Search Results (21,223)

Zinc (Zn) deficiency represents a significant global concern, affecting both plant and human health, particularly in regions with Zn-depleted soils. Agronomic biofortification strategies, such as the application of Zn fertilizers, offer a cost-effective approach to increase Zn levels in crops. This study aimed to assess the efficacy of soil and foliar Zn biofortification, applied as an aqueous solution of 0.5% zinc sulphate (ZnSO₄·7H₂O), on triticale (x Triticosecale) grown under Mediterranean conditions. The study was conducted over two growing seasons (2017/18 and 2018/19) in southern Spain, evaluating the effects on biomass yield; forage quality, including crude protein, Van Soest detergent fiber, organic matter digestibility, and relative forage value; and nutrient accumulation. Soil treatment consisted in the application of 50 kg of ZnSO₄·7H₂O ha⁻¹ solely at the beginning of the first campaign to assess the residual effect on the second year. In contrast, the foliar treatment consisted of two applications of 4 kg of ZnSO₄·7H₂O ha⁻¹ per campaign, one at the beginning of tillering and the other at the appearance of the first node. The foliar application increased the Zn content of the forage to adequate levels, while the soil application resulted in a 33% increase in biomass production, which is particularly beneficial for farmers. Overall quality was favored by the combined soil + foliar application, and no adverse antagonistic effects on other nutrients were detected. Instead, a synergistic interaction between Se and Zn was observed, which improved the efficacy of this important micronutrient for livestock and human wellbeing. Full article

Extended synaptotagmins (E-Syts) are endoplasmic reticulum (ER)-associated proteins that facilitate the tethering of the ER to the plasma membrane (PM), participating in lipid transfer between the membranes and supporting the Orai1–STIM1 interaction at ER–PM junctions. Orai1 and STIM1 are the core proteins of store-operated Ca²⁺ entry (SOCE), a major mechanism for Ca²⁺ influx that regulates a variety of cellular functions. Aberrant modulation of SOCE in cells from different types of cancer has been reported to underlie the development of several tumoral features. Here we show that estrogen receptor-positive (ER+) breast cancer MCF7 and T47D cells and triple-negative breast cancer (TNBC) MDA-MB-231 cells overexpress E-Syt1 and E-Syt2 at the protein level; the latter is also overexpressed in the TNBC BT20 cell line. E-Syt1 and E-Syt2 knockdown was without effect on SOCE in non-tumoral MCF10A breast epithelial cells and ER+ T47D breast cancer cells; however, SOCE was significantly attenuated in ER+ MCF7 cells and TNBC MDA-MB-231 and BT20 cells upon transfection with siRNA E-Syt1 or E-Syt2. Consistent with this, E-Syt1 and E-Syt2 knockdown significantly reduced cell migration and viability in ER+ MCF7 cells and the TNBC cells investigated. To summarize, E-Syt1 and E-Syt2 play a relevant functional role in breast cancer cells. Full article

Dynamic wrinkle reduction continues to challenge aesthetic dermatology, predominantly addressed through Botulinumtoxin (Botox) injections. Despite Botox’s robust efficacy with up to an 80% reduction in wrinkle visibility within just one week, its invasive administration and specific mechanism of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex inhibition prompt the exploration of safer, non-invasive alternatives. This review critically assesses recent innovations in non-invasive effects, with a focus on peptides and botanical extracts that exhibit a diverse array of mechanisms including SNARE complex inhibition, modulation of calcium and sodium channels, and interactions with acetylcholine receptors, contributing to their effectiveness in muscle relaxation on dynamic wrinkle approaches. Noteworthy peptides such as Argireline and SYN-Ake replicate the neuromodulatory effects of Botox, achieving up to a 52% reduction in wrinkles within four weeks without injections. Moreover, botanical extracts meet the rising demand for clean beauty solutions by enhancing skin elasticity and health through gentle yet potent mechanisms. However, the main concern with peptides is their low absorption rate, with only six clinical validations regarding Botox-like peptide anti-wrinkle efficacy available. These advancements not only deepen our understanding of cosmetic dermatology but also significantly influence market dynamics and consumer behavior, underscoring their pivotal role in redefining the future landscape of anti-aging effects. Full article

Entamoeba histolytica is the protozoan causative of human amoebiasis. The EhADH adhesin (687 aa) is a protein involved in tissue invasion, phagocytosis and host-cell lysis. EhADH adheres to the prey and follows its arrival to the multivesicular bodies. It is an accessory protein of the endosomal sorting complexes required for transport (ESCRT) machinery. Here, to study the role of different parts of EhADH during virulence events, we produced trophozoites overexpressing the three domains of EhADH, Bro1 (1–400 aa), Linker (246–446 aa) and Adh (444–687 aa) to evaluate their role in virulence. The TrophozBro1_1–400 slightly increased adherence and phagocytosis, but these trophozoites showed a higher ability to destroy cell monolayers, augment the permeability of cultured epithelial cells and mouse colon, and produce more damage to hamster livers. The TrophozLinker_226–446 also increased the virulence properties, but with lower effect than the TrophozBro1_1–400. In addition, this fragment participates in cholesterol transport and GTPase binding. Interestingly, the TrophozAdh_444–687 produced the highest effect on adherence and phagocytosis, but it poorly influenced the monolayers destruction; nevertheless, they augmented the colon and liver damage. To identify the protein partners of each domain, we used recombinant peptides. Pull-down assays and mass spectrometry showed that Bro1 domain interplays with EhADH, Gal/GalNAc lectin, EhCPs, ESCRT machinery components and cytoskeleton proteins. While EhADH, ubiquitin, EhRabB, EhNPC1 and EhHSP70 were associated to the Linker domain, and EhADH, EhHSP70, EhPrx and metabolic enzymes interacted to the Adh domain. The diverse protein association confirms that EhADH is a versatile molecule with multiple functions probably given by its capacity to form distinct molecular complexes. Full article

The high rate of rejection and failure of orthopedic implants is primarily attributed to incomplete osseointegration and stress at the implant-to-bone interface due to significant differences in the mechanical properties of the implant and the surrounding bone. Various surface treatments have been developed to enhance the osteoconductive properties of implants. The aim of this work was the in vitro characterization of titanium alloy modified with a nanocrystalline hydroxyapatite surface layer in relative comparison to unmodified controls. This investigation focused on the behavior of the surface treatment in relation to the physiological environment. Moreover, the osteogenic response of human osteoblasts and adipose stem cells was assessed. Qualitative characterization of cellular interaction was performed via confocal laser scanning microscopy focusing on the cell nuclei and cytoskeletons. Filipodia were assessed using scanning electron microscopy. The results highlight that the HA treatment promotes protein adhesion as well as gene expression of osteoblasts and stem cells, which is relevant for the inorganic and organic components of the extracellular matrix and bone. In particular, cells grown onto HA-modified titanium alloy are able to promote ECM production, leading to a high expression of collagen I and non-collagenous proteins, which are crucial for regulating mineral matrix formation. Moreover, they present an impressive amount of filipodia having long extensions all over the test surface. These findings suggest that the HA surface treatment under investigation effectively enhances the osteoconductive properties of Ti6Al4V ELI. Full article

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19 and responsible for the global coronavirus pandemic which started in 2019. Despite exhaustive efforts to trace its origins, including potential links with pangolins and bats, the precise origins of the virus remain unclear. Bats have been recognized as natural hosts for various coronaviruses, including the Middle East respiratory coronavirus (MERS-CoV) and the SARS-CoV. This study presents a comparative analysis of the SARS-CoV-2 nucleocapsid protein (N) interactome in human and bat cell lines. We identified approximately 168 cellular proteins as interacting partners of SARS-CoV-2 N in human cells and 196 cellular proteins as interacting partners with this protein in bat cells. The results highlight pathways and events that are both common and unique to either bat or human cells. Understanding these interactions is crucial to comprehend the reasons behind the remarkable resilience of bats to viral infections. This study provides a foundation for a deeper understanding of host–virus interactions in different reservoirs. Full article

A transcriptome-wide association study (TWAS) was conducted on genome-wide association study (GWAS) summary statistics of malignant melanoma of skin (UK Biobank dataset) and The Cancer Genome Atlas-Skin Cutaneous Melanoma (TCGA-SKCM) gene expression weights to identify melanoma susceptibility genes. The GWAS included 2465 cases and 449,799 controls, while the gene expression testing was conducted on 103 cases. Afterward, a gene enrichment analysis was applied to identify significant TWAS associations. The melanoma’s gene–microRNA (miRNA) regulatory network was constructed from the TWAS genes and their corresponding miRNAs. At last, a disease enrichment analysis was conducted on the corresponding miRNAs. The TWAS detected 27 genes associated with melanoma with p-values less than 0.05 (the top three genes are LOC389458 (RBAK), C16orf73 (MEIOB), and EIF3CL). After the joint/conditional test, one gene (AMIGO1) was dropped, resulting in 26 significant genes. The Gene Ontology (GO) biological process associated the extended gene set (76 genes) with protein K11-linked ubiquitination and regulation of cell cycle phase transition. K11-linked ubiquitin chains regulate cell division. Interestingly, the extended gene set was related to different skin cancer subtypes. Moreover, the enriched pathways were nsp1 from SARS-CoV-2 that inhibit translation initiation in the host cell, cell cycle, translation factors, and DNA repair pathways full network. The gene-miRNA regulatory network identified 10 hotspot genes with the top three: TP53, BRCA1, and MDM2; and four hotspot miRNAs: mir-16, mir-15a, mir-125b, and mir-146a. Melanoma was among the top ten diseases associated with the corresponding (106) miRNAs. Our results shed light on melanoma pathogenesis and biologically significant molecular interactions. Full article

Amaranthus retroflexus L. (redroot pigweed) is one of the most problematic weeds in maize, sugar beet, vegetables, and soybean crop fields in Europe. Two pigweed amaranth biotypes (R1 and R2) from the Czech Republic resistant to photosystem II (PSII)-inhibiting herbicides were analyzed in this study. This study aimed to identify the genetic mechanisms that underlie the resistance observed in the biotypes. Additionally, we also intended to establish the use of chlorophyll fluorescence measurement as a rapid and reliable method for confirming herbicide resistance in this weed species. Both biotypes analyzed showed high resistance factors in a dose–response study and were thus confirmed to be resistant to PSII-inhibiting herbicides. A sequence analysis of the D1 protein revealed a well-known Ser-Gly substitution at amino acid position 264 in both biotypes. Molecular docking studies, along with the wild-type and mutant D1 protein’s secondary structure analyses, revealed that the S264G mutation did not reduce herbicide affinity but instead indirectly affected the interaction between the target protein and the herbicides. The current study identified the S264G mutation as being responsible for conferring herbicide resistance in the pigweed amaranth biotypes. These findings can provide a strong basis for future studies that might use protein structure and mutation-based approaches to gain further insights into the detailed mechanisms of resistance in this weed species. In many individuals from both biotypes, resistance at a very early stage (BBCH10) of plants was demonstrated several hours after the application of the active ingredients by the chlorophyll fluorescence method. The effective PS II quantum yield parameter can be used as a rapid diagnostic tool for distinguishing between sensitive and resistant plants on an individual level. This method can be useful for identifying herbicide-resistant weed biotypes in the field, which can help farmers and weed management practitioners develop more effective weed control tactics. Full article

Cell-to-cell communication is fundamental to the organization and functionality of multicellular organisms. Intercellular signals orchestrate a variety of cellular responses, including gene expression and protein function changes, and contribute to the integrated functions of individual tissues. Dictyostelium discoideum is a model organism for cell-to-cell interactions mediated by chemical signals and multicellular formation mechanisms. Upon starvation, D. discoideum cells exhibit coordinated cell aggregation via cyclic adenosine 3′,5′-monophosphate (cAMP) gradients and chemotaxis, which facilitates the unicellular-to-multicellular transition. During this process, the calcium signaling synchronizes with the cAMP signaling. The resulting multicellular body exhibits organized collective migration and ultimately forms a fruiting body. Various signaling molecules, such as ion signals, regulate the spatiotemporal differentiation patterns within multicellular bodies. Understanding cell-to-cell and ion signaling in Dictyostelium provides insight into general multicellular formation and differentiation processes. Exploring cell-to-cell and ion signaling enhances our understanding of the fundamental biological processes related to cell communication, coordination, and differentiation, with wide-ranging implications for developmental biology, evolutionary biology, biomedical research, and synthetic biology. In this review, I discuss the role of ion signaling in cell motility and development in D. discoideum. Full article

Metformin (MTF) is the only biguanide included in the World Health Organization’s list of essential medicines; representing a widespread drug in the management of diabetes mellitus. With its accessibility and affordability being one of its biggest assets, it has become the target of interest for many trying to find alternative treatments for varied pathologies. Over time, an increasing body of evidence has shown additional roles of MTF, with unexpected interactions of benefit in other diseases. Metformin (MTF) holds significant promise in mitigating ischemia-reperfusion injury (IRI), particularly in the realm of organ transplantation. As acceptance criteria for organ transplants expand, IRI during the preservation phase remain a major concern within the transplant community, prompting a keen interest in MTF’s effects. Emerging evidence suggests that administering MTF during reperfusion may activate the reperfusion injury salvage kinase (RISK) pathway. This pathway is pivotal in alleviating IRI in transplant recipients, potentially leading to improved outcomes such as reduced rates of organ rejection. This review aims to contextualize MTF historically, explore its current uses, pharmacokinetics, and pharmacodynamics, and link these aspects to the pathophysiology of IRI to illuminate its potential future role in transplantation. A comprehensive survey of the current literature highlights MTF’s potential to recondition and protect against IRI by attenuating free radical damage, activating AMP-activated protein kinase to preserve cellular energy and promote repair, as well as directly reducing inflammation and enhancing microcirculation. Full article

Background: This study was part of a larger comprehensive project (BIOACID) addressing the physiological resilience of Polar cod, Boreogadus saida, to ocean acidification and global warming and aimed to unravel underlying molecular mechanisms of the observed physiological responses. Methods: Fish were acclimated long-term to three CO₂ concentrations comprising control conditions (390 ppm) and two projected climate scenarios (780 ppm and 1170 ppm). Each CO₂ treatment was combined with four temperatures: 0, 3, 6, and 8 °C. Here, we focused on the hepatic transcriptomic profiles from these previously physiologically characterized fish. Results: Generally, we did not detect signs of a classical stress response. Consistent with functional observations, warming induced much stronger molecular responses compared to elevated PCO₂, but an interaction between both factors existed to some extent. Gene ontology analysis revealed a strong response in lipid, amino acid, and protein metabolism. With increasing temperature, we observed a shift away from lipid metabolism, while carbohydrate metabolic pathways remained stable. Conclusions: Although we found Polar cod to be quite resilient to ocean acidification, temperature will remain a critical parameter for this valuable Arctic keystone species, and the question remains as to whether the observed acclimation strategies can be implemented in its natural habitat, especially when food supply is limited. Full article

The melanocortin-4 receptor (MC4R) is a key player in the hypothalamic leptin–melanocortin pathway that regulates satiety and hunger. MC4R belongs to the G protein-coupled receptors (GPCRs), which are known to form heterodimers with other membrane proteins, potentially modulating receptor function or characteristics. Like MC4R, thyroid hormones (TH) are also essential for energy homeostasis control. TH transport across membranes is facilitated by the monocarboxylate transporter 8 (MCT8), which is also known to form heterodimers with GPCRs. Based on the finding in single-cell RNA-sequencing data that both proteins are simultaneously expressed in hypothalamic neurons, we investigated a putative interplay between MC4R and MCT8. We developed a novel staining protocol utilizing a fluorophore-labeled MC4R ligand and demonstrated a co-localization of MC4R and MCT8 in human brain tissue. Using in vitro assays such as BRET, IP1, and cAMP determination, we found that MCT8 modulates MC4R-mediated phospholipase C activation but not cAMP formation via a direct interaction, an effect that does not require a functional MCT8 as it was not altered by a specific MCT8 inhibitor. This suggests an extended functional spectrum of MCT8 as a GPCR signaling modulator and argues for the investigation of further GPCR-protein interactions with hitherto underrepresented physiological functions. Full article

Members of the LGD/CC2D1 protein family contain repeats of the family-defining DM14 domains. Via this domain, they interact with members of the CHMP family, which are essential for the ESCRT machinery-mediated formation of intraluminal vesicles during endosome maturation. Here, we investigate the requirement of the DM14 domains for the function of Lgd in detail. We found that although both odd-numbered DM14s can act in a functionally redundant manner, the redundancy is not complete and both contribute to the full function of Lgd. Our analysis indicates that some of the AAs that form the KARRxxR motif of the onDM14s are not exchangeable by similarly charged AAs without loss of function, indicating that they not only provide charge, but also fulfil structural roles. Furthermore, we show that the region of Lgd between DM14-4 and the C2 domain as well as its C-terminal region to the C2 domain are important for protein stability/function. Moreover, we analysed the importance of AAs that are conserved in all DM14 domains. Finally, our analysis of the C. elegans ortholog of Lgd revealed that it has only one DM14 domain that is functionally equivalent to the onDM14s. Altogether, the results further the understanding of how Lgd family members regulate the ESCRT machinery. Full article

Aberrant estrogen receptor (ERα) signaling mediates detrimental effects of tamoxifen including drug resistance and endometrial hyperplasia. ERα36, an alternative isoform of ERα, contributes to these effects. We have demonstrated that CK2 modulates ERα expression and function in breast cancer (BCa). Here, we assess if CX-4945 (CX), a clinical stage CK2 inhibitor, can disrupt ERα66 and ERα36 signaling in BCa. Using live cell imaging, we assessed the antiproliferative effects of CX in tamoxifen-sensitive and tamoxifen-resistant BCa cells in monolayer and/or spheroid cultures. CX-induced alterations in ERα66 and ERα36 mRNA and protein expression were assessed by RT-PCR and immunoblot. Co-immunoprecipitation was performed to determine the differential interaction of ERα isoforms with HSP90 and CK2 upon CX exposure. CX caused concentration-dependent decreases in proliferation in tamoxifen-sensitive MCF-7 and tamoxifen-resistant MCF-7 Tam1 cells and significantly repressed spheroid growth in 3D models. Additionally, CX caused dramatic decreases in endogenous or exogenously expressed ERα66 and ERα36 protein. Silencing of CK2β, the regulatory subunit of CK2, resulted in destabilization and decreased proliferation, similar to CX. Co-immunoprecipitation demonstrated that ERα66/36 show CK2 dependance for interaction with molecular chaperone HSP90. Our findings show that CK2 functions regulate the protein stability of ERα66 and ERα36 through a mechanism that is dependent on CK2β subunit and HSP90 chaperone function. CX may be a component of a novel therapeutic strategy that targets both tamoxifen-sensitive and tamoxifen-resistant BCa, providing an additional tool to treat ERα-positive BCa. Full article

Multiple sclerosis (MS) is a chronic disease characterized by inflammation and neurodegeneration of the central nervous system. Despite the significant role of oxidative stress in the pathogenesis of MS, its precise molecular mechanisms remain unclear. This study utilized microarray datasets from the GEO database to analyze differentially expressed oxidative-stress-related genes (DE-OSRGs), identifying 101 DE-OSRGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicate that these genes are primarily involved in oxidative stress and immune responses. Through protein–protein interaction (PPI) network, LASSO regression, and logistic regression analyses, four genes (MMP9, NFKBIA, NFKB1, and SRC) were identified as being closely related to MS. A diagnostic prediction model based on logistic regression demonstrated good predictive power, as shown by the nomogram curve index and DAC results. An immune-cell infiltration analysis using CIBERSORT revealed significant correlations between these genes and immune cell subpopulations. Abnormal oxidative stress and upregulated expression of key genes were observed in the blood and brain tissues of EAE mice. A molecular docking analysis suggested strong binding potentials between the proteins of these genes and several drug molecules, including isoquercitrin, decitabine, benztropine, and curcumin. In conclusion, this study identifies and validates potential diagnostic biomarkers for MS, establishes an effective prediction model, and provides new insights for the early diagnosis and personalized treatment of MS. Full article