruited and hematochemical analyses and intestinal hormones tests have been performed before and after 30 days of pasta intake. Stool specimens have been studied for Lactobacillus Fermentum, Lactobacillus acidophilus, Lactobacillus salivarius, Bifidobacterium longum, and Enterococcus faecium presence before and after 30 days of nutritional intervention. After 30 days of regular intake of pasta enriched by β-glucans results have been evaluated. In conclusion, pasta prepared from barley flour enriched with β-glucans at 6% exhibit promising responses on glucose metabolism, on intestinal hormones responses and on microbiota modification.

3-(3,4-Dichlorophenyl)-5-(1H-indol-5-yl)-1,2,4-oxadiazole was synthesized via the condensation of 3,4-dichlorobenzamidoxime and methyl 1H-indole-5-carboxylate using superbasic medium (NaOH/DMSO). The compound was tested as a potential inhibitor of human monoamine oxidase (MAO) A and B. It demonstrated notable inhibition with an IC50 value of 0.036 μM for MAO-B and isoform specificity. The product was characterized by 1H NMR, 13C NMR, and HRMS. In conclusion, the new active MAO-B inhibitor may serve as a candidate for the future discovery of therapeutic agents for neurodegenerative disorders such as Parkinson’s disease.

Oleuropein, glycosylated secoiridoid present in the olive leaves, is known as an important antioxidant phenolic compound. We studied the antioxidant effect of low dose of oleuropein aglycone (3,4-DHPEA-EA) and oleuropein aglycone peracetylated (3,4-DHPEA-EA(P)) in murine C2C12 myocytes treated with hydrogen peroxide (H2O2). Both compounds were used at a concentration of 10 μM and were able to inhibit cell death induced by H2O2 treatment, with 3,4-DHPEA-EA(P) being more. Under our experimental conditions H2O2 efficiently induced the phosphorylated-active form of JNK and of its downstream target c-Jun. We demonstrated, by Western blot analysis, that 3,4-DHPEA-EA(P) was efficient in inhibiting the phospho-active form of JNK. This data suggest that growth arrest and cell dead of C2C12 proceeds via the JNK/c-Jun pathway. Moreover, we demonstrated that 3,4-DHPEA-EA(P) affects myogenesis of C2C12 cells; because the MyoD mRNA levels and the differentiation process are restored after treatment with 3,4-DHPEA-EA(P). Overall, the results indicate that 3,4-DHPEA-EA(P) prevents ROS-mediated degenerative process by functioning as an efficient antioxidant.

Background: Colorectal adenoma undergoes neoplastic progression via the normal epithelium-adenoma-adenocarcinoma sequence as reported in the Vogelgram. The risk of developing cancer is strongly associated with the number and size of adenoma and with the subtype. Currently, adenomatous polyps can be distinguished on the basis of histology: the prevalence are tubular, 5-15% are villous and tubular/villous. Considering the increased risk for malignant transformation described for tubular/villous adenomas, patients diagnosed with adenomatous polyposis are at increased risk of developing CRC. The Wnt/β-catenin pathway plays a key role in the onset of colorectal adenoma, in particular intestinal cells first acquire loss-of-function mutations in APC gene that induce the formation of adenomas. Methods: Wnt/β-catenin pathway APC, Wnt3a, Wnt5a, LEF1, BCL9 genes and protein expression analyses were conducted by qRT-PCR and western blot in 68 colonic samples (polyps and adjacent mucosa) from 41 patients, of which 17 affected by FAP. Ten normal colonic mucosal samples were collected from 10 healthy donors. Results: In this study both APC gene and protein resulted less expressed in colon tumor compared to the adjacent colonic mucosa. Conversely, activated β-catenin was more expressed in polyps than in the adjacent mucosa. All results confirmed literature data on carcinomas. A statistically significant correlation between Wnt3a and BCL9 both in polyps and in the adjacent mucosa underlies that the canonical Wnt pathway is activated in early colon carcinogenesis and that the adjacent mucosa is already altered. Conclusion: This is the first study analyzing the difference in expression of Wnt/β-catenin pathway in human colorectal adenomas. Understanding the progression from adenomas to colorectal carcinomas is essential for the development of new therapeutic strategies and improving clinical outcomes.

We introduce a series of twisted donor-acceptor (D-A) carbazole-benzophenone based electroactive bipolar derivatives that were synthesized through the reaction of 4-fluorobenzophenone with various partially alkylated 3,3’-bicarbazoles. The comprehensive structural characterization of these compounds is provided. These amorphous materials exhibit suitable glass transition temperatures ranging from 57 to 102 °C and demonstrate high thermal stability, with decomposition temperatures reaching 400 °C. Moreover, the developed materials exhibit elevated photoluminescence quantum yields (PLQY) of up to 75.5% and favorable HOMO-LUMO levels, along with suitable triplet-singlet state energy values. Due to their good solubility and suitable film-forming properties, all the compounds were evaluated as blue emitters dispersed in 4,4’-bis(N-carbazolyl)-1,10-biphenyl (CBP) host for the fabrication of organic light-emitting diodes (OLEDs) in concentration dependent experiments. Among these experiments, the device containing 15 wt% of the guest 4-(9’-{2-ethylhexyl}-[3,3’]-bicarbazol-9-yl)benzophenone demonstrated the best characteristics, achieving maximum brightness of 3581 cd/m2, current efficiency of 5.7 cd/A, power efficiency of 4.1 lm/W and external quantum efficiency of 2.7%.

The present study was performed to examine that transforming growth factor beta (TGF-β) in root-surrounding tissues on deciduous teeth during the physiological root resorption regulates the differentiation induction into odontoclast. We prepared root-surrounding tissues with (R) or without (N) physiological root resorption scraped off at three regions (R1-R3 or N1-N3) from the cervical area to the apical area of the tooth and measured both TGF-β and the tartrate-resistant acid phosphatase (TRAP) activities. The TGF-β activity level was increased in N1-N3, whereas the TRAP activity was increased in R2 and R3. In vitro experiments for RANKL-mediated osteoclast differentiation revealed that TGF-β in N1-N3 and R1-R3 enhanced the TRAP activity in RAW264 cells. A genetic study indicated that the mRNA level of TGF-β1 in N1 and N2 was significantly increased, and corresponded with that of osteoprotegerin (OPG). In contrast, the expression level of receptor activator of NF-κB ligand (RANKL) was increased in R2 and R3. Our findings suggest that TGF-β is closely related to the regulation of OPG induction and RANKL-mediated odontoclast differentiation depending on the timing of RANKL and OPG mRNA expression in the root-surrounding tissues of deciduous teeth during physiological root resorption.

Based on DFT (density functional theory) using B3LYP/6-31G method, theoretical investigations applied to demonstrate the structural, electronic properties and stability of (N,Nˊ-(1,4-phenylene)bis(1,8-naphthalimide)) is more stable than the compound (N-(4-amino phenyl)1,8-naphthalimide) by (-1.2762 eV or -29.4299 Kcal.mol-1) depending on the values of HOMO, synthesis reaction of imide is spontaneous and endothermic at temperature 275˚C according to the values of ∆rS, ∆rG and ∆rH.

Visible-light photocatalysis, particularly in its application to organic synthesis, has experienced a big renaissance in the past decade. The rational design of new photocatalysts with designed and improved photocatalytic properties, that at the same time circumvents the necessity of using scarce and toxic transition metals, will predictably play a key role in photocatalysis in the next few years. Although free-base porphyrins were identified some years ago as a promising, easily accessible and easily tunable class of organic photoredox catalysts, a systematic study on the effect of the electronic nature and of the position of the substituents on both the ground-state and the excited-state redox potentials of these compounds is still lacking. We have prepared a set of known functionalized derivatives of meso-tetraphenyl porphyrin containing different substituents either in one of the meso-positions or at a beta-pyrrole carbon and we have determined their ground- and (singlet) excited-state redox potentials. This survey has led us to conclude that the introduction of a carbonyl group at the beta-pyrrolic position strongly increases the facility of the monoelectronic reduction of the porphyrin both in the ground state and in the singlet excited state. We have also prepared a second set of four previously unknown benzoyl derivatives of meso-tetraphenylporphyrin, and we have confirmed the validity of our conclusions.

In this paper, the synthesis of two novel luminescent Eu3+ ion complexes [Eu(TFT)3(phen) (1) and Eu(TFT)3(bpy)•Hex (2)] based on the combination of 2-(2,2,2-trifluoroethyl)-1-tetralone (TFT), containing n-donor ligands (1,10-phenanthroline or 2,2'-Bipyridine) and Eu3+ ion is reported herein, and their structural features are discussed on the basis of X-ray crystallographic and thermal analyses. We observed that the ligands transfer energy effectively to the metal center by fluorescence, IR and UV spectrograms studies. The structures and properties of complexes 1-2 were optimized by the DFT theoretical calculation, and the calculation results were consistent with the experimental X-ray structure data and spectral analysis.

3,4-Dihydro-2(1H)-pyridones (3,4-DHPo) and their derivatives are privileged structures present in natural products, which has been increased its relevance due to its biological activity in front of a broad range of targets, but especially for its importance as synthetic precursors of a variety of compounds with marked biological activity. Taking into account the large number of contributions published over the years regarding this kind of heterocycle, here we presented a current view of 3,4-dihydro-2(1H)-pyridones (3,4-DHPo), which include general aspects such as those related to nomenclature, synthesis, and biological activity; but also highlighting the importance of DHPo as building blocks of other relevance structures.

Chagas disease (CD) is a neglected tropical parasitic disease caused by the protozoan Trypanosoma cruzi. Unfortunately, the current etiological treatment for CD is unsatisfactory, due to the high toxicity and low cure efficacy of compounds, mainly during the chronic phase of this disease. Thus, the discovery of new drugs for the treatment of CD is urgent. In the present study, we report the synthesis of a series of guanidines and its evaluation in in vitro assays to determine the trypanocidal effects on the Tulahuen T. cruzi strain, transfected with a β-galactosidase reporter gene, in comparison to the cytotoxic effects on vertebrate cells. The most potent and selective compounds LQOF-G1 and LQOF-G29 were considered good drug prototypes and candidates for in vivo tests using mice. Both compounds possess an electron withdrawing group on the aniline moiety, namely a NO2 and Br group, respectively, which effectively decrease the electron density. LQOF-G29 stands out among the investigated compounds due to the replacement of the benzyl group by methyladamantane.

Thalassemia syndromes are common monogenic disorders that represent a significant global health issue. No systematic epidemiological and molecular investigations on thalassemias in Croatian population have been reported to date. This prospective study included 70 children with a presumptive diagnosis of thalassemia, and their 42 first-degree relatives. Molecular characterization was performed using direct sequencing and gap-PCR methods. We identified 46 (30 children and 16 first-degree relatives) β-thalassemia heterozygous carriers from 24 unrelated families, carrying eight different mutations and one hemoglobin variant. Five variants account for approximately 85% of all affected β-globin alleles: Hb Lepore-Boston-Washington (32,6%), HBB: c.93-21G>A (19,6%), HBB:c.315+1G>A (13,1%), HBB:c.92+1G>A (10,9%), and HBB:c.92+6T>C variant (8,7%). A need for more detailed genetic profiling of β-thalassemia carriers is emphasized since genetic modifiers can significantly impact their phenotype. Our study provides important new insights into the relevance of β-thalassemia heterozygosity in the pediatric clinical practice.

3,4-methylenedioxypyrovalerone (MDPV) is a new psychoactive substance (NPS) and the most widespread and life-threatening synthetic cathinone of the “bath salts”. Preclinical research has proven the cocaine-like psychostimulant effects of MDPV and its potential for abuse. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid that has emerged as a new potential treatment for drug addiction. Here, we tested the effects of CBD (20 mg/kg) on MDPV (2 mg/kg)-induced conditioned place preference and MDPV (0.05 and 0.075 mg/kg/infusion) self-administration paradigm. We also assessed the effects of the combination of CBD, and MDPV (3 and 4 mg/kg) on anxiety-like behaviour using the elevated plus maze (EPM). CBD mitigated the MDPV-induced conditioned place preference. On the contrary, CBD administration throughout the MDPV (0.075 mg/kg/infusion) self-administration increased drug-seeking and taking behaviours, but only in the high-responders group of mice. Additionally, CBD exerted anxiolytic-like effects, but only in MDPV-treated mice. Taken together, our results indicate that CBD modulation of MDPV-induced motivational responses in mice vary depending on the requirements of the learning task, resulting in a complex response. More research attempting to decipher the behavioural and molecular interactions between CBD and MDPV is needed.

This study investigated the neuroprotective effects of methyl 3,4-dihydroxybenzoate (MDHB) against t-butylhydroperoxide(TBHP) induced oxidative damage in SH-SY5Y (human neuroblastoma cells) and the underlying mechanisms. SH-SY5Y were cultured in DMEM+10% FBS for 24 hours and pretreated with different concentrations of MDHB or N-acetyl-L-cysteine (NAC) for 4 hours prior to the addition of 40 μM TBHP for 24 hours. Cell viability was analyzed using the methyl thiazolyl tetrazolium (MTT) and lactate dehydrogenase (LDH) assays. An annexin V-FITC assay was used to detect cell apoptosis rate. The 2',7'-dichlorofluorescin diacetate (DCFH-DA) assay was used to determine intracellular ROS levels. The activities of antioxidative enzymes (GSH-Px and SOD) were measured using commercially available kits. The oxidative DNA damage marker 8-OHdG was detected using ELISA. Western blotting was used to determine the expression of Bcl-2, Bax, caspase 3, p-Akt and Akt proteins in treated SH-SY5Y cells. Our results showed that MDHB is an effective neuroprotective compound that can mitigate oxidative stress and inhibit apoptosis in SH-SY5Y cells

Antimicrobial resistance is on the rise, and there aren't enough new treatments to combat it. This might send the modern world back to the pre-antibiotic age. The molecular hybrids of pyrazolo[3,4-b]pyridine and triazole have been designed, synthesized, and analyzed for their drug-like molecule nature and in vitro analyses for their inhibition potentials against S. Aureus and K. Pneumoniae. The compounds CY-R2-25 and CY-R2-28 have been identified as the high potential molecules in this series based on in vitro experiments. CY-R2-25 has zone of inhibition values of 15 0.82 and 14 0.7, whilst CY-R2-28 has the zone of inhibition values of 18 0.95 and 16 0.82 against S. Aureus and K. Pneumoniae, respectively. MIC and MIB values for CY-R2-25 and CY-R2-28 against S. Aureus and K. Pneumoniae are 0.25 and 0.5, respectively.

The over use of pharmaceutical compounds, essentially antibiotics, led to an increase of their concentrations in aquatic ecosystems. In this study, the white-rot fungus Coriolopsis gallica (high-laccase-producing fungus) was investigated for the biodegradation of ampicillin (AMP) under different cultivation conditions. The biotransformation of the antibiotic was confirmed by means of high-performance liquid chromatography (HPLC), and the antibacterial activity was evaluated via the bacterial growth inhibition agar well diffusion method using Escherichia coli as an ampicillin-sensitive test strain. The results showed that AMP (50 mg L-1) was totally removed by C. gallica after 6 days of incubation in a liquid medium. The antibiotic removal rate was maximal with a fungal culture aged 9 days. Such a culture achieved the removal of a higher concentration of up to 500 mg L-1 of ampicillin in 3 days. This higher antibiotic removal rate was concomitant with the maximal laccase production in culture supernatant. In addition, four consecutive doses of 500 mg L-1 of ampicillin were transformed by the same fungal culture in 24 days. After that, the fungus was unable to remove the antibiotic. The measurement of ligninolytic enzyme activity showed that laccase of C. gallica might participate in the biotransformation of AMP.

The aim of the study was the comparison of conventional sintering versus additive manufacturing techniques for β-TCP bioceramics, focusing on mechanical properties and biocompatibility. A "critical" bone defect requires surgical intervention beyond simple stabilization. Autologous bone grafting is the gold standard treatment for such defects but it has its limitations. Alloplastic bone grafting using synthetic materials is becoming increasingly popular. The use of bone graft substitutes has increased significantly and current research was focused on optimizing these substitutes, whereas this study compares two existing manufacturing techniques and the thereby produced β-TCP implants. The 3D-printed β-TCP hybrid structure implant was fabricated using two components, a column structure and a freeze-foam, which were sintered together. The conventionally manufactured ceramics were made by pouring. Both scaffolds were characterized according to porosity, mechanical properties and biocompatibility. The hybrid structure had a total porosity of 74.4 ± 0.5%. Microporous β-TCP implants had a porosity of 43.5 ± 2.4%, while macroporous β-TCP implants had a porosity of 61.81%. Mechanical testing revealed that the hybrid structure had a compressive strength of 10.4 ± 6 MPa, significantly lower than the microporous β-TCP implant’s with 32.9 ± 8.7 MPa. Biocompatibility evaluations showed a steady increase in cell proliferation over time for all β-TCP implants, with minimal cytotoxicity. This study provides valuable insight into the potential of additive manufacturing for β-TCP bioceramics in the treatment of bone defects.

Liver fibrosis, a consequence of chronic liver damage or inflammation, is characterized by the excessive buildup of extracellular matrix components. This progressive condition significantly raises the risk of severe liver diseases like cirrhosis and hepatocellular carcinoma. The lack of approved therapeutics underscores the urgent need for novel anti-fibrotic drugs. Hepatic stellate cells (HSCs), key players in fibrogenesis, are promising targets for drug discovery. This study investigated the anti-fibrotic potential of Citrus hystrix DC. (KL) and its bioactive compound, β-citronellol (β-CIT), in a human HSC cell line (LX-2). Cells exposed to TGF-β1 to induce fibrogenesis were co-treated with crude KL extract and β-CIT. Gene expression was analyzed by Real-Time qRT-PCR to assess fibrosis-associated genes (ACTA2, COL1A1, TIMP1, SMAD2). The releasing of matrix metalloproteinase 9 (MMP-9) was measured by ELISA. Proteomic analysis and molecular docking identified potential signaling proteins and modeled protein-ligand interactions. Results showed that both crude KL extract and β-CIT suppressed HSC activation genes and MMP-9 levels. The MAPK signaling pathway emerged as a potential target of β-CIT. This study demonstrates the ability of KL extract and β-CIT to inhibit HSC activation during TGF-β1-induced fibrogenesis, suggesting a promising role of β-CIT in anti-hepatic fibrosis therapies.

In the present study, we aimed to observed hair follicle development and describe Wnt10b/β-catenin signaling pathways related to hair follicle development in different ages of Rex rabbits. Six Rex rabbits (3 male and 3 female) of 15, 30, 60, 90, 120 and 150 days of age were selected and skin samples were collected for hair follicle development and Wnt/β-catenin signaling pathway genes expresion detection. The results showed that the the values for body weight, coat length, skin thickness, skin area, and skin weight of Rex rabbits were increased significantly with age (p < 0.05). The total hair follicle density, secondary hair follicle density and the ratio of the secondary hair follicle density to the primary hair follicle density in 120 days of Rex rabbits was higher than that in the other ages (p < 0.05), and the major hair follicles were in the growing period at 15 days and 30 days of age, some of them had already entered the degeneration period at 60 days of age, and most of them entered the degeneration period at 90 days of age, the presence of quiescent hair follicles and the enlargement of primary hair follicles were also observed. At 120 and 150 days of age, the back hair follicles entered the growing period, and the secondary hair follicles had obvious differentiation. Furthermore, the expression of the Wnt10b, CTNNB1, adenomatosis polyposis protein (APC), Disheveled 2 (DVL2), glycogen synthase kinase 3β（GSK-3β）, Lymphoid enhancer-binding factor 1 (LEF1), dickkopf-1 (DKK1) and transforming growth factor beta 1 (TGFβ-1) genes in the skin tissue of Rex rabbits at different age was significantly differences (p < 0.05), and the expression of the Wnt10b, CTNNB1, DVL2, GSK-3β, and TGFβ-1 genes at 90 days was higher than that in the other days, the expression of the LEF1 and DKK1 genes at 60 days was higher than that in the other days. As western blotting indicated, the β-catenin protein phosphorylation (P-CTNNB1) levels in the skin tissue of Rex rabbits shows the trend of first increasing, then decreasing and then increasing, 60 days, 120 days and 150 days significantly higher than 15 days, 30 days or 90 days (p < 0.05). With the increasing of ages, the GSK-3β protein phosphorylation (P-GSK-3β) levels in the skin tissue of Rex rabbits were increasing, and maximum at 120 days of age (p < 0.05). These results show that ages could influence on the fur quality and hair follicle traits of Rex rabbits, and Wnt10b/β-catenin signaling pathways is involved in the biological process of periodic hair follicle development in Rex rabbits. Considering the rule of fur growth, the slaughter age of Rex rabbits should not be earlier than 120 days.

Pathogenicity of many bacteria including Bacillus cereus and Staphylococcus aureus depends on pore-forming toxins (PFTs), which cause lysis of host cells by forming pores in membranes of eukaryotic cells. Bioinformatic analysis revealed in over 600 PFTs a region homologous to the Lys171-Gly250 sequence in hemolysin II (HlyII) from B. cereus, which we designated as “homologous peptide”. Three β-barrel PFTs were used for a detailed comparative analysis. Two of them –HlyII and cytotoxin K2 (CytK2), – are synthesized in Bacillus cereus sensu lato; the third – S. aureus α-toxin (Hla) – is the most investigated representative of the family. Protein modeling showed certain amino acids of homologous peptide to be located on the surface of the monomeric forms of these β-barrel PFTs. We obtained monoclonal antibodies against both a cloned homologous peptide and a 14-membered synthetic peptide DSFNTFYGNQLFMK as part of homologous peptide. The HlyII, CytK2 and Hla regions recognized by the obtained antibodies, as well as an antibody capable of suppressing the hemolytic activity of CytK2, were identified in the course of the work. Antibodies capable of recognizing PFTs of various origins can be useful tools for both identification and suppression of the cytolytic activity of PFTs.

Breast cancer (BC) ranks among the most prevalent cancers diagnosed in women. Its treatment necessitates precision tailored to the cancer's genetic makeup for enhanced efficacy. Research has been directed towards natural compounds for their anti-BC properties, aiming to augment existing treatment modalities. Chromolaena tacotana (Klatt) R.M. King and H. Rob, commonly referred to as Ch. tacotana, is a notable source of bioactive hydroxy-methylated flavonoids. However, the specific anti-BC mechanisms of these flavonoids, particularly those present in the plant's inflorescences, remain partly undefined. This study focuses on assessing a chalcone derivative extracted from Ch. tacotana inflorescences for its potential to concurrently activate regulated autophagy and intrinsic apoptosis in Luminal A and triple-negative BC cells. We determined the chemical composition of the chalcone using ultraviolet (UV) and nuclear magnetic resonance (NMR) spectroscopy. Its selective cytotoxicity against BC cell lines was assessed using the MTT assay. Flow cytometry and western blot analysis were employed to examine the modulation of proteins governing autophagy and the intrinsic apoptosis pathway. Additionally, in silico simulations were conducted to predict interactions between the chalcone and various anti-apoptotic proteins, including the mTOR protein. The chalcone was identified as 2',4-dihydroxy-4',6'-dimethoxy-chalcone (DDC), also known as Flavokavain C (FKC). This compound demonstrated selective inhibition of BC cell proliferation and triggered autophagy and intrinsic apoptosis. It induced cell cycle arrest in the G0/G1 phase and altered mitochondrial outer membrane potential (∆ψm). The study observed the activation of autophagic LC3-II and mitochondrial pro-apoptotic proteins in both BC cell lines. The regulation of Bcl-XL and Bcl-2 proteins varied according to BC subtype, yet they showed promising molecular interactions with DDC. Among the examined pro-survival proteins, mTOR and Mcl-1 exhibited the most favorable binding energies and were downregulated in MCF-7 and MDA-MB-231 cell lines. Further research is needed to fully understand the molecular dynamics involved in the activation and interaction of autophagy and apoptosis pathways in cancer cells in response to potential anticancer agents like the hydroxy-methylated flavonoids from Ch. tacotana.

Glycerol conversion to valuable biomolecules has been a research avenue that has attracted a significant interest in recent years due to its increasing over production, with possibilities for chemical transformation for eco-friendly processes and distinct compounds with biological activities. Also, in the current climate change in which a major emphasis is being placed on the design of green processes, solvents are key factors from both an economic and environmental point of view. In this context, due to its abundance and low-price, glycerol represents an innovative solvent coming from biomass and produce in high amount. On the other hand, Epichlorydrin, Glycidol and Solketal have become useful intermediates in chemical transformations when using glycerol as a raw material. This review focuses on glycerol as a green solvent in the synthesis of complex molecules, Epichlorydrin, Glycidol, Solketal and Tosyl solketal as an efficient recycling process for glycerol, as well as building blocks in the synthesis of glycerol derivatives, which are undeniable new source of potentials drugs.

This study unveils verapamil's compelling cytoprotective and proliferative effects on pancreatic β-cells amidst diabetic stressors, spotlighting its unforeseen role in augmenting cholecystokinin (CCK) expression. Through rigorous investigations employing MIN6 β-cells and zebrafish models under type 1 and type 2 diabetic conditions, we demonstrate verapamil's capacity to significantly boost β-cell proliferation, enhance glucose-stimulated insulin secretion, and fortify cellular resil-ience. A pivotal revelation of our research is verapamil's induction of CCK, a peptide hormone known for its role in nutrient digestion and insulin secretion, which signifies a novel pathway through which verapamil exerts its therapeutic effects. Furthermore, our mechanistic insights reveal that verapamil orchestrates a broad spectrum of gene and protein expressions pivotal for β-cell survival and adaptation to immune-metabolic challenges. In vivo validation in a zebrafish larvae model confirms verapamil's efficacy in fostering β-cell recovery post-metronidazole inflic-tion. Collectively, our findings advocate for verapamil's reevaluation as a multifaceted agent in diabetes therapy, highlighting its novel function in CCK upregulation alongside enhancing β-cell proliferation, glucose sensing, and oxidative respiration. This research enriches the therapeutic landscape, proposing verapamil not only as a cytoprotector but also as a promoter of β-cell re-generation, thereby offering fresh avenues for diabetes management strategies aimed at pre-serving and augmenting β-cell functionality.

5-(4-aminophenyl )-2-amino -1,3,4-thiadiazole was prepared by reaction of Thiosemicarbazide with 4-amino benzoic acid under reflux condition for 7 hours. The compound which has been synthesized successfully was subjected to addition reaction with 4-(Dimethylamino) benzaldehyde under reflux condition for 6 hours to synthesize Schiff bases. These compounds was characterized by using FTIR) and evaluated for their anticancer activity. The effect of (1, 3, 4-thiadiazole derivative) on the activity of malignant cells was studied by using different types of cell lines [Breast cancer, and human prostate cancer]. And was used the Electron microscope to show that the effect of the derivative on the cancer cells before and after 3 days of the injection time. It was found that the Schiff base of thiadiazole-1,3,4-(Dimethylamino)benzylidineamino]- [4-2-phenyl]amino was effective in reducing the size and density of malignant cells. That of 46.7 while in breast ) 145(DUprostate for growth inhibition produce of equal 85.9 µg/ml.

The bilateral tempered fractional derivatives are introduced generalising previous works on the one-sided tempered fractional derivatives and the two-sided fractional derivatives. An analysis of the tempered Riesz potential is done and showed that it cannot be considered as a derivative.

Carbapenem-resistant Acinetobacter baumannii (CRAB) infections represent the fourth-leading cause of death attributable to antimicrobial resistance globally, but a standardized therapy is still lacking. In this narrative review we focused the antibiotic treatment of CRAB infections in view of newly β-lactam agents (NBLs) like sulbactam/durlobactam and cefiderocol, discussing the main hot points such as the superiority of combination treatment over monotherapy and the best antibiotic partner to use in combination. Sulbactam/durlobactam seems to be the best candi-date to replace current back-bone agents. Cefiderocol, could play a crucial role in combina-tion-regimen. Due to toxicity and the PK/PD limitations, colistin (or polymyxin B) should be used as an alternative agent (when no other options are available). Tigecycline (or minocycline) and fosfomycin could represent suitable partners for both NBLs. Randomized clinical trials (RCTs) are needed to better evaluate the role of NBLs in CRAB infection treatment and to compare the ef-ficacy of tigecycline and fosfomycin as partner antibiotics. Synergism should be tested between NBLs and “old” drugs (rifampicin and trimethoprim/sulfamethoxazole). Huge efforts should be made to accelerate pre-clinical and clinical studies on safer polymyxin candidates with lung im-proved activity, as well as on the i.v. rifabutin formulation.

This paper investigates pseudo-polymorphism in 2-pyridylmethoxy derivatives of p-tert-butylcalix[4]arene (PyC4), p-tert-butyldihomooxa-calix[4]arenes (PyHOC4), and p-tert-butylhexahomotrioxacalix[3]arenes (PyHO3C3), presenting 11 crystal structures with 15 crystallographically independent molecules. The macrocycle of PyC4 is smaller and less flexible with respect to those of PyHOC4 and PyHO3C3 and in solution, the cone conformation of these three molecules exhibit different point symmetries: C4, Cs and C3, respectively. A correlation is observed between the macrocycle's structural rigidity and the number of pseudo-polymorphs formed. The more rigid PyC4 displays a higher number (6) of pseudo-polymorphs compared to PyHOC4 and PyHO3C3, which exhibit a smaller number of crystalline forms (3 and 2, respectively). The X-ray structures obtained show that the conformation of the macrorings is primarily influenced by the presence of an acetonitrile guest molecule within the cavity, with limited impact from crystal packing and intermolecular cocrystallized solvent molecules. Notably, both calix[4]arene derivatives produce host-guest complex with acetonitrile, while the most flexible and less aromatic PyHO3C3 do not give crystals with acetonitrile as guest. Intertwined 1D and 2D solvent channel networks were observed in the PyHOC4-hexane and in the PyHO3C3-H2O-MeOH crystal structures, respectively, while the other pseudopolymorphs of PyHOC4 and PyHO3C3 and all PyC4 crystal forms exhibit a closely packed crystal structures without open channels.

Diarrhea remains one of the leading causes of mortality worldwide, especially among children. Recent epidemiological studies conducted in developing countries identified Shigella species as the most predominant pathogenic bacteria responsible for diarrhea. Antimicrobial therapy is necessary for Shigella infections; however, the rapid emergence of resistance against existing antimicrobials in Shigella spp. poses a serious global health problem. To identify alternative antimicrobial compounds with activity against Shigella species, the pathogens responsible for bacterial diarrhea. In this study, we have applied antibacterial phenotypic screening to identify potent anti-Shigella compounds across a broad chemical diversity, including selected acetaminophen derivatives containing benzothiazoles backbone, and their combination with certain antibiotics. In continuation to our effort in searching potent antimicrobial compounds, we have found this time around that two acetaminophen derivatives containing benzothiazoles backbone (4a and 4b) could inhibit the growth of Shigella flexneri with common MIC value of 12.5 µg/ml. These compounds were established through a time-kill kinetics’ study to be bactericidal. Meanwhile, the 2-aminobenzothiazoles (1a and 1b) used for the synthesis of compounds 4 (a & b) were found to be poorly active (MIC: 100 µg/ml) against this pathogen. Combination studies of 4a and 4b with the least susceptible antibiotics (ceftriaxone and cotrimoxazole) demonstrated synergistic anti-Shigella activity. The present study demonstrates that the azobenzothiazole dyes 4 (a & b) can be repurposed as potential anti-Shigella compounds, which can serve as scaffolds for the development of new agents against infectious diarrhea caused by Shigella and other enteric pathogens, especially in developing countries.

Advanced glycation end-products (AGEs) form through non-enzymatic glycation of various proteins. Optic nerve degeneration is a frequent complication of diabetes, and retinal AGEs accumulation is strongly linked to diabetic retinopathy development. Type 2 diabetes mellitus (T2DM) is a major risk factor for Alzheimer's disease (AD), with patients often exhibiting optic axon degeneration in the nerve fiber layer. Notably, a gap exists in our understanding of how AGEs contribute to neuronal degeneration in the optic nerve within the context of both diabetes and AD. Our previous work demonstrated that glyceraldehyde (GA)-derived toxic advanced glycation end-products (TAGE) disrupt neurite outgrowth through TAGE-β-tubulin aggregation and tau phosphorylation in neural cultures. In this study, we further illustrated GA-induced suppression of optic nerve axonal elongation via abnormal β-tubulin aggregation in mouse retinas. Elucidating this optic nerve degeneration mechanism holds promise for bridging the knowledge gap regarding vision loss associated with DM and AD.

Biomaterials have been the subject of extensive research, with their applications in medicine and pharmacy expanding rapidly. Collagen and its derivatives stand out as valuable biomaterials due to their high biocompatibility, biodegradability, and lack of toxicity and immunogenicity. This review comprehensively examines collagen from various sources, its extraction and processing methods, and its structural and functional properties. Preserving the native state of collagen is crucial for maintaining its beneficial characteristics. The challenges associated with chemically modifying collagen to tailor its properties for specific clinical needs are also addressed. The review discusses various collagen-based biomaterials, including solutions, hydrogels, powders, sponges, scaffolds, and thin films. These materials have broad applications in regenerative medicine, tissue engineering, drug delivery, and wound healing. Additionally, the review highlights current research trends related to collagen and its derivatives. These trends may significantly influence future developments, such as using collagen-based bioinks for 3D bioprinting or exploring new collagen nanoparticle preparation methods and drug delivery systems.

The need for solvating and encapsulating hydro-sensitive molecules drives noticeable trends in the applications of cyclodextrins in pharmaceutical industry, food, polymer, materials, and agricultural science. Among them, β-cyclodextrin is one of the most used for the entrapment of phenolic acid compounds to mask the bitterness of wheat bran. In this regard, there is still a need for a good predictive model that assesses β-cyclodextrin bitterness masking capabilities for various phenolic compounds. This study uses a dataset of 20 phenolic acids docked to the β-cyclodextrin cavity to generate three different binding constants. The data from docking study were combined with topological, topographical and quantum-chemical features from the ligands in a machine learning-based structure-activity relationship study. Three different models for each binding constant were computed using a combination of Genetic Algorithm (GA) and Multiple Linear Regression (MLR) approaches. The developed ML/QSAR models showed a very good performance, with high predictive ability and correlation coefficients of 0.969 and 0.984, for training and test sets, respectively. The models revealed several factors responsible for a binding with cyclodextrin, showing positive contributions toward the binding affinity values, including such features as presence of six-membered rings in the molecule, branching, electronegativity values, and polar surface area.

Bovine respiratory disease (BRD) is the leading cause of morbidity and mortality in cattle raised in North America. At the feedlot, cattle are subject to metaphylactic treatment with macrolides to prevent BRD, a practice that may promote antimicrobial resistance and has resulted in an urgent need for novel strategies. Mannheimia haemolytica is one of the major bacterial agents of BRD. The inhibitory effects of two amphipathic, α-helical (PRW4, WRL3) and one β-sheet (WK2) antimicrobial peptides were evaluated against multidrug-resistant (MDR) M. haemolytica isolated from Alberta feedlots. WK2 was not cytotoxic against bovine turbinate (BT) cells by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. All three peptides inhibited M. haemolytica, with WK2, being the most efficacious against multiple isolates. At 8-16 µg/ml, WK2 was bactericidal against Mh 330 in broth and at 32 µg/ml in the presence of BT cells, reduced the population by 3 logs CFU/ml without causing cytotoxic effects. The membrane integrity of Mh 330 was examined using NPN (1-N-phenylnaphthylamine), and ONPG (o-Nitrophenyl β-D-galactopyranoside) with both the inner and outer membranes being compromised. Thus, WK2 may be a viable alternative to the use of macrolides as part of BRD prevention and treatment strategies.

Xanthone derivatives, a class of natural compounds abundantly found in plants such as mangosteen (Garcinia mangostana) and certain herbs, have garnered substantial interest due to their diverse pharmacological properties, including antioxidant, anti-inflammatory, and anti-cancer activities. Recent investigations have unveiled their potential as modulators of enzymatic activity, prompting exploration into their effects on hyaluronidase-mediated HA degradation, and their effects in topical treatment of telangiectasia and rosacea. Telangiectasia and rosacea are common dermatological conditions characterized by chronic skin inflammation, vascular abnormalities, and visible blood vessels, resulting in significant cosmetic concerns and impaired quality of life for affected individuals. This review aims to provide a comprehensive overview of the current understanding regarding the interplay between mechanisms of action by which xanthone derivatives exert their therapeutic effects, including the inhibition of pro-inflammatory cytokines, modulation of oxidative stress pathways, and regulation of vascular endothelial growth factors. Furthermore, we will discuss the implications of harnessing xanthone derivatives as therapeutic agents for mitigating vascular dysfunction and its associated pathologies, thereby offering insights into future research directions and therapeutic strategies in the field of vascular biology.

Dunaliella salina is a rich source of 9-cis β-carotene, which has been identified as important in the treatment of retinal dystrophies and other diseases. We previously showed that chlorophyll absorption of red light photons in D. salina is coupled to oxygen reduction and phytoene desaturation and increases the pool size of β-carotene [1]. Here we show for the first time that growth under red light also controls conversion of extant all-trans β-carotene to 9-cis β-carotene by β-carotene isomerases. Cells illuminated with red light from a light emitting diode (LED) during cultivation contained a higher 9-cis β-carotene content compared to cells illuminated with white or blue LED light. The 9-cis/all-trans β-carotene ratio in red light treated cultures reached >2.5:1 within 48 hours and was independent of light intensity. Illumination using red light filters that eliminated blue wavelength light also increased the 9-cis/all-trans β-carotene ratio. With norflurazon, a phytoene desaturase inhibitor which blocked downstream biosynthesis of β-carotene, extant all-trans β-carotene was converted to 9-cis β-carotene during growth with red light and the 9-cis/all-trans β-carotene ratio was ~2:1. With blue light under the same conditions, 9-cis β-carotene was likely destroyed at a greater rate than all-trans β-carotene (9-cis/all-trans ratio 0.5:1). Red light perception by the red light photoreceptor, phytochrome, may increase the pool size of anti-oxidant, specifically 9-cis β-carotene, both by upregulating phytoene synthase to increase the rate of biosynthesis of β-carotene and to reduce the rate of formation of reactive oxygen species (ROS), and by upregulating β-carotene isomerases to convert extant all-trans β-carotene to 9-cis β-carotene.

Alzheimer’s disease (AD) and the therapies of AD with anti-amyloid1-42 (Aβ) monoclonal antibodies are associated with the vascular complications of brain edema, hemorrhage, and cerebral amyloid angiopathy (CAA) termed amyloid-related imaging abnormalities (ARIAs). The neuropathology of normal and AD brains demonstrates that monocyte/macrophages (MMs) are critical in successful brain clearance in healthy brain by up-loading, transporting, and degrading Aβ but fail degradation and clearance in AD patients by releasing Aβ into vessels at the blood-brain barrier, causing vasculitis and ARIAs. The naturally-formed epoxides (EpFAs) of polyunsaturated fatty acids (PUFA’s), including arachidonic, docosahexaenoic, and eicosapentaenoic fatty acids, may repair degradation of Aβ by regulating Aβ-degrading enzymes, inflammatory cytokines, and unfolded protein response (UPR) to endoplasmic reticulum stress in a homeostatic fashion. EpFAs are, however, degraded by the soluble epoxide hydrolase enzyme (sEH) but are protected by the sEH inhibitor (sEHI) TPPU. In the cultures of AD patients’ macrophages, TPPU with the epoxide EEQ, and the cGAS/STING inhibitor H-151 increased uptake of Aβ at 2 hours and degradation of Aβ at 24 hours. In conclusion, the soluble epoxide hydrolase inhibitor TPPU with omega-3 fatty acids and the cGAS/STING inhibitor H-151 increase Aβ uptake and degradation in macrophages of AD patients, and potentially enhancing Aβ clearance in the AD brain.

Background: The identification of novel therapeutic strategies for Ovarian cancer (OC), the most lethal gynecological neoplasm, is of utmost urgency. Here, we have tested the effectiveness of the compound 2c (4-Hydroxy-2,6-bis(4-nitrobenzylidene)cyclohexanone 2). 2c interferes with cyste-ine-dependent deubiquitinating enzymes (DUBs), thus affecting the ubiquitin-proteasome de-pendent degradation of proteins. Methods: 2c phenotypic/molecular effects were studied in two OC cell lines, primary tumor cells cultured in 2D/3D and in a mouse xenograft model. We also propose an in-silico model of 2c interaction with DUBs. Finally, we tested the effect of 2c conju-gated to several linkers to generate 2c-derivatives usable for improved drug delivery. Results: 2c effectively impairs OC cell line and primary tumor cell viability in both 2D and 3D conditions. The effectiveness is confirmed in a xenograft mouse model of OC. We show that 2c impairs pro-teasome activity and triggers apoptosis most likely by interacting with DUBs; we propose a mechanism for the interaction with a model DUB via an in-silico evaluation of the en-zyme-inhibitor complex. 2c also reduces cell growth by down-regulating the level of the transcrip-tion factor E2F1. Finally, 2c activity is often retained after the conjugation with linkers. Conclu-sion: Our data strongly support the potential therapeutic value of 2c/derivatives in OC.

Cordycepin has good antitumor activity, but its clinical application is limited due to the easy deamination of N6 in structure. In this study, a large lipopolysis group was introduced at the cordycepin N6 to improve the problem, Cordycepin derivatives(3a-4c) were synthesized, and biological evaluation of compounds were studied. In the study, the vitro antitumor activity of the compounds against MCF7 cells, HepG2 cells and SGC-7901 cells was evaluated by MTT assay. In the results, compound 4a showed the most obvious inhibitory effect on MCF7 cells with IC50 value of 27.566±0.52 μM, which was much lower than cordycepin. Compound 4a showed high selectivity between MCF7 and normal MCF-10A cells. Further biological evaluation showed that compound 4a promoted apoptosis and blocked the cell cycle in G0/G1 phase. Then, Western Blot was used to detect related apoptotic proteins. It was found that Compound 4a could down-regulate the expression of Bcl-2 protein and up-regulate the expression of p53, Bax, Caspase-3, and Caspase-9 proteins. The mitochondrial membrane potential decreased continuously and the positive expression rate decreased. It was speculated that compound 4a induced the apoptosis of MCF7 cells through the mitochondrial pathway.

Most neurodegenerative diseases have the characteristics of proteinopathies, i.e. they cause lesions to appear in vulnerable regions of the nervous system, corresponding to protein aggregates that progressively spread through the neuronal network as the symptoms progress. Alzheimer's disease is one of these proteinopathies. It is characterized by two lesions, neurofibrillary tangles (NFTs) and senile plaques, formed essentially of amyloid peptides (Aβ). A combination of factors ranging from genetic mutations to age-related changes in the cellular context converge in this disease to accelerate Aβ deposition. Over the last two decades, numerous studies have attempted to elucidate how structural determinants of its precursor (APP) modify Aβ production, and to understand the processes leading to the formation of different Aβ aggregates; e.g. fibrils and oligomers. The synthesis proposed in this review indicates that the same motifs can control APP function and Aβ production essentially by regulating membrane dimerization, and subsequently Aβ aggregation processes. The distinct properties of these motifs and the cellular context regulate the APP conformation to trigger the transition to the amyloid pathology. This concept can be transposed to the study of other proteinopathies, providing a framework for improving our understanding of these mechanisms that devastate neuronal functions.

Indole is a versatile pharmacophore widely distributed in bioactive natural products. This privileged scaffold has been found in a variety of molecules isolated from marine organisms such as algae and sponges. Among these, indole alkaloids represent one of the biggest, most promising family of compounds, having shown a wide range of pharmacological properties, including anti-inflammatory, antiviral and anticancer activities. The aim of this review is to show the current scenario of marine indole alkaloid derivatives, covering not only the most common chemical structures, but also new synthetic routes developed during the last years as well as promising therapeutic applications.

Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder. A wealth of evidence indicates that the amyloid β (Aβ) aggregates result from dyshomeostasis between Aβ production and clearance, which plays a pivotal role in the pathogenesis of AD. Consequently, therapies targeting Aβ reduction represent a promising strategy of AD intervention. Tetramethylpyrazine nitrone (TBN) is a novel tetramethylpyrazine derivative with the potential for the treatment of AD. Previously, we demonstrated that TBN markedly improved cognitive functions and reduced Aβ, APP, BACE 1 and hyperphosphorylated tau levels in 3 × Tg-AD mice. However, the mechanism by which TBN inhibits Aβ deposition still unclear. In this study, we employed the APP/PS1 mice treated with TBN (60 mg/kg, ig, bid) for six months and N2a/APP695swe cells treated with TBN (300 μM) to explore the mechanism of TBN on the Aβ reduction. Our results indicated that TBN significantly alleviated cognitive impairment and reduced Aβ depositions in APP/PS1 mice. Further investigation of the underlying mechanisms revealed that TBN decreased the expression of APP and BACE1, activated the AMPK/mTOR/ULK1 autophagy pathway and inhibited the PI3K/AKT/mTOR/ULK1 autophagy pathway, as well as decreased the phosphorylation levels of JNK and ERK in APP/PS1 mice. Moreover, TBN was found to significantly reduce the mRNA levels of APP and BACE1, as well as those of SP1, CTCF, TGF-β, and NF-κB, transcription factors involved in regulating gene expression. Additionally, TBN was observed to decrease the level of miR-346 and increase the levels of miR-147 and miR-106a in the N2a/APP695swe cells. These findings indicate that TBN may reduce Aβ levels likely via reducing APP expression by regulating APP gene transcriptional factors and miRNAs, reducing BACE1 expression, and promoting autophagy activities.

Precipitates are the primary source of strength for the Al-Mg-Si alloy. Aluminum alloy in the peak-aged state mainly contain β'' and β' precipitates. In the past, most of the literature only considered the strengthening effect of β''. Here we develop a single crystal intensity model including both precipitate enhancement effects for the first time. This model was subsequently implemented into a crystal plastic finite element method to model the uniaxial tensile process of a polycrystalline aggregate model of Al-Mg-Si alloy. The simulation results for uniaxial stretching are in good agreement with the experimental results, confirming that the constitutive parameters used for the single crystal strength model with two precipitates are based on realistic physical implications. Furthermore, by comparing the uniaxial tensile simulation results of a peak-aged alloy considering the actual precipitated phase composition of the alloy with those assuming that the precipitated phase is only the β'' phase, the predicted tensile strength of the former is around 5.65% lower than that of the latter, suggesting that the two kinds of precipitation should be considered separately when simulating the mechanical response of Al-Mg-Si alloy. It is highly expected that the present simulation strategy is not limited to the Al-Mg-Si alloys, and it can be equally applied to the other age-enhanced alloys.

The goal of this study is to synthesize, determine the structure, and examine the antimicrobial properties of novel metal complexes of 2,4-dithiouracil and its derivatives. These complexes were obtained by mixing aqueous solutions of the corresponding metal salts with the ligand dissolved in DMSO and aqueous NaOH, using a metal-to-ligand ratio of 1:4:2. The structures of the new compounds were analyzed by melting point determination, microwave plasma atomic emission spectrometry (MP-AES) for Cu and Au, inductively coupled plasma optical emission spectrometry (ICP-OES) for S, ATR, solution and solid-state NMR and Raman spectroscopy. The interpretation of the complex spectra was aided by data for 2,4-dithiouracil obtained from 1H-1H COSY, DEPT-135, HMBC, and HMQC spectra. Additionally, the antimicrobial activity of these complex-es and the free ligands was evaluated against Gram-positive and Gram-negative bacteria, as well as yeasts.

Fibrosis is a ubiquitous pathology, and prior studies have indicated that various artemisinin (ART) derivatives (including artesunate (AS), artemether (AM), and dihydroartemisinin (DHA)) can reduce fibrosis in vitro and in vivo. The medicinal plant, Artemisia annua L., is the natural source of ART and is widely used, especially in underdeveloped countries, to treat a variety of diseases including malaria, while A. afra contains no ART but is also antimalarial. Using human dermal fibroblasts (CRL-2097), we compared the effects of A. annua and A. afra tea infusions, ART, AS, AM, DHA, and a liver metabolite of ART, deoxyART (dART), on fibroblast viability and expression of key fibrotic marker genes after 1 and 4 days of treatment. AS, DHA, and Artemisia tea significantly reduced fibroblast viability at 1 and 4 d post-treatment. After 4 d post treatment, AS, DHA, and A. afra tea downregulated ACTA2, and upregulated MMP3, with other genes either being unaffected or differentially affected. ART and AM had no significant effect on either fibroblast viability or fibrotic gene expression. Although A. annua contains ART, it had a significantly greater anti-fibrotic effect than ART alone. Immunofluorescent staining for smooth muscle α-actin (α-SMA) correlated well with transcriptional responses of drug-treated fibroblasts. Together, proliferation, qPCR, and immunofluorescence results show that treatment with ART, AS, DHA, and the two Artemisia teas yield differing responses, including those related to fibrosis, in human dermal fibroblasts.

Silybin is a natural compound extensively studied for its hepatoprotective, neuroprotective and anti-cancer properties. Envisioning the enhancement of silybin potential by suitable modifications in its chemical structure, here, a series of new 7-O alkyl silybins derivatives were synthesized by Mitsunobu reaction starting from the silybins and tyrosol-based phenols, such as tyrosol (TYR, 3), 3-methoxytyrosol (MTYR, 4) and 3-hydroxytyrosol (HTYR, 5). This research sought to explore the antioxidant and anticancer properties of new eighteen derivatives and their mechanisms. In particular, the antioxidant properties of new derivatives outlined by DPPH assay, showed a very pronounced activity depending on the tyrosyl moiety (HTYR>MTYR>>TYR). A significant contribution of the HTYR moiety was observed for silybins and 2,3-dehydro-silybin based derivatives. According to the very potent antioxidant activity, 2,3-dehydro-silybin derivatives 15ab, 15a and 15b exerted the most potent anticancer activity in human prostate cancer PC-3 cells. Furthermore, flow cytometric analysis for cell cycle and apoptosis revealed that 15ab, 15a and 15b induce strong G1 phase arrest and increase late apoptotic population in PC-3 cells. Additionally, western blotting for apoptotic marker cleaved caspase-3 confirmed apoptosis induction by these silybin derivatives in PC-3 cells. These findings hold significant importance in the investigation of anticancer properties of silybin derivatives and strongly encourage swift investigation in pre-clinical models and clinical trials.

Muscle mass and strength decrease with aging, but habitual exercise can maintain muscle health. β-Hydroxy-β-methyl butyrate calcium (HMB) and black ginger (BG) are anti-oxidants that have been reported to improve muscle protein metabolism and energy production; these molecules may have synergistic effects. The senescence-accelerated mouse-prone 8 (SAMP8) model is a useful model of muscle aging. Therefore, in this study, we explored how the combination of habitual exercise, HMB, and BG affected muscle aging. We used 28-week-old SAMP8 mice divided into five groups: control, exercise (Ex), Ex+BG, Ex+HMB, and Ex+BG+HMB (Ex+Comb). Mice were required to run on a treadmill for 16 weeks at 5 days per week. In 44-week-old mice, grip strength tests and dissection were conducted. Muscle weight was measured, and the gastrocnemius muscle was subjected to quantitative polymerase chain reaction and immunoblotting. Muscle mass and strength were preserved in the Ex+Comb group, and mitochondrial function was preserved through suppressing oxidative stress. Muscle protein synthesis signaling was improved in the Ex+Comb group. Autophagy and the ubiquitin system were normalized by Ex+Comb treatment. Overall, habitual exercise and HMB plus BG treatment maintained muscle health by suppressing oxidative stress, preserving mitochondrial function, and maintaining muscle protein metabolism in SAMP8 mice.

The aim of this study was to investigate the effect of β-Hydroxy-β-methylbutyrate (HMB) supplementation on anti-inflammatory cytokines including IL-4, IL-10 and TGF-β during an acute bout of resistance exercise (RE) in young resistance trained men. Ten resistance-trained men in a randomized, double-blind, placebo-controlled and crossover study, were administered a 7-day HMB supplementation (3×1 g.d-1 of HMB) and placebo (3×1 g.d-1 of Maltodextrin) with a 7 days washout period. After supplementation periods, subjects performed three sets of bench press, lat pull down, leg extension, leg curl, biceps curl, triceps curl and shoulder press to failure with 85% of one repetition to maximum (1RM). Blood samples were obtained before- (Pre), immediately post- (IP) and 1 hour-post RE (1h P) to assess serum concentrations of IL-4, IL-10 and TGF-β1. The data were analyzed using 2 (treatment: HMB and PL) × 3 (time points: Pre, IP and 1hP) repeated measures analysis of variance (ANOVA) followed by the Bonferroni post hoc test with a significant level of p<0.05. Serum IL-4 was significantly higher at IP resistance exercise in HMB compared to placebo. Circulating IL-4 and TGF-β1 were significantly raised at IP compared to Pre in both HMB and placebo treatments. No significant differences between treatments were observed for IL-10 and TGF-β1at any time points. In conclusion, HMB supplementation increased the circulating level of IL-4 during RE in resistance-trained men, which may attenuate inflammation and facilitate adaptation to RE.

The article describes facile one-pot, hi-yielding reactions to synthesize substituted 3,4-dimethyl-1H-pyrrole-2-carboxamide (3a–m) and carbohydrazide analogues (5a–l) as potential antifungal and antimicrobial agents. The structural integrity and purity of the synthesized compounds were assigned based on appropriate spectroscopic techniques. Synthesized compounds were assessed in vitro for antifungal and antibacterial activity. The compound 5h, 5i and 5j were found to be the most potent against A. fumigatus, with MIC value of 0.031 mg/mL. The compound 5f bearing a 2,6-dichloro group on the phenyl ring was found to be the most active broad spectrum antibacterial agent with MIC value of 0.039 mg/mL. The mode of action of the most promising antifungal compounds (one representative from each series; 3j and 5h) was established by their molecular docking to the active site of sterol 14α-demethylase. Molecular docking studies revealed a highly spontaneous binding ability of the tested compounds in the access channel away from catalytic heme iron of the enzyme, which suggested that the tested compounds inhibit this enzyme and would avoid heme iron related deleterious side effects observed with existing antifungal compounds.

The role of foods is shifting from focusing on the provision of energy and basic nutrients to also include bioactive compounds that prevent the development of chronic age-related diseases. Mi-croalgae offer a source of nutritional compounds with important health effects, and have the po-tential for production of health-promoting products, without increasing agricultural land use and negatively impacting the environment. Here we investigate the health effects of microalgal ex-tracts with high levels of the colourless carotenoid phytoene. Phytoene is widely available from dietary sources and can be detected across different tissues in the human body. However, it is usually regarded as a precursor for the synthesis of other carotenoids, rather than a bioactive molecule. We utilised the model organism C. elegans to show that phytoene-rich extracts from Chlorella sorokiniana and Dunaliella bardawil have anti-ageing properties. The extracts protect against oxidative damage and amyloid-β42 proteotoxicity (a major pathology of Alzheimer's disease), and extends lifespan. We show that pure phytoene also has these anti-ageing effects, suggesting that phytoene is a bioactive molecule with positive effects on ageing and longevity.

The tetracyclic pyrido[4,3-b]carbazole olivacine and four of its oxygenated derivatives have been synthesized by a late-stage palladium-catalyzed Heck-type cyclization of the pyrrole ring as key step. In a test for inhibition of the growth of Mycobacterium tuberculosis 9-methoxyolivacine showed the most significant inhibiting activity against Mycobacterium tuberculosis with an MIC₉₀ value of 1.5 μM.

The results of the most recent investigation of triterpenoid-based antiviral agents effective namely in the HIV-1 and HSV-1 treatment were reviewed and summarized. Several key historical achievements are included to stress consequences and continuity in this research. Most of the agents studied belong into a series of compound derived from betulin or betulinic acid, and their synthetic derivative called bevirimat. A termination of clinical trials of bevirimat in the Phase IIb initiated a search for more successful compounds partly derived from bevirimat or designed independently of bevirimat structure. Surprisingly, a majority of bevirimat mimics are derivatives of betulinic acid, while other plant triterpenoids, such as ursolic acid, oleanolic acid, glycyrrhetinic acid or other miscellaneous triterpenoids, are relatively rarely involved in a search for novel antiviral agent. Therefore, this review article is divided into three parts based on the leading triterpenoid core structure.

Monoterpenes as natural products are the subject of increased attention in the search for new pharmacological agents because of their numerous biological activities including antifungal, antibacterial, antioxidant, anticancer, antispasmodic, hypotensive, vasodilating effects, etc. In vitro and in vivo studies reveal their antidepressant, anxiolytic, and memory-enhancing in experimental dementia and Parkinson’s disease effects. Chemical modification of natural substances by conjugation with various synthetic components is a modern method of obtaining new biologically active compounds. The discovery of new potential drugs among monoterpene derivatives is a progressive direction in experimental pharmacology and a promising approach to the therapy of various pathologies. Biologically active substances such as monoterpenes borneol, camphor, geraniol, pinene, and thymol, were used to synthesize compounds with different properties, including analgesic, anti-inflammatory, anticonvulsant, anti-depressant, anti-Alzheimer’s, anti-parkinsonian, antiviral and antibacterial (anti-tuberculosis). Myrtenal is a perspective monoterpenoid with therapeutic potential in various fields of medicine. Its chemical modifications often lead to new or more pronounced biological effects. As an example, conjugation of myrtenal with the known pharmacophore adamantane allows one to enhance some of its key properties. Myrtenal-adamantane derivatives exhibited a variety of beneficial properties – antimicrobial, antifungal, antiviral, anticancer, anxiolytic, and neuroprotective, which are worth examining in more detail and at length.

A series of derivatives of trans-3-(2,4,6-trimethoxy phenyl)-4,5-dihydro isoxazolo-4,5-bis(aroylcarbohydrazide) and of trans-3-(2,4,6-trimethoxyphenyl)4,5-dihydroisoxazolo-4,5-bis[carbonyl-(4’phenyl)thiosemi- carbazide (9) were synthesized from trans-3-(2,4,6-trimethoxyphenyl)-4,5-dihydro-4,5-bis(hydrazenocarbonyl) Isoxazole (8). The structures of the Compounds were elucidated by elemental and spectral (IR, NMR, and MS) analysis. The compound 9 show activity against some bacterial species. Whereas, no activity was observed for compounds 10a, 10b and 10c against all bacterial species. The antioxidant activity of new compounds has been screened. Compound 9 showed higher antioxidant activity using the DPPH and ATBS method.

Using the techniques of computer-aided drug design, the docking of Survivin and known active small molecules was simulated and then the key amino acid residue fragment of the target protein was analyzed. It led to the discovery of active groups capable of binding to the critical sites. Through the use of the natural product, Oleanolic Acid, as a lead compound, the introduction of the active groups onto the A-ring, and the modification of the carboxyl group at the C-28 position using esterification or amidation, twenty new Oleanolic acid derivatives had been designed and synthesized.A549 and SGC-7901 cells were used to screen the antitumor activity in vitro through the standard MTT method. The compounds, II₃, III₅ and Ⅳ_4, exhibited more potent cytotoxicity than positive drugs.

A number of chemical modifications were carried out in order to synthesize new compounds based on the triterpenoid betulonic acid. Triazolation reactions were carried out for the synthesis of new 1,2,3-triazole derivatives based on betulonic acid. Chemical changes were made on the carbonyl group at the C-3 position of the initial molecule and on the carboxyl and hydroxyl groups at the C-28 position. Chromatographic methods were used to separate and purify the formed products. Spectroscopic (NMR-, mass-) methods were used to establish the structure of synthesized compounds. As a result of the chemical transformations carried out, a number of new derivatives of betulonic acid were obtained. All synthesized compounds were tested for antimicrobial and cytotoxic activity. As a result, compounds with pronounced antimicrobial activity were identified.

2-Methylquinazolin-4(3H)-one was prepared by reaction of anthranilic acid, acetic anhydride and ammonium acetate. The reaction of 2-methylquinazolin-4(3H)-one with N-aryl-2-chloroacetamides in acetone in the presence of potassium carbonate gave nine N-aryl-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide compounds. The structures of these compounds were elucidated on the basis of their IR, 1H-NMR, 13C-NMR and HR-MS spectral data. These synthesized compounds containing the 2-methyl-3,4-dihydroquinazolin-4-one moiety exhibited excellent activity against Aedes aegypti mosquito larvae with LC50 values in the range of 2.085-4.201 μg/mL after 72 h exposure. Interestingly, these compounds did not exhibit toxicity to the non-target organism Diplonychus rusticus. In silico molecular docking revealed acetylcholine binding protein (AChBP) and acetylcholinesterase (AChE) to be potential molecular targets. These data indicated the larvicidal potential and environmental friendliness of these N-aryl-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide derivatives.

In our tactic to construct bio-active molecules, a series of novel pyrimido[2,1-c][1,2,4]triazine-3,4-diones based heterocycles, were synthesized and evaluated for their in vitro antimicrobial impacts. The exploratory bioassay results declared that, the majority of the evaluated compounds exhibited considerable anti-microbial activity comparable to the reference drugs. Conjugates 15j, 15f, 15i, 15h, 15g and 15a were found to be the most potent antibacterial, indicating that conjugates bearing electron-attracting substituents exhibited higher potency than these with electron-releasing substituents.

3,4-Dihydroquinolin-2(1H)-ones represent a class of valuable bioactive compounds with six-membered nitrogen-containing heterocyclic structures. The development of simple, mild and efficient synthetic methods has been widely concerned by synthetic chemists. In this review, we have summarized a series of different synthetic strategies for the synthesis of dihydroquinoline-2(1H)-ones via catalytic annulation of α,β-unsaturated N-arylamides in the past decade, including covering electrophilic cyclization, radical initiated cyclization and photochemical cyclization reactions. Besides, the substrate scope and mechanistic details are also discussed. This paper will provide a useful reference for the development of diverse synthesis methodologies of 3,4-dihydroquinolin-2(1H)-ones.

Modified nucleobases are potentially useful building blocks when containing catalytically active functionalities and could be introduced in chiral tridimensional molecules such as nucleic acids, which creates the premises for the development of novel catalytic species. Herein we describe the synthesis of a novel β-C-nucleoside bearing a diol group at anomeric position, amenable as metal ligand or as organo-catalyst. The abasic ligand was successfully prepared and inserted into complementary DNA strand.

Crosstalk between the BMP and TGF-β signaling pathways regulates many complex developmental processes from the earliest stages of embryogenesis throughout adult life. In many situations, the two signaling pathways act reciprocally. For example, TGF-β signaling is generally pro-fibrotic whereas BMP signaling is anti-fibrotic and pro-calcific. Sex-specific differences occur in many diseases including cardiovascular pathologies. Differing ratios of fibrosis and calcification in stenotic valves suggests that BMP/TGF-β signaling may vary in men and women. In this review, we focus on the current understanding of the interplay between sex and BMP/TGF-β signaling and pose several unanswered questions.

The opportunistic pathogen Pseudomonas aeruginosa is responsible for numerous chronic infections and has a case fatality rate of 50%. All P. aeruginosa strains express β–lactamase, an enzyme capable of inactivating β–lactam antibiotics, including penicillins. However, β–lactams are still considered desirable therapeutics by physicians due to their low toxicity. The short-term goal of this study was to create an optimal model for ampC expression in P. aeruginosa and determine the selecting antibiotic to be used during mutagenesis. In the long term, this study aims to renew effectiveness of β–lactams by identifying potential allosteric binding sites on β–lactamase for the development of novel β–lactamase inhibitors. To create a system for ampC expression, the chromosomal P. aeruginosa ampC gene encoding for β–lactamase was cloned into Escherichia coli, then conjugated into P. aeruginosa ∆ampC. β– lactamase assays on recombinant E. coli and P. aeruginosa detected much higher production of β–lactamase in pMMB67HE, which was confirmed with antibiotic susceptibility testing (AST) to numerous β-lactams. From AST, carbenicillin was chosen as the antibiotic to select functional β–lactamase production during mutagenesis. Future work includes conducting mutagenesis on ampC to identify allosteric binding sites on the β–lactamase enzyme that may enable the discovery of new β–lactamase inhibitors. This work allows for the development of novel β–lactamase inhibitors that could renew the utility of β–lactams and drastically reduce morbidity and mortality from chronic Pseudomonas infections.

The ribonuclease H (RNase H) active site of HIV-1 reverse transcriptase (RT) is the only viral enzyme not targeted by approved antiretroviral drugs. Using a fluorescence-based in vitro assay, we screened 65,239 compounds at a final concentration of 10 µM to identify inhibitors of RT RNase H activity. We identified 41 compounds that exhibited 50% inhibitory concentration (i.e., IC50) values &lt; 1.0 µM. Two of these compounds, 2-(4-methyl-3-(piperidin-1-ylsulfonyl)phenyl)benzo[d]isothiazol-3(2H)-one (1) and ethyl 2-(2-(3-oxobenzo[d]isothiazol-2(3H)-yl)thiazol-4-yl)acetate (2), which both share the same benzisothiazolone pharmacophore, demonstrate robust antiviral activity (50% effective concentrations of 1.68 ± 0.94 µM and 2.68 ± 0.54, respectively) in the absence of cellular toxicity. A limited structure-activity relationship analysis identified two additional benzisothiazolone analogs, 2-methylbenzo[d]isothiazol-3(2H)-one (3) and N,N-diethyl-3-(3-oxobenzo[d]isothiazol-2(3H)-yl)benzenesulfonamide (4), which also resulted in inhibition of RT RNase H activity and virus replication. Compounds 1, 2 and 4, but not 3, inhibited the DNA polymerase activity of RT (IC50 values ~ 1 to 6 µM). In conclusion, benzisothiazolone derivatives represent a new class of multifunctional RT inhibitors that warrants further assessment for the treatment of HIV-1 infection.

Modern organic synthesis is majorly focused on developing environmentally benign synthetic protocols by employing green chemistry principles. Accordingly, in our recent research work, we herein report the use of modified supramolecular host cyclodextrin as an effective solid based green catalyst for accessing structurally diverse and medicinally relevant pyrimidone architectures. The catalyst and the synthesized compounds 4 (a-r) were characterized using FT-IR, NMR and GC-Mass spectroscopy. Major highlights of the reported work include: atom economical process, extremely milder reaction conditions, operational simplicity, high isolated yields, and excellent catalyst turnover number. The molecular docking studies suggest that the compound 4n has the hydrogen bonding, hydrophobic and π-pair interactions with the active site of active sites of CXT M 15 receptor.

Natural cytokinins are a promising group of cytoprotective and anti-tumor agents. In this research, we synthesized a set of novel cytokinin analogs with alkyl substituents at various positions of the aromatic moiety, as well as with oxygen-containing groups, and tested their antiproliferative activity in MDA-MB-231, A-375, and U-87 MG cell lines, and cytoprotective properties in H2O2 and CoCl2 models. Two amino-linked compounds were anti-proliferative with the ability to act synergistically with doxorubicin, and two carbamate-based ones were cytoprotective. According to the molecular docking data, anti-proliferation was based on the A2AR and APRT inhibition and cytoprotection on the CDK2 inhibition. The obtained results are promising for the development of novel anti-cancer therapeutics.

Schiff bases attract research interest due to their applications in chemical synthesis and medicinal chemistry. In recent years, benitrobenrazide and benserazide containing imine moiety, have been synthesized and characterized as promising inhibitors of hexokinase 2 (HK2) an enzyme overexpressed in most cancer cells. Both compounds possess a common structural fragment, a 2,3,4-trihydroxybenzaldehyde moiety connected through hydrazone or hydrazine linker with acylated on N’-nitrogen atom by serine or 4-nitrobenzoic acid fragment. To avoid presence of toxicophoric nitro group in benitrobenrazide molecule we introduced common pharmacophores 4-fluorophenyl or 4-aminophenyl substituents. Modification of benserazide regards an introduction of other endogenous amino acids instead of serine. Herein we report the synthesis of benitrobenrazide and benserazide analogues and preliminary results of inhibitory activity against HK2 evoked by these structural changes. The derivatives contain a fluorine atom or amino group instead of a nitro group in BNB, exhibited the most potent inhibitory effects against HK2 at a concentration of 1 µM, with HK2 inhibition rates of 60% and 54%, respectively.

As a part of our ongoing effort in the search for promising antileishmanial agents based on the thiochroman scaffold, we prepared a series of substituted 2H-thiochromenes. Thirty-three compounds were evaluated against intracellular amastigotes forms of L. (V) panamensis. Twelve compounds were active with EC₅₀ values lower than 40 μM, and among those three compounds displayed the highest antileishmanial activity with EC₅₀ values below 10 uM. Cytotoxicity was determined against human U-937 macrophages; thus, compounds having electrophilic alkenes (α,β-unsaturated carbonyl, or nitriles) displayed the highest antileishmanial activity but also moderate to high cytotoxicities. Based on SAR analysis, compounds 8d and 10, which differ only in the hydroxy group at C4, were selected as the most promising compounds in this library because good antiparasitic activity and Selectivity Index.

In recent decades, there has been a startling rise in the number of cancer patients worldwide, which has led to an amazing upsurge in the development of novel anticancer treatment candidates. On a positive note, arylpiperazines have garnered attention in cancer research due to their potential as scaffolds for developing anticancer agents. These compounds exhibit a diverse array of biological activities, including cytotoxic effects against cancer cells. Indeed, one of the key advantages of aryl piperazines lies in their ability to interact with various molecular targets implicated in cancer pathogenesis. Here, we focus on the chemical structures of several arylpiperazine derivatives, highlighting their anti-proliferative activity in different tumor cell lines. The modular structure, diverse biological activities, and potential for combination therapies of arylpiperazine com-pounds make them valuable candidates for further preclinical and clinical investigations in the fight against cancer. This review, providing a careful analysis of different arylpiperazine deriva-tives and their biological applications, allows researchers to refine the chemical structures to improve potency, selectivity, and pharmacokinetic properties, thus advancing their therapeutic potential in oncology.

Biomimetic materials are substances that replicate natural structures. There are several methods for producing such materials with highly developed surfaces from a wide range of polymers, but electrospinning is of particular interest due to its simplicity of implementation and the ability to modify the produced fibrous materials resembling structures found in living organisms. This study explores new biomimetic materials based on polyhydroxyalkanoates, specifically poly-3-hydroxybutyrate, modified with chlorophyll derivatives. The research investigates the impact of chlorophyll derivatives on the morphology, supramolecular structure, and key properties of nonwoven materials. The obtained results are of interest for the development of new biomimetic environmentally friendly materials for biomedicine with special properties.

A series of pyrazolopyrimidines derivatives 4– 11 were synthesized using 1-(6-(3-methoxyphenyl)-4-methylpyridazin-3-yl)-1H-pyrazolo [3,4-d] pyrimidin-4-amine 3 as a starting material. The detailed synthesis, structure assignments of the novel compounds based on chemical and spectroscopic evidence, spectroscopic data, pharmacological properties and molecular docking are reported. The pharmacological evaluation illustrated that many of these compounds have good analgesic, anti-inflammatory and antimicrobial activities.

A series of cysteine-based perfluoroaromatic (hexafluorobenzene (I) and decafluorobiphenyl (II) were synthesized and established as a chemoselective and available core to simple or more complex systems since small molecules to biomolecules with interesting properties. As proof of concept of the potential application of perfluorinated derivatives as non-cleavable linkers, some antibody-perfluorinated conjugates were prepared via thiol, demonstrating that the bioconjugation process doesn’t affect to the macromolecular entity. Besides, some molecular properties of synthesized compounds are evaluated using a combination of spectroscopic characterization (FT-IR and 19F-NMR chemical shifts) and theoretical calculations. Moreover, molecular Docking was also developed to predict cysteine-based hexafluorobenzene and decafluorobiphenyl derivatives’ affinity against topoisomerase Il and cyclooxygenase 2 (COX-2). The results suggested that mainly cysteine-based decafluorobiphenyl derivatives could be potential topoisomerase II α and COX-2 inhibitors, becoming potential anticancer agents and candidates for anti-inflammatory treatment.

This paper discusses the concept of fractional derivative with complex order from the application point of view. It is shown that a fractional derivative is hermitian, if and only if the order is real. The hermitian part of complex order derivatives behave like allpass filters with almost logarithmic phase.

Alzheimer’s Disease (AD) is a debilitating neurodegenerative disease characterized by the accumulation of extracellular amyloid-β peptides (Aβ) within the cerebral parenchyma and vasculature, the latter termed cerebral amyloid angiopathy (CAA). This study utilized confocal imaging to investigate heparan sulfate (HS) within the cerebrovasculature and its potential associations with CAA, gender, and ApoE4 genotype. Our investigation revealed elevated levels of HS in the cerebrovasculature of AD patients with severe CAA. Additionally, these patients exhibited higher colocalization of HS with Aβ in the cerebrovasculature, including both endothelial and vascular smooth muscle cell compartments. Intriguingly, a reversal in the polarized expression of HS within the cerebral vasculature was detected in AD patients with severe CAA, suggesting a potential role in CAA development. Furthermore, male patients exhibited lower levels of both parenchymal and cerebrovascular HS. Additionally, ApoE4 carriers displayed heightened cerebrovascular Aβ expression and a tendency of elevated cerebrovascular HS levels in AD patients with severe CAA. Overall, these findings shed light on the intricate interplay between HS, Aβ, ApoE, and vascular pathology in AD, underscoring the potential roles of cerebrovascular HS in CAA development and AD pathology. Further exploring the underlying mechanisms may present novel therapeutic avenues for AD treatment.

Extracellular enzymes catalyze biogeochemical reactions in soil, cycling carbon and nutrients in agricultural systems. Enzymes respond quickly to soil management, including organic amendment inputs, such as biochar, a charcoal-like solid byproduct of bioenergy production. In a previous agricultural field trial, a pine biochar amendment caused an approximately 40% decrease in the enzyme activities of β-glucosidase (BG) and phosphatase (PHOS). The large surface area of the pine biochar has the potential to sorb nutrients and other organic molecules. To test if sorption caused decreased enzyme activity, we used a laboratory assay to quantify the activity of two sorbed enzymes: BG and acid PHOS, involved in the cycling of carbon and phosphorous. The enzymes were incubated with three solid phases: (1) the high surface area pine biochar, (2) the agricultural soil, and (3) a low surface area grass biochar, for an additional comparison. We quantified the sorbed enzymes at pH 6, 7, and 8, using a Bradford protein assay, and measured the immobilized enzyme activities via high-throughput fluorometric analysis. After sorption onto pine biochar, detectable BG and PHOS activity levels dropped by over 95% relative to the soil, supporting direct sorption as one mechanism that reduces enzyme activity in biochar amended soil. This laboratory assay demonstrated that sorption could account for the lack of priming of native soil organic matter and changes in soil phosphorous cycling after pine biochar addition.

In this study, we report a detailed experimental and theoretical investigation of three glycols, namely ethane-1,2-diol, 2-methoxyethan-1-ol and 1,2-dimethoxy ethane. For the first time, the X-Ray spectra of the latter two liquids was measured at room temperature, and they were compared with the newly measured spectrum of ethane-1,2-diol. The experimental diffraction patterns were interpreted very satisfactorily with molecular dynamics calculations, and suggest that in liquid ethane-1,2-diol most molecules are found in gauche conformation, with intramolecular hydrogen bond between the two hydroxyl groups. Intramolecular H-bonds are established in the mono-alkylated diol, but the interaction is weaker. The EDXD study also evidences strong intermolecular hydrogen-bond interactions, with short O···O correlations in both systems, while longer methyl-methyl interactions are found in 1,2-dimethoxy ethane. X-Ray studies are complemented by micro Raman investigations at room temperature and at 80°C, that confirm the conformational analysis predicted by X-Ray experiments and simulations.

Background In many African countries, clinical samples are not routinely tested for carbapenem-resistant bacteria, the resistance data remaining limited. Material and methods In March 2020 –June 2022, we collected extended spectrum β-lactamase (ESBL) -producing Enterobacterales (ESBL-PE) isolates from five hospitals in Burkina Faso. The species were identified using API20E and ESBL production confirmed by double-disc synergy test. Production of carbapenemases and AmpC-β-lactamases and phenotypic co-resistance were determined. Results Among the 473 ESBL-PE, 356 were ESBL- E. coli (ESBL-Ec) and 117 Klebsiella spp. (ESBL-K). Of the isolates, 5.3% were carbapenemase and 5.3% AmpC-β-lactamase positive Three types of carbapenemases were identified: 19 NDM, 3 OXA-48 like and 1 VIM. Two isolates produced both NDM and OXA48-like carbapenemases. Carbapenemase rates were highest among isolates in tertiary hospitals. Co-resistance rates were up to 85% for aminoglycosides, 90% for sulfonamides, 95% for fluoroquinolones and 25% for chloramphenicol, Fosfomycin resistance was 6% for ESBL-Ec and 49% for ESBL-K (49%). Conclusion Many ESBL-Ec and ESBL-K co-produced carbapenemases and/or AmpC-β-lactamases, at all healthcare levels and in various samples, with high co-resistance rates to non-betalactams. Carbapenem resistance is no longer rare, calling for testing in routine diagnostics, vigorous resistance surveillance system, and infection control within healthcare.

Cardiac fibrosis is a pathological process associated with development of heart failure. TGF-β and WNT signaling have been implicated in pathogenesis of cardiac fibrosis, however little is known about molecular cross-talk between these two pathways. The aim of this study was to examine the effect of exogenous canonical WNT3a and non-canonical WNT5a in TGF-β-activated human cardiac fibroblasts. We found that WNT3a and TGF-β induced -catenin-dependent response, whereas WNT5a prompted AP-1 activity. TGF-β triggered profibrotic signature in cardiac fibroblasts, and co-stimulation with WNT3a or co-activation of the β-catenin pathway with GSK3β inhibitor CHIR99021 enhanced collagen I and fibronectin production and development of active contractile stress fibers. In the absence of TGF-β, neither WNT3a nor CHIR99021 exerted profibrotic response. On a molecular level, in TGF-β-activated fibroblasts WNT3a enhanced phosphorylation of TAK1 and production and secretion of IL-11 but showed no effect on Smad pathway. Neutralization of IL-11 activity with the blocking anti-IL-11 antibody effectively reduced profibrotic response of cardiac fibroblasts activated with TGF-β and WNT3a. In contrast to canonical WNT3a, co-activation with non-canonical WNT5a suppressed TGF-β-induced production of collagen I. In conclusion, WNT/β-catenin signaling promotes TGF-β-mediated fibroblast-to-myofibroblast transition by enhancing IL-11 production. Thus, the uncovered mechanism broadens our knowledge on molecular basis of cardiac fibrogenesis and defines novel therapeutic targets for fibrotic heart diseases.

Biodiesel has several drawbacks, such as being prone to oxidation, having reduced stability, and having limited storage time. Antioxidants compatible with biodiesel are being used to address its drawbacks. Utilizing antioxidants effectively improves the quality of biodiesel. Enhancing the quality of biodiesel for use as a clean energy source benefits both the global economy and ecology. Therefore, we believe that our work will contribute to the advancement of the worldwide industry. The study used blends consisting of 20% biodiesel and 80% diesel fuel. Isatin-thiosemicarbazones were tested as additives in blends at a concentration of 3000 parts per million (ppm) using an oxifast device. Comparing them to the chemical antioxidant Trolox. FT-IR, DSC, and TGA were used to characterize these samples. DSC measured sample crystallization temperatures (Tc). Samples with antioxidants showed decreased values compared to the non-antioxidant diesel sample D100. Several DSC tests were conducted to determine the antioxidant strengths of various samples. The results showed that the FT-IR spectrum's antioxidant effect regions grow clearer with antioxidants. The extra antioxidant is effective. Biodiesel's oxidative stability improves with isatin-thiosemicarbazones at varying concentrations. The kinetics of thermal decomposition of isatin-thiosemicarbazones under non-isothermal conditions have been determined using the Kissinger, Ozawa, and Boswell techniques. The activation energies of compounds 1 and 2 were calculated 137–147 kJ mol^-1 and 173–183 kJ mol^-1, respectively.

This work aims to introduce a novel concept: the Riesz-Dunkl fractional derivatives, within the context of Dunkl type operators. A particularly noteworthy revelation is that when a specific parameter $\kappa$ equals zero, the Riesz-Dunkl fractional derivative smoothly reduces to both the well-known Riesz fractional derivative and the fractional second-order derivative. Furthermore, we introduce a new concept: the fractional Sobolev space. This space is defined and characterized using the versatile framework of the Dunkl transform.

Fourteen quinolizidine derivatives, structurally related to the alkaloids lupinine and cytisine and previously studied for other pharmacological aims, were presently tested for antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig heart tissues, and to assess calcium antagonism in comparison to amiodarone, lidocaine, procainamide, and quinidine. All compounds, but two, compared favorably with the reference drugs. Potent antiarrhythmic activity was observed for compounds (in increasing order) 4, 1, 6 and 5. The last compound N-(3,4,5-trimethoxybenzoyl)aminohomolupinane) was outstanding, exhibiting a nanomolar potency (EC50 = 0.017 µM) for the increase of threshold of ac-arrhythmia, and being devoid of antihypertensive activity against spontaneously hypertensive rats.

Human metapneumovirus is one of major causes of common cold among children, especially infants. Its key enzyme is RNA-dependent RNA-polymerase, which performs both replication and transcription, including capping and cap methylation. The goal of the work is to find possible inhibitors of RNA-dependent RNA-polymerase across the active compounds of Rosaceae plants. The candidates were selected by molecular docking to cap-transferring domain of RNA-polymerase (PDB ID: 4UCZ) in Autodock VINA. Among all the substances tested by docking, ellagic acid derivatives showed the most promising results (affinity values below -10 kcal/mol). Hence, they could be treated as possible candidate drugs against metapneumoviral infection after experimental examination. The main advantage of using these substances should be their low toxicity, which is quite uncommon for selective RNA polymerase inhibitors used in clinical practice. Occurrence of ellagic acid derivatives among the plants from Rosaceae family like raspberry could explain their effect during common cold.

We propose a methodology for the quantification of model risk in the context of credit derivatives pricing and CVA, where the uncertain or unmodelled parameter is often the correlation between rates and credit. We take the rates model to be Hull-White (normal) and the credit model to be Black-Karasinski (lognormal). We show how highly accurate analytic pricing formulae, hitherto unpublished, can be derived for CDS and extended to address instruments with defaultable Libor flows which may in addition be capped and/or floored. We also consider the pricing of a contingent CDS with an interest rate swap underlying. We derive explicit expressions showing how to good accuracy the dependence of model prices on the uncertain parameter(s) can be captured in analytic formulae which are readily amenable to computation without recourse to Monte Carlo or lattice-based computation. In so doing, we take into account the impact on model calibration of the uncertain (or unmodelled) parameter.

Cattle slurry is an important nitrogen source for maize on dairy farms. Slurry injection is an effective measure to reduce ammonia emissions after field application, but with higher risk of nitrous oxide emission than surface application. This study compared soil mineral nitrogen dynamics and nitrous oxide emissions with two ways of application. First, traditional injection at 25 cm spacing between rows followed by ploughing (called “non-placed slurry”), and second, injection using a new so-called goosefoot slurry injector that placed the slurry in ploughed soil as a c. 30 cm broad band at 10 cm depth below maize crop rows with 75 cm spacing (named “placed slurry”). Furthermore, the effect of treating slurry with the nitrification inhibitor 3,4-dimethylpyrazole phosphate (DMPP) in Vizura® was tested with both application methods. The field experiment was conducted on a sandy loam soil in a temperate climate. Both nitrous oxide emissions, and the dynamics of soil mineral nitrogen, were monitored for eight weeks after slurry application and seeding of maize using static chambers. The level of nitrous oxide emissions was higher with non-placed compared to placed slurry, mainly due to higher emissions during the first four weeks. That might be due to higher rates of nitrification rate and in turn stimulation of denitrification process. In both placed and non-placed slurry treatments, Vizura® caused higher soil ammonium concentrations and lower nitrate concentrations, particularly from 3 to 8 weeks after slurry application. The final level of soil nitrate was similar with and without the nitrification inhibitor, but higher with placed compared to non-placed slurry. Adding Vizura® to non-placed slurry reduced nitrous oxide emissions by 70 % when compared to placed slurry. Surprisingly, there was a non-significant trend towards higher cumulative emissions from placed slurry with the nitrification inhibitor compared to untreated slurry, which were due to higher emissions in the last part of the monitoring period (5-7 weeks after slurry application). Possibly degradation of the nitrification inhibitor, and nitrification activity inside the slurry band as the soil dried, promoted nitrous oxide emissions by this time. In summary, placement of untreated slurry in a broad band under maize seeds reduced nitrous oxide emissions compared to non-placed slurry with more soil contact. A comparable reduction was achieved by adding a nitrification inhibitor to non-placed slurry. The pattern of nitrous oxide emissions from placed slurry treated with the inhibitor was complex and requires more investigation.

Two ferrocene derivatives, namely, 1,2-(tetramethylene)-ferrocene and 1,2,1’,2’-bis(tetramethylene)-ferrocene, were synthesized in a four-step reaction sequence starting from ferrocene. Friedel-Craft acylation of ferrocene with succinic anhydride gave mono- or bis(3-carboxypropinoyl)ferrocene depending on the stoichiometry of succinic anhydride. The reduction of the keto groups to methylene, followed by ring-closing using trifluoroacetic anhydride gave 1,2-(α-ketotetramethylene)-ferrocene or 1,2,1’,2’-bis(α-ketotetramethylene)ferrocene. The diastereomeric mixture of the latter diketones was separated by column chromatography, characterized by single-crystal X-ray analysis, and assigned their stereochemistry. Reduction of the keto groups to methylene under Clemmensen conditions gave homoannular mono- or bis(tetramethylene) ferrocene derivatives. The molecular structure of 1,2-(tetramethylene)-ferrocene revealed that the ipso carbon atoms of the cyclopentadienyl group are 0.023(3) Å farther away from Fe(II) compared to the remaining three carbon atoms. Both complexes exhibit lower half-wave oxidation potentials than ferrocene, possibly due to the electron-releasing effects of the tetramethylene bridges.

Alzheimer’s disease is associated with prion-like aggregation of the amyloid β (Aβ) peptide and the subsequent accumulation of misfolded neurotoxic aggregates in the brain. Therefore, it is critical to clearly identify the factors that trigger the cascade of Aβ misfolding and aggregation. Numerous studies have pointed out the association between microorganisms and their virulence factors and Alzheimer’s disease; however, their exact mechanisms of action remain unclear. Recently, we discovered a new pathogenic role of bacterial extracellular DNA, triggering the formation of misfolded Tau aggregates. In this study, we investigated the possible role of DNA extracted from different bacterial and eukaryotic cells in triggering Aβ aggregation in vitro. Interestingly, we found that the extracellular DNA of some, but not all, bacteria is an effective trigger of Aβ aggregation. Furthermore, the acceleration of Aβ nucleation and elongation can vary based on the concentration of the bacterial DNA and the bacterial strain from which this DNA had originated. Our findings suggest that bacterial extracellular DNA might play a previously overlooked role in the Aβ protein misfolding associated with Alzheimer’s disease pathogenesis. Moreover, it highlights a new mechanism of how distantly localized bacteria can remotely contribute to protein misfolding and diseases associated with this process. These findings might lead to the use of bacterial DNA as a novel therapeutic target for the prevention and treatment of Alzheimer’s disease.

β-hydroxy β-methylbutyrate (HMB) is a bioactive metabolite formed from breakdown of the branched-chain amino acid leucine. Given the popularity of HMB supplements among different athletes, specifically, those who engage in regular resistance training, this review was performed to summarize current literature on some aspects of HMB supplementation that have received less attention. Because of the small number of published studies, it has not been possible to conclude the exact effects of HMB on cardiovascular parameters, oxidative stress and inflammatory markers. Thus, the interpretation of outcomes should be taken cautiously. However, the data presented here suggest that acute HMB supplementation may attenuate pro-inflammatory response following an intense resistance exercise in athletes. Also, the available findings collectively indicate that chronic HMB consumption in conjunction with resistance training has no more adaptive advantages associated with decreasing cardiovascular risk factors and oxidative stress markers. Taken together, there is clearly a need for further well-designed, longer duration studies to support these findings and determine whether HMB supplementation affects the adaptations induced by resistance training associated with body’s inflammatory condition, antioxidative defense system, and cardiovascular risk factors in humans.