Search Results (146)

Background/Objectives: The anti-Müllerian hormone (AMH) is a key biomarker of the ovarian reserve, correlating with ovarian follicle count, fertility outcomes, and menopause timing. Understanding its genetic determinants has broad implications for female reproductive health. However, prior genome-wide association studies (GWASs) have focused exclusively on women of European ancestry, limiting insights into diverse populations. Methods: We conducted a GWAS to identify genetic loci associated with circulating AMH levels in a sample of 1185 Samoan women from two independently recruited samples. Using a Cox mixed-effects model we accounted for AMH levels below detectable limits and meta-analysed the summary statistics using a fixed-effect model. To prioritize variants and genes, we used FUMA and performed colocalization and transcriptome-wide association analysis (TWAS). We also assessed whether any previously reported loci were replicated in our GWAS. Results: We identified eleven genome-wide suggestive loci, with the strongest signal at ARID3A (19-946163-G-C; p = 2.32 × 10⁻⁷) and replicated rs10093345 near EIF4EBP1. The gene-based testing revealed ARID3A and R3HDM4 as significant genes. Integrating GWAS results with expression quantitative trait loci via TWAS, we detected seven transcriptome-wide significant genes. The lead variant in ARID3A is in high linkage disequilibrium (r² = 0.79) with the known age-at-menopause variant 19-950694-G-A. Nearby KISS1R is a biologically plausible candidate gene that encodes the kisspeptin receptor, a regulator of ovarian follicle development linked to AMH levels. Conclusions: This study expands our understandings of AMH genetics by focusing on Samoan women. While these findings may be particularly relevant to Pacific Islanders, they hold broader implications for reproductive phenotypes such as the ovarian reserve, menopause timing, and polycystic ovary syndrome. Full article

Emerging evidence highlights the biological risks associated with electromagnetic fields (EMFs) generated by electronic devices. The toxic effects and mechanisms induced by exposure to EMFs on microglial cells and natural substances that inhibit them are limited to date. Here, we investigated whether exposure to 3.5 GHz EMF radiation, potentially generated by smartphones working in 5G communication or cooking using microwave ovens, affects the growth of BV2 mouse microglial cells and polydeoxyribonucleotide (PDRN), a DNA preparation derived from salmon sperm, inhibits it. Of note, exposure to 3.5 GHz EMF radiation for 2 h markedly inhibited the growth and triggered apoptosis in BV2 cells, characterized by the reduced number of surviving cells, increased genomic DNA fragmentation, increased reactive oxygen species (ROS) levels, and altered phosphorylation and expression levels of JNK-1/2, p38 MAPK, ERK-1/2, eIF-2α, and procaspase-9. Pharmacological inhibition studies revealed that JNK-1/2 and p38 MAPK activation and ROS generation were crucial for 3.5 GHz EMF-induced BV2 cytotoxicity. Of interest, PDRN effectively countered these effects by inhibiting the activation of JNK-1/2, p38 MAPK, and caspase-9, and the production of ROS, although it did not affect eIF-2 phosphorylation. In conclusion, this study is the first to report that PDRN protects against 3.5 GHz EMF-induced toxicities in BV2 microglial cells, and PDRN’s protective effects on 3.5 GHz EMF-induced BV2 cytotoxicity are mediated primarily by modulating ROS, JNK-1/2, p38 MAPK, and caspase-9. Full article

Guanidinoacetic acid (GAA) has been used in ruminant feeding, but it is still unclear whether the exogenous addition of methyl donors, such as methionine (Met), can enhance the effects of GAA. This study investigated the effects of dietary GAA alone or combined with Met on beef cattle growth performance and explored the underlying mechanisms via blood analysis, liver metabolomics, and transcriptomics. Forty-five Simmental bulls (453.43 ± 29.05 kg) were assigned to three groups for 140 days: CON (control), GAA (0.1% GAA), and GAM (0.1% GAA + 0.1% Met), where each group consisted of 15 bulls. Compared with the CON group, the average daily gain (ADG) and feed conversion efficiency (FCE) of the two feed additive groups were significantly increased, and the digestibility of neutral detergent fiber (NDF) was improved (p < 0.05). Among the three treatment groups, the GAM group showed a higher rumen total volatile fatty acids (TVFAs) content and digestibility of dry matter (DM) and crude protein (CP) in the beef cattle. The serum indices showed that the contents of indicators related to protein metabolism, lipid metabolism, and creatine metabolism showed different increases in the additive groups (p < 0.05). It is worth noting that the antioxidant indexes in the serum and liver tissues of beef cattle in the two additive groups were significantly improved (p < 0.05). The liver metabolites related to protein metabolism (e.g., L-asparagine, L-glutamic acid) and lipid metabolism (e.g., PC (17:0/0:0)) were elevated in two additive groups, where Met further enhanced the amino acid metabolism in GAM. In the two additive groups, transcriptomic profiling identified significant changes in the expression of genes associated with protein metabolism (including PIK3CD, AKT3, EIF4E, HDC, and SDS) and lipid metabolism (such as CD36, SCD5, ABCA1, APOC2, GPD2, and LPCAT2) in the hepatic tissues of cattle (p < 0.05). Overall, the GAA and Met supplementation enhanced the growth performance by improving the nutrient digestibility, serum protein and creatine metabolisms, antioxidant capacity, and hepatic energy and protein and lipid metabolisms. The inclusion of Met in the diet was shown to enhance the nutrient digestibility and promote more efficient amino acid metabolism within the liver of the beef cattle. Full article

Translation regulation is essential to the survival of hosts. Most translation initiation falls under the control of the mTOR pathway, which regulates protein production from mono-methyl-guanosine (m7G) cap mRNAs. However, mTOR does not regulate all translation; hosts and viruses alike employ alternative pathways, protein factors, and internal ribosome entry sites to bypass mTOR. Trimethylguanosine (TMG)-caps arise from hypermethylation of pre-existing m7G-caps by the enzyme TGS1 and are modifications known for snoRNA, snRNA, and telomerase RNA. New findings originating from HIV-1 research reveal that TMG-caps are present on mRNA and license translation via an mTOR-independent pathway. Research has identified TMG-capping of selenoprotein mRNAs, junD, TGS1, DHX9, and retroviral transcripts. TMG-mediated translation may be a missing piece for understanding protein synthesis in cells with little mTOR activity, including HIV-infected resting T cells and nonproliferating cancer cells. Viruses display a nuanced interface with mTOR and have developed strategies that take advantage of the delicate interplay between these translation pathways. This review covers the current knowledge of the TMG-translation pathway. We discuss the intimate relationship between metabolism and translation and explore how this is exploited by HIV-1 in the context of CD4+ T cells. We postulate that co-opting both translation pathways provides a winning strategy for HIV-1 to dictate the sequential synthesis of its proteins and balance viral production with host cell survival. Full article

Maize lethal necrosis (MLN) is a significant threat to food security in Sub-Saharan Africa (SSA), with limited commercial inbred lines displaying tolerance. This study analyzed the transcriptomes of four commercially used maize inbred lines and a non-adapted inbred line, all with varying response levels to MLN. RNA-Seq revealed differentially expressed genes in response to infection by maize chlorotic mottle virus (MCMV) and sugarcane mosaic virus (SCMV), the causative agents of MLN. Key findings included the identification of components of the plant innate immune system, such as differentially regulated R genes (mainly LRRs), and activation/deactivation of virus resistance pathways, including RNA interference (RNAi) via Argonaute (AGO), Dicer-like proteins, and the ubiquitin–proteasome system (UPS) via RING/U-box and ubiquitin ligases. Genes associated with redox signaling, WRKY transcription factors, and cell modification were also differentially expressed. Additionally, the expression of translation initiation and elongation factors, eIF4E and eIF4G, correlated with the presence of MLN viruses. These findings provide valuable insights into the molecular mechanisms of MLN resistance and highlight potential gene candidates for engineering or selecting MLN-resistant maize germplasm for SSA. Full article

Non-healing diabetic foot ulcers (DFUs) not only significantly increase morbidity and mortality but also cost a lot and drain healthcare resources. Persistent inflammation, decreased angiogenesis, and altered extracellular matrix remodeling contribute to delayed healing or non-healing. Recent studies suggest an increasing trend of DFUs in diabetes patients, and non-healing DFYs increase the incidence of amputation. Despite the current treatment with offloading, dressing, antibiotics use, and oxygen therapy, the risk of amputation persists. Thus, there is a need to understand the molecular and cellular factors regulating healing in DFUs. The ongoing research based on proteomics and transcriptomics has predicted multiple potential targets, but there is no definitive therapy to enhance healing in chronic DFUs. Increased or decreased expression of various proteins encoded by genes, whose expression transcriptionally and post-transcriptionally is regulated by transcription factors (TFs) and microRNAs (miRs), regulates DFU healing. For this study, RNA sequencing was conducted on 20 DFU samples of ulcer tissue and non-ulcerated nearby healthy tissues. The IPA analysis revealed various activated and inhibited transcription factors and microRNAs. Further network analysis revealed interactions between the TFs and miRs and the molecular targets of these TFs and miRs. The analysis revealed 30 differentially expressed transcription factors (21 activated and 9 inhibited), two translational regulators (RPSA and EIF4G2), and seven miRs, including mir-486, mir-324, mir-23, mir-186, mir-210, mir-199, and mir-338 in upstream regulators (p < 0.05), while causal network analysis (p < 0.05) revealed 28 differentially expressed TFs (19 activated and 9 inhibited), two translational regulators (RPSA and EIF4G2), and five miRs including mir-155, mir-486, mir-324, mir-210, and mir-1225. The protein–protein interaction analysis revealed the interaction of various novel proteins with the proteins involved in regulating DFU pathogenesis and healing. The results of this study highlight many activated and inhibited novel TFs and miRs not reported in the literature so far, as well as the targeted molecules. Since proteins are the functional units during biological processes, alteration of gene expression may result in different proteoforms and protein species, making the wound microenvironment a complex protein interaction (proteome complexity). Thus, investigating the effects of these TFs and miRs on protein expression using proteomics and combining these results with transcriptomics will help advance research on DFU healing and delineate potential therapeutic strategies. Full article

Ribavirin and its analogues exhibit an in vitro antiproliferative effect in cancer cells. In this work, we studied the biological activities of a number of alkyl/aryloxymethyl derivatives of ribavirin’s aglycon—1,2,4-triazole-3-carboxamide. Alkyl/arylxymethyl derivatives of 1,2,4-triazole-3-carboxamide with substitutions at the fifth or first position of the triazole ring, were synthesized and their antiproliferative and antimicrobial effects were assessed. For both series, the presence of an antiproliferative effect was investigated, and 1-alkyl/aryloxymethyl derivatives were shown an antimicrobial potential against a Gram-positive bacteria Micrococcus luteus and Gram-negative bacterium Pseudomonas aeruginosa. The obtained results showed that the n-decyloxymethyl derivatives induced leukemia cell death at low micromolar concentrations. We confirmed that n-decyloxymethyl derivatives of ribavirin inhibited the cell cycle progression and induced an accumulation of leukemia cells in the subG1-phase. The molecular docking results suggest that alkyl/aryloxymethyl derivatives may act by inhibiting translation initiation, due to interference with eIF4E assembly. The outcome results revealed that active derivatives (1- or 5-n-decyloxymethyl-1,2,4-triazole-3-carboxamides) can be considered as a lead compound for anticancer treatments. Full article

The chirality of a chemical differentiates it from its mirror-image counterpart. This unique property has significant implications in chemistry, biology, and drug discovery, where chiral chemicals display high selectivity and activity in achieving target specificity and reducing attrition rates in drug development. Stress granules (SGs) are dynamic assemblies of proteins and RNA that form in the cytoplasm of cells under stress conditions. Modulating their formation or disassembly could offer a novel approach to treating a wide range of diseases. This has led to significant interest in SGs as potential therapeutic targets. This study examined the NTF2-like domain of G3BP1 as a possible target for SG modulation. Molecular docking was used to simulate the interactions of compounds with the domain, and a potential candidate with a chiral structure was identified. The experiments showed that the compound induced the formation of SG-like granules. Importantly, the ability of this compound to modulate SG offers valuable insights into a new mechanism underlying the dynamics and promoting the assembly of SGs, and this new mechanism, in turn, holds potential for the development of drugs with diverse mechanisms of action and potentially synergistic effects. Full article

Our examination of RNA helicases for effects on HIV-1 protein production and particle assembly identified Rocaglamide (RocA), a known modulator of eIF4A1 function, as an inhibitor of HIV-1 replication in primary CD4⁺ T cells and three cell systems. HIV-1 attenuation by low-nM RocA doses was associated with reduced viral particle formation without a marked decrease in Gag production. Rather, the co-localization of Gag and HIV-1 genomic RNA (gRNA) assemblies was impaired by RocA treatment in a reversible fashion. Ribonucleoprotein (RNP) immunoprecipitation studies recapitulated the loss of Gag-gRNA assemblies upon RocA treatment. Parallel biophysical studies determined that neither RocA nor eIF4A1 independently affected the ability of Gag to interact with viral RNA, but together, they distorted the structure of the HIV-1 RNP visualized by electron microscopy. Taken together, several lines of evidence indicate that RocA induces stable binding of eIF4A1 onto the viral RNA genome in a manner that interferes with the ordered assembly of Gag along Gag-gRNA assemblies required to generate infectious virions. Full article

Caliciviruses have positive-sense RNA genomes, typically with short 5′-untranslated regions (5′UTRs) that precede the long open reading frame 1 (ORF1). Exceptionally, some avian caliciviruses have long 5′UTRs containing a picornavirus-like internal ribosomal entry site (IRES), which was likely acquired by horizontal gene transfer. Here, we identified numerous additional avian calicivirus genomes with IRESs, predominantly type 2, and determined that many of these genomes contain a ~200–300 codon-long ORF (designated ORF1*) that overlaps the 5′-terminal region of ORF1. The activity of representative type 2 IRESs from grey teal calicivirus (GTCV) and Caliciviridae sp. isolate yc-13 (RaCV1) was confirmed by in vitro translation. Toeprinting showed that in cell-free extracts and in vitro reconstituted reactions, ribosomal initiation complexes assembled on the ORF1* initiation codon and at one or two AUG codons in ORF1 at the 3′-border and/or downstream of the IRES. Initiation at all three sites required eIF4A and eIF4G, which bound to a conserved region of the IRES; initiation on the ORF1* and principal ORF1 initiation codons involved eIF1/eIF1A-dependent scanning from the IRES’s 3′-border. Initiation on these IRESs was enhanced by the IRES trans-acting factors (ITAFs) Ebp1/ITAF₄₅, which bound to the apical subdomain Id of the IRES, and PTB (GTCV) or PCBP2 (RaCV1). Full article

(1) Background: Cervical cancer, caused mainly by high-risk Human Papillomavirus (hrHPV), is a significant global health issue. While a Pap smear remains a reliable method for early detection, identifying new biomarkers to stratify the risk is crucial. For this purpose, extensive research has been conducted on detecting DNA methylation. (2) Methods: This cross-sectional study aimed to assess the expression levels of EIF4G3 and SF3B1 in precursor lesions and cervical tumor tissues through qRT-PCR and evaluate the methylation status of their promoters through bisulfite conversion. (3) Results: Both genes showed similar mRNA expression patterns, with the highest levels observed in squamous cell carcinoma (SCC) samples (p < 0.0001). Additionally, methylation analysis indicated increased percentages in the control group for both factors. Notably, the expression levels of both genes were inversely correlated with promoter methylation (EIF4G3—p = 0.0016; SF3B1—p < 0.0001). (4) Conclusions: Regarding the methylation pattern for both genes, we observe a decreasing trend from NILM to SCC patients. Therefore, we concluded that the decrease in methylation at the promoter level for both genes could be an indicator of abnormal cytology. Full article

The best-characterized functional motifs of the potyviral Helper-Component protease (HC-Pro) responding for aphid transmission, RNA silencing suppression, movement, symptom development, and replication are gathered in this review. The potential cellular protein targets of plant virus proteases remain largely unknown despite their multifunctionality. The HC-Pro catalytic domain, as a cysteine protease, autoproteolytically cleaves the potyviral polyproteins in the sequence motif YXVG/G and is not expected to act on host targets; however, 146 plant proteins in the Viridiplantae clade containing this motif were searched in the UniProtKB database and are discussed. On the other hand, more than 20 interactions within the entire HC-Pro structure are known. Most of these interactions with host targets (such as the 20S proteasome, methyltransferase, transcription factor eIF4E, and microtubule-associated protein HIP2) modulate the cellular environments for the benefit of virus accumulation or contribute to symptom severity (interactions with MinD, Rubisco, ferredoxin) or participate in the suppression of RNA silencing (host protein VARICOSE, calmodulin-like protein). On the contrary, the interaction of HC-Pro with triacylglycerol lipase, calreticulin, and violaxanthin deepoxidase seems to be beneficial for the host plant. The strength of these interactions between HC-Pro and the corresponding host protein vary with the plant species. Therefore, these interactions may explain the species-specific sensitivity to potyviruses. Full article

Coxsackievirus B3 (CVB3) is a positive single-strand RNA genome virus which belongs to the enterovirus genus in the picornavirus family, like poliovirus. It is one of the most prevalent pathogens that cause myocarditis and pancreatitis in humans. However, a suitable therapeutic medication and vaccination have yet to be discovered. Caboxamycin, a benzoxazole antibiotic isolated from the culture broth of the marine strain Streptomyces sp., SC0774, showed an antiviral effect in CVB3-infected HeLa cells and a CVB3-induced myocarditis mouse model. Caboxamycin substantially decreased CVB3 VP1 production and cleavage of translation factor eIF4G1 from CVB3 infection. Virus-positive and -negative strand RNA was dramatically reduced by caboxamycin treatment. In addition, the cleavage of the pro-apoptotic molecules BAD, BAX, and caspase3 was significantly inhibited by caboxamycin treatment. In animal experiments, the survival rate of mice was improved following caboxamycin treatment. Moreover, caboxamycin treatment significantly decreased myocardial damage and inflammatory cell infiltration. Our study showed that caboxamycin dramatically suppressed cardiac inflammation and mouse death. This result suggests that caboxamycin may be suitable as a potential antiviral drug for CVB3. Full article

We aimed to identify serum exosomal microRNAs (miRNAs) associated with the transition from atrial fibrillation (AF) to sinus rhythm (SR) and investigate their potential as biomarkers for the early recurrence of AF within three months post-treatment. We collected blood samples from eight AF patients at Chang Gung Memorial Hospital in Taiwan both immediately before and within 14 days following rhythm control treatment. Exosomes were isolated from these samples, and small RNA sequencing was performed. Using DESeq2 analysis, we identified nine miRNAs (16-2-3p, 22-3p, 23a-3p, 23b-3p, 125a-5p, 328-3p, 423-5p, 504-5p, and 582-3p) associated with restoration to SR. Further analysis using the DIABLO model revealed a correlation between the decreased expression of miR-125a-5p and miR-328-3p and the early recurrence of AF. Furthermore, early recurrence is associated with a longer duration of AF, presumably indicating a more extensive state of underlying cardiac remodeling. In addition, the reads were mapped to mRNA sequences, leading to the identification of 14 mRNAs (AC005041.1, ARHGEF12, AMT, ANO8, BCL11A, DIO3OS, EIF4ENIF1, G2E3-AS1, HERC3, LARS, NT5E, PITX1, SLC16A12, and ZBTB21) associated with restoration to SR. Monitoring these serum exosomal miRNA and mRNA expression patterns may be beneficial for optimizing treatment outcomes in AF patients. Full article

Oxidative stress is implicated in the pathogenesis of various acute disorders including ischemia/reperfusion injury, ultraviolet/radiation burn, as well as chronic disorders such as dyslipidemia, atherosclerosis, diabetes mellitus, chronic renal disease, and inflammatory bowel disease (IBD). However, the precise mechanism involved remains to be clarified. We formerly identified a novel apoptosis-inducing humoral protein, in a hypoxia/reoxygenation-conditioned medium of cardiac myocytes, which proved to be 69th tyrosine-sulfated eukaryotic translation initiation factor 5A (eIF5A). We named this novel tyrosine-sulfated secreted form of eIF5A Oxidative Stress-Responsive Apoptosis-Inducing Protein (ORAIP). To investigate the role of ORAIP in a dextran sulfate sodium (DSS)-induced murine model of ulcerative colitis (UC), we analyzed the effects of in vivo treatment with anti-ORAIP neutralizing monoclonal antibody (mAb) on the DSS-induced disease exacerbation. The body weight in anti-ORAIP mAb-treated group was significantly heavier than that in a mouse IgG-treated control group on day 8 of DSS-treatment ((85.21 ± 1.03%) vs. (77.38 ± 2.07%); (mean ± SE0, n = 5 each, p < 0.01, t-test). In vivo anti-ORAIP mAb-treatment also significantly suppressed the shortening of colon length as well as Disease Activity Index (DAI) score ((5.00 ± 0.44) vs. (8.20 ± 0.37); (mean ± SE), n = 5 each, p < 0.001, t-test) by suppressing inflammation of the rectal tissue and apoptosis of intestinal mucosal cells. These data reveal the pivotal role of ORAIP in DSS-induced oxidative stress involved in an animal model of UC. Full article