Search Results (1,633)

Aim: Finding innovative paraclinical parameters is necessary for advancing clinical research, in obstetrics and gynecology for subjective symptoms such as pain, especially in patients with a weakened immune system, following, for example, different obstetrical and gynecological surgeries. The purpose of this study was to analyze if genetic markers can correlate with the postoperative outcome and surgical results in obstetrics and gynecology. We wanted to analyze whether patients carrying the G gene responsible for the A11G polymorphism of the OPRM1 receptor really have a higher need for analgesic doses for postoperative pain control, depending on the histopathological results, benign or malignant tumors, dimensions of tumors, type of incision performed, and hospitalization period. Materials and Methods: We analyzed 111 patients, including both obstetrical and gynecological cases. Blood samples (2 mL) for DNA analysis were obtained before surgery in a tube containing EDTA as an anticoagulant and immediately stored at −20 °C until required for further use. The blood samples, which were collected at the time of intravenous cannulation before surgery, were analyzed for the presence of SNP 118AG. Results: We examined the mutation of the opioid receptor called OPRM1 for the polymorphism noted with AG with a plus sign (+) (present) in 24.3% of the patients, with a minus sign (−) (AA) (absent) in 66.7% of the patients, and with a result with both genes modified (GG) in 9%. We correlated the data obtained in histopathology and clinical anamnesis with these results. The OPRM1(+) morphine receptor mutation was more frequently encountered in patients with biopsy uterine curettage (60%) with benign results in anatomopathology, uterine myomectomy of at least 5 cm fibromas with benign results in anatomopathology (50%), Madden mastectomy (50%), interventional hysteroscopy (33.3%) with extraction of benign tumors such as polyps or endometrial hyperplasia, caesarean section-associated surgeries (20.7%), and ovarian cystectomy (20%) (p = 0.048) that had a final benign anatomopathology result. Conclusions: Pain management in the postoperative phase is difficult for clinicians because of the response of patients to opioid therapy. Some of this variability in pain response may result from single nucleotide polymorphisms (SNPs) in the human opioid receptor mu-1 (OPRM1) that alter receptor binding or signal transduction. Part of the difficulty in identifying genes and variants that affect postsurgical pain is the inconsistent findings and poor replicability of results. Full article

Background/Objectives: The KRAS rs61764370 T>G single-nucleotide polymorphism (SNP), located in a let-7 microRNA binding site within the 3′ untranslated region (3′UTR) of the KRAS gene, may modulate tumor aggressiveness by altering post-transcriptional gene regulation. This study evaluated its association with adverse histopathological features in colorectal cancer (CRC). Methods: A preliminary study on 83 CRC patients carrying either the TT (wild-type, n = 64) or TG (heterozygous, n = 19) genotype was analyzed. Clinicopathological variables included patient sex, tumor location, American Joint Committee on Cancer (AJCC) staging system, histological grade, perineural invasion (PNI), and lymphovascular invasion (LVI). A composite “tumor aggressiveness” score was defined based on the presence of Grade 3 differentiation, LVI, and/or PNI. Group comparisons were performed using the Chi-square test or Fisher’s exact test, as appropriate. Results: No statistically significant differences were observed in sex (p = 0.689), tumor location (p = 0.781), or stage at diagnosis (p = 0.812). Poorly differentiated tumors (Grade 3) were present in 20.3% of TT patients and absent in TG carriers (p = 0.06), while low-grade tumors (Grade 1) were more prevalent among TG patients (47.4%) compared to TT (29.7%). The composite high-aggressiveness score was lower in TG (36.8%) than in TT (48.4%), while co-occurrence of PNI and LVI was similar in both groups (~26%). Conclusions: Although no significant associations were identified, TG carriers showed a tendency toward lower-grade, less aggressive tumors. Given the limited sample size, these findings should be interpreted with caution, necessitating larger cohorts in order to validate results. Full article

Nucleotide-binding and leucine-rich repeat receptors (NLRs) play an important role in plant innate immunity. Previous reports indicate that SUT1 (SUPPRESSOR OF TOPP4 1) is required for the autoimmune response mediated by TYPE ONE PROTEIN PHOSPHATASE 4 (TOPP4) mutation topp4-1 (namely TOPP4^T246M) in Arabidopsis. We observed that co-expression of SUT1 with TOPP4 mutant versions, instead of wild-type TOPP4, produced robust cell death in N. benthamiana. The YFP-labeled SUT1 was localized on the plasma membrane (PM), and Gly2, Cys4, and Ser6 are crucial amino acid sites for its PM localization and function. Further dissection proclaimed that the function and localization of SUT1 are influenced by mutations in conserved specific residues. These findings may provide a new perspective for elucidating the activation mechanism of SUT1. Full article

Abiotic stress of cold is one of the limitation factors that hinder the production of alfalfa (Medicago sativa). Although there are a large number of studies suggesting that non-coding RNAs (ncRNAs) play an important role in plant response to abiotic stress, the mechanism by which ncRNAs and competing endogenous RNAs (ceRNAs) influence the low-temperature tolerance of alfalfa remains understudied. In this study, we integrated whole-transcriptome RNA-seq and genome-wide association studies (GWASs) to identify cold stress-related metabolic pathways and candidate genes, differentially expressed (DE) mRNAs, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Degradome sequencing was used to verify the ceRNA network under cold stress. A total of 46,936 DEmRNAs were identified. Ribosome (ko03010), amino sugar and nucleotide sugar metabolism (ko00520), ribosome biogenesis in eukaryotes (ko03008), circadian rhythm–plant (ko00270), and starch and sucrose metabolism (ko00500) were the top five KEGG terms with the highest p-value, enriching the most number of DEmRNAs. MS.gene53818 (MsUAM1) was considered to be the critical candidate gene for alfalfa response to cold stress by conjoint analysis of GWASs and DEmRNAs. A total of 223 DEmiRNAs, 1852 DElncRNAs, and 13 DEcircRNAs were identified under cold stress. Functional analysis indicates that they play important roles in GO terms such as leaf development (GO:0048366), DNA-binding transcription factor activity (GO:0003700), central vacuole (GO:0042807), response to auxin (GO:0009733), and water channel activity (GO:0015250), as well as in KEGG pathways such as plant hormone signal transduction, starch and sucrose metabolism, and flavone and flavonol biosynthesis (ko00944). A ceRNA network comprising 28 DElncRNAs, 8 DEcircRNAs, 11 DEmiRNAs, and 23 DEmRNA triplets was constructed. In this study, mRNAs and ncRNAs were identified that may be involved in alfalfa’s response to cold stress, and a ceRNA regulatory network related to cold stress was established, providing valuable genic resources for further research on the molecular mechanisms underlying alfalfa cold stress. Full article

Helicobacter pylori is a prevalent gastric pathogen that establishes chronic infection and contributes to gastritis, peptic ulcer disease, and gastric cancer. Its persistence depends on immune evasion strategies that promote sustained low-grade inflammation in the gastric mucosa. Nucleotide-binding oligomerization domain-like receptors (NLRs) are cytosolic pattern recognition receptors that play key roles in innate immune responses against H. pylori. Nod1 and Nod2 detect bacterial peptidoglycan delivered via the type IV secretion system or outer membrane vesicles, activating NF-κB, MAPK, and interferon signaling pathways that regulate inflammatory cytokine production, epithelial barrier function, autophagy, and antimicrobial defense. The NLRP3 inflammasome mediates the maturation of IL-1β and IL-18 primarily in myeloid cells, thereby shaping inflammatory and immunoregulatory responses during infection. In contrast, NLRC4 functions in a context-dependent manner in epithelial cells and is largely dispensable for myeloid IL-1β production. Emerging evidence also implicates noncanonical NLRs, including NLRP6, NLRP9, NLRP12, NLRX1, and NLRC5, in regulating inflammation, epithelial homeostasis, and gastric tumorigenesis. In addition, genetic polymorphisms in NLR genes influence host susceptibility to H. pylori-associated diseases. This review highlights the interplay between NLR signaling, bacterial virulence, and host immunity and identifies potential therapeutic targets. Full article

Growing evidence suggests that persistent oral infectious diseases (OIDs) contribute to systemic disease, highlighting the importance of understanding their pathogenic mechanisms. Conventional dental treatments, primarily mechanical debridement, surgical intervention, or antimicrobial therapy, often struggle to fully control inflammation or prevent progressive tissue destruction. The nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome is a key regulator of innate immunity, mediating the maturation of proinflammatory cytokines (IL-1β and IL-18) and the pyroptosis-inducing protein gasdermin D. Dysregulated or excessive activation of NLRP3 contributes to the initiation and progression of major oral diseases, including periodontitis, peri-implantitis, pulpitis, and oral mucosal inflammation. Despite growing interest in NLRP3, comprehensive and up-to-date reviews integrating its pathogenic mechanisms and therapeutic potential remain limited. This review summarizes current and past evidence on the role of the NLRP3 inflammasome in oral disease development, highlights emerging pharmacological strategies, and outlines future research directions. Existing studies demonstrate that microbial components and danger signals from injured tissues activate NLRP3, thereby amplifying inflammation, tissue degradation, and bone resorption. Preclinical studies indicate that inflammasome inhibitors and several natural compounds reduce tissue damage; however, their clinical translation remains limited. These findings emphasize the need for deeper understanding of NLRP3-mediated pathways, with translational and clinical research offering promising therapeutic opportunities for oral diseases. Full article

Hyperphosphorylated collapsin response mediator protein 2 (CRMP2) is elevated in the cerebral cortex of an APP-SAA knock-in mouse model of Alzheimer’s disease and binds the adenine nucleotide translocase (ANT) in a phosphorylation-dependent manner. We propose that, in Alzheimer’s disease (AD) mitochondria, dissociation of hyperphosphorylated CRMP2 from ANT promotes opening of the permeability transition pore (PTP). We showed that purified ANT, when reconstituted into giant liposomes, forms large calcium-dependent channels resembling the PTP, which are effectively blocked by recombinant, unphosphorylated CRMP2. In synaptic mitochondria isolated from the cortices of APP-SAA knock-in mice and control B6J hAbeta mice, we observed an increased susceptibility to permeability transition pore (PTP) induction in AD mitochondria, accompanied by reduced viability of cultured cortical neurons. Pre-treatment of AD mice with the CRMP2-binding small molecule (S)-lacosamide ((S)-LCM), which prevents CRMP2 hyperphosphorylation and restores its interaction with ANT, attenuated PTP induction and improved neuronal viability. Interestingly, direct application of (S)-LCM to isolated mitochondria failed to suppress PTP induction, indicating that its protective effect requires upstream cellular mechanisms. These findings support a phosphorylation-dependent role for CRMP2 in regulating PTP induction in AD mitochondria and highlight (S)-LCM as a promising therapeutic candidate for mitigating mitochondrial dysfunction and enhancing neuronal viability in AD. Full article

MicroRNAs (miRNAs) are small non-coding RNA molecules approximately 20–22 nucleotides in length that regulate gene expression at the post-transcriptional level. By binding to target messenger RNAs (mRNAs), miRNAs inhibit translation or induce degradation, thus influencing a wide array of biological processes including development, inflammation, apoptosis, and tissue remodeling. Owing to their remarkable stability and tissue specificity, miRNAs have emerged as promising biomarkers in both clinical and forensic settings. In recent years, increasing evidence has demonstrated their utility in cardiovascular diseases, where they may serve as diagnostic, prognostic, and therapeutic tools. This systematic review aims to comprehensively summarize the role of miRNAs in cardiovascular pathology, focusing on their diagnostic potential in myocardial infarction, sudden cardiac death (SCD), and cardiomyopathies, and their applicability in post-mortem investigations. Following PRISMA guidelines, we screened PubMed, Scopus, and Web of Science databases for studies up to December 2024. The results highlight several miRNAs—including miR-1, miR-133a, miR-208b, miR-499a, and miR-486-5p—as robust markers for ischemic injury and sudden death, even in degraded or formalin-fixed autopsy samples. The high stability of miRNAs under extreme post-mortem conditions reinforces their potential as molecular tools in forensic pathology. Nevertheless, methodological heterogeneity and limited standardization currently hinder their routine application. Future studies should aim to harmonize analytical protocols and validate diagnostic thresholds across larger, well-characterized cohorts to fully exploit miRNAs as reliable molecular biomarkers in both clinical cardiology and forensic medicine. Full article

Avian influenza viruses are predominantly associated with waterfowl and shorebirds, and are rarely detected in other avian hosts in nature. In 2021, an H1N1 virus was isolated from a Fieldfare Turdus pilaris in Zaporizhzhia Oblast, Ukraine. A phylogenetic analysis revealed that all eight gene segments belonged to the Eurasian low-pathogenic avian influenza lineages. The highest nucleotide identity of the HA gene was observed with viruses detected in Georgia, Sweden, and Ukraine (99.11%), while the NA gene showed the greatest identity to viruses from Western Europe (99.14–99.57%). Genetic analysis of the HA cleavage site showed a sequence (PSIQSR↓GLF) that contained a single basic amino acid. No deletions were detected in the stalk region of NA gene, and no specific mutations in PB2 protein were found. However, several amino acid substitutions were identified in the HA gene (D204E, S207T, and D239G) that may affect the binding affinity to specific antibodies. The occurrence of this virus in a wild, seemingly healthy thrush indicate that additional surveillance in poorly studied ecological groups such as Passeriformes is warranted. Full article

Background/Objectives: Variants in the lipoprotein lipase (LPL) gene have been associated with lipid level variability and obesity; however, their role in energy homeostasis remains unclear. The aim of this study was to investigate the association of LPL single-nucleotide variants (SNVs) with lipid parameters and leptin concentrations in a cohort of prepubertal children. The sample population comprised 635 boys and 631 girls, with available information on lipid profiles and leptin levels. Methods: Five LPL SNVs (rs258, rs316, rs326, rs320, and rs328) were genotyped by Real-Time PCR using predesigned TaqMan™ Genotyping Assays. Results: An association of the LPL SNV rs258 was found with non-esterified fatty acid (NEFA) levels in males and with leptin concentrations in both sexes. On the other hand, an association of the LPL SNV rs326 was observed with low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (Apo-B) levels, displaying opposite trends in males and females. No significant associations with any of the parameters under study were observed for the remaining LPL SNVs. Conclusions: These results suggest that functional differences among LPL SNVs may either be related to an enhancement of catalytic activity or modulation of lipoprotein binding affinity, influencing the efficiency of remnant lipoprotein clearance. Full article

N6-methyladenosine (m⁶A) constitutes the most prevalent nucleotide modification within eukaryotic messenger RNA (mRNA). Variations in m⁶A levels are associated with numerous human diseases and health conditions, including various forms of cancer, diabetes, neurological disorders, male infertility, and obesity. Nevertheless, the molecular mechanisms underpinning the recognition of m⁶A by different ‘reader’ proteins remain incompletely elucidated. In this study, we used phage display to identify key sequence features that methyl readers recognize in m⁶A. This study shows that m⁶A modifications affect the mRNA interactome. A peptide motif recognizing m⁶A in DRACH sequences suggests a common recognition mechanism, though proteins may use different methods to detect m⁶A in less accessible areas. The sequence of the hnRNP A1 RRM domain that aligns with the newly discovered m⁶A-binding peptide, m1p1, is crucial for the binding of m⁶A-modified RNAs, indicating a strong link between the m1p1 sequence and m⁶A recognition, which is key for recognizing m⁶A-modified, unstructured RNAs. Gaining a comprehensive understanding of the evolutionary influence of m⁶A on its reader proteins may facilitate the identification of additional m⁶A readers. These signature peptides could enhance theranostic approaches across cancers, enabling more targeted therapies. Full article

Metabolic reprogramming allows cancer cells to proliferate rapidly, survive nutrient limitation, and resist stress, making tumor metabolism an important therapeutic target. However, pharmacological inhibition of metabolic enzymes often causes systemic toxicity and compensatory pathway activation. To overcome these limitations, recent studies have highlighted an alternative host-centered strategy based on increasing systemic energy expenditure. Recent studies highlight an alternative strategy in which the host increases energy expenditure through uncoupling protein 1 (UCP1) dependent thermogenesis, thereby lowering systemic glucose, fatty acid, and nucleotide availability for tumors. Engineered beige adipocytes overexpressing UCP1, PR domain-containing protein 16 (PRDM16), or peroxisome proliferator–activated receptor gamma coactivator 1 alpha (PPARGC1A/PGC1A) suppress tumor growth through nutrient competition, suggesting that activating endogenous UCP1 may provide a non-genetic and physiologically aligned anticancer approach. Building on this concept, natural products such as polyphenols, terpenoids, alkaloids, and carotenoids have emerged as promising UCP1 activators that stimulate beige and brown adipocyte thermogenesis through pathways involving AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), PGC1A, PRDM16, and mitochondrial biogenesis. In parallel, computational studies further indicate that several plant-derived compounds bind directly to the central cavity of UCP1 with high affinity, offering structural support for their thermogenic action. Importantly, many of these compounds also inhibit cancer cell intrinsic metabolism by reducing glycolysis, oxidative phosphorylation, lipid synthesis, and amino acid dependent anaplerosis. This review integrates UCP1 biology, natural product mediated thermogenesis, molecular docking evidence, and tumor metabolic suppression, proposing a unified framework in which natural compounds impose coordinated metabolic pressure on cancer through both adipocyte-driven nutrient competition and direct inhibition of tumor metabolism. Full article

Group A rotaviruses (RVAs) remain the leading cause of acute gastroenteritis (AGE) in young children in low- and middle-income countries. In Brazil, the oral attenuated RVA vaccine (Rotarix^®), monovalent genotype G1P[8], is distributed by the national immunization program and has drastically reduced morbidity and mortality associated with RVA etiology. In this study, Rotarix^® G1P[8] was detected using specific qRT-PCR from the fecal shedding of children living in the Amazon region, and 18.3% (29/158) were positive and 75.8% (22/29) presented with AGE. The VP4 (VP8*) gene of these sheddings, submitted to Sanger nucleotide sequencing, showed an occurrence of mutations, including the silent mutation at 144C > G (one child) and the following missense mutations— 499T > C (F167L) (two children), 644G > C (C215S) (one child), and 787G > A (E263K) (one child). These mutations had no impact on the protein model structure in silico deduced from the VP4 (VP8*) mutants. The in silico protein model deduced from the VP4 (VP8*) nucleotide sequences, bound to type 1H sugar antigens (H1) and its precursor Lac-para-N-biose (LNB), had a stronger binding to the G1P[8] genotype, when compared to G3P[8]. Rotarix^® shedding was higher in HBGA secretors than in non-secretors (79.3%; 23/29). A total of 11.4% (18/158) of children with Rotarix^® G1P[8] shedding were unvaccinated, indicating the occurrence of indirect protection. Stability evidence of Rotarix^® VP4 (VP8*) spike protein from samples collected in vivo is presented. Full article

Nelumbo nucifera (Lotus) is an economically important aquatic crop frequently challenged by abiotic stresses. The plant cell wall, a primary interface with the environment, undergoes dynamic remodeling to balance structural integrity with adaptation. UDP-glucuronic acid decarboxylase (UXS), a key enzyme synthesizing the nucleotide sugar precursor UDP-xylose, exists in distinct membrane-bound (e.g., Golgi) and cytosolic forms, channeling substrates into compartmentalized polysaccharide biosynthesis pathways and positioning the UXS family as a crucial regulator linking cell wall metabolism to plant adaptation. Here, we systematically characterized the NnUXS gene family in lotus through genome-wide identification, evolutionary synteny analysis, and functional validation. Integrated bioinformatic analysis revealed their physicochemical properties, motif patterns, and regulatory cis-elements, suggesting potential roles in growth and salt stress responses. Among the family, NnUXS3 was prioritized due to its preferentially upregulated in small plant architecture (SPA) varieties, its early induction under salt stress (0.5 days, 200 mM NaCl), and its highest predicted binding affinity for UDP-GlcA (−8.9 kcal/mol). Subsequent functional validation confirmed its dual role: heterologous overexpression in tobacco reduced plant height (47.22%) and leaf area (67.61%), while transient overexpression in lotus enhanced salt tolerance and shortened the petioles. This enhanced tolerance was achieved by upregulating key genes involved in polysaccharide biosynthesis (NnCSLC4, NnXTH22, NnCESA1) and antioxidant defense (NnSOD, NnPOD). Our findings establish NnUXS3 as a key mediator in balancing plant architecture and abiotic stress resilience. This work not only identifies a valuable genetic target for lotus breeding but also provides insights into the growth-stress trade-off, highlighting the importance of UXS subcellular localization in tailoring cell wall remodeling for environmental adaptation. Full article

P-glycoprotein (P-gp) is an ATP-driven transporter that effluxes a wide range of xenobiotics from cells, and its overexpression is a primary cause of multidrug resistance (MDR) in cancer. It is well-established that P-gp functions through conformational changes, yet its large-scale structural dynamics at work have been unexplored. Here, we directly visualized single P-gp molecules reconstituted in nanodiscs using high-speed atomic force microscopy (HS-AFM). The HS-AFM movies revealed that P-gp is intrinsically dynamic in its apo state, with its nucleotide-binding domains (NBDs) undergoing large, spontaneous opening and closing motions. However, addition of ATP stabilized a conformation characterized by NBD proximity with a strong tendency toward closure. We then leveraged this dynamic viewpoint to elucidate the relationship between Elacridar’s function and the resulting structural dynamics of P-gp. Elacridar is designed to overcome multidrug resistance (MDR) in cancer and acts as a potent dual inhibitor of both P-gp and the Breast Cancer Resistance Protein (BCRP), effectively blocking the drug efflux function of these transporters. This inhibitor has suggested concentration-dependent function: it is effluxed as a substrate at low concentrations and acts as an inhibitor at high concentrations. Our direct observations revealed that low concentrations induced active dynamics in P-gp, whereas high concentrations severely restricted its motion, leading to a rigid, non-productive state. Our study provides critical insights into how observing molecular motion itself can unravel complex biological mechanisms. Full article