Search Results (2,179)

Winter survival of crops is influenced by multiple environmental stress factors, including low temperature, excessive soil moisture, and pathogen pressure. With climate change, the role of flooding during cold acclimation has become increasingly important. This study examined the effect of cold flooding on frost tolerance of two winter rye (Secale cereale L.) lines differing in resistance to snow mould. Plants were subjected to cold acclimation for three weeks at 4 °C, followed by ten days of flooding at the same cold temperature. Cold flooding improved frost tolerance only in the snow mould-resistant line (343), which maintained the presence of a 50 kDa β-1,3-glucanase isoform and exhibited a flooding-induced decrease in cytosolic sucrose synthase (SuS) activity in leaves, while maintaining higher SuS activity in roots. In contrast, the less resistant line (620) lacked the 50 kDa isoform in roots and showed substantially lower SuS activity than line 343; however, leaf SuS activity increased during prolonged flooding to levels comparable with those of line 343. The 35 kDa isoform was no longer detectable in the leaves of either line after one or ten days of flooding, whereas in the roots of both lines, its accumulation was maintained after one day but was abolished after ten days of flooding. Additionally, line 620 exhibited prolonged flooding-induced upregulation of glu-8 and TLP3 genes, which, in the absence of protein accumulation, suggests post-transcriptional or translational constraints associated with prolonged stress. These findings demonstrate that higher frost tolerance under cold flooding involves the accumulation of specific pathogenesis-related (PR) proteins, maintaining a high reduced and oxidised glutathione ratio and metabolic adjustment of sucrose synthesis. Furthermore, cold acclimation alone did not differentiate frost tolerance between rye genotypes differing in snow mould resistance, whereas flooding under low-temperature conditions enhanced freezing tolerance only in the resistant line, indicating that flooding may function as a positive signal involved in frost tolerance induction. Full article

Mechanical stress is thought to be involved in the pathogenesis and pathophysiology of osteoarthritis (OA). However, much remains to be elucidated regarding how chondrocytes sense and respond to mechanical stress (stress sensing and response factors). Additionally, it still remains unclear whether there are defensive responses and mechanisms to protect against pathological agents and mechanical stress in articular cartilage tissue. This study was designed to determine whether repetitive mechanical force, at physiologic levels, affects the expression of factors regulating autophagy such as the autophagy-related proteins ATG5, Beclin-1, and Parkin, and the autophagy process as well as cellular activity in cultured chondrocytes. Three-dimensional cultured tissue was generated from human chondrocytes using a collagen sponge scaffold. After physiological mechanical loading of the 3D cell–collagen sponge construct, comparative analyses of expression levels of ATG5, Beclin-1, and Parkin were performed in human chondrocytes. Chondrocyte activity and Transmission Electron Microscopy (TEM) analysis for detecting autophagy process were also analyzed with or without repetitive compressive loading. In chondrocytes, 60 min or 180 min repetitive compressive loading significantly decreased the expression of ATG5, Beclin-1 and Parkin in comparison with the non-loading group. TEM analysis indicated that, in normal chondrocytes of the non-loading group, the autophagy process was shown to be progressing. In contrast, repetitive loading decreased the number of autophagosomes and autolysosomes in chondrocytes. In addition, numerous degenerated organelles that had not undergone autophagy were observed within the chondrocytes under repetitive loading. The ATG5 and Beclin-1 proteins are known to play crucial roles in regulating cellular autophagy. Furthermore, repetitive mechanical loading caused a decreased expression of Parkin, a mitophagy regulator in chondrocytes. Our results indicate for the first time that a decrease in mitophagy, as well as cellular autophagy, in response to mechanical stress, even at the physiologic level, leads to the accumulation of defective mitochondria and abnormal cellular proteins, resulting in reduced chondrocyte activity and affecting the maintenance of cartilage tissue homeostasis, ultimately contributing to the progression of OA. Full article

Background/Objectives: The molecular mechanisms underlying susceptibility to severe COVID-19 remain incompletely understood. We aimed to identify the signaling pathways associated with disease severity by integrating transcriptomic data and characterizing ligand–receptor interactions involved in the host response to SARS-CoV-2 infection. Methods: We integrated publicly available bulk RNA-sequencing data from nasopharyngeal (NP) swabs (GSE152075) and single-cell RNA-sequencing data from bronchoalveolar lavage fluid samples (GSE145926). Analyses focused on secreted ligands and their cognate receptors and were performed in relation to demographic and clinical characteristics associated with susceptibility to severe COVID-19, including sex, age, and viral load. Results: Patients with characteristics associated with increased susceptibility to severe disease, including male sex, advanced age, and high viral load, exhibited transcriptional programs enriched for inflammatory and immune-response pathways. In contrast, individuals with lower susceptibility displayed reduced expression of 43 ligand genes compared with matched negative controls, suggesting distinct secretory programs associated with the host response to infection. We identified an association between the expression of lactoferrin (LTF) and its receptor, LDL receptor-related protein 11 (LRP11), and susceptibility to severe COVID-19. LRP11 was predominantly expressed in human pulmonary epithelial cells, and its expression increased during SARS-CoV-2 infection in monkeys. Conclusions: Our findings provide insight into the molecular mechanisms associated with susceptibility to severe COVID-19 through the analysis of ligand and receptor expression in nasopharyngeal swabs and bronchoalveolar lavage fluid samples. The association between LTF and LRP11 highlights a potentially relevant signaling axis in disease pathogenesis and provides a rationale for future functional studies aimed at clarifying its role in COVID-19 severity. Full article

COVID-19 remains a relevant area of biomedical investigation because its pathogenesis involves complex virus–host interactions. This study aimed to explore, through purely in silico and hypothesis-generating insights, the predicted molecular associations between benzyl isothiocyanate (BITC) from Salvadora persica and COVID-19-associated host-response pathways. BITC-associated targets were collected from compound-target databases, while COVID-19-associated targets were obtained from disease-gene databases and transcriptomic datasets. Overlapping targets were analyzed using protein–protein interaction network construction, hub-gene prioritization, Gene Ontology and KEGG enrichment analyses, and molecular docking. A total of 271 unique BITC-associated targets and 1890 COVID-19-associated targets were identified, with 36 candidate targets overlapping. PPI analysis generated a connected network of 24 nodes and 39 edges. Hub-gene analysis prioritized ACE, JUN, MAOA, CDK1, MAOB, HCK, CCNA2, ACHE, GADD45A, and ADRA2A. Enrichment analysis indicated associations with inflammatory response, vascular regulation, calcium homeostasis, monoamine oxidase activity, NF-κB signaling, serotonergic synapse, and tryptophan metabolism. Validated active-site docking of six targets yielded comparative Vina scores ranging from −5.380 to −6.437 kcal/mol. These preliminary findings provide theoretical target–pathway associations supporting further investigation of BITC as a potential immunomodulatory candidate within COVID-19-related host-response pathways. Full article

Heat shock proteins of the HSP70 family and their BAG co-chaperones regulate responses to oxidative stress, inflammation, apoptosis, and ischemia, all central to coronary artery disease (CAD) pathogenesis. The contribution of genetic variants within HSP70-family and BAG co-chaperone genes to CAD susceptibility remains unclear. Thus, we sought to evaluate associations of HSP70- and BAG-related SNPs with CAD risk and to characterize their potential regulatory effects using comprehensive bioinformatic analyses. A case–control cohort of 834 CAD patients and 1328 controls of Russian ethnicity was genotyped for 13 SNPs. Associations with CAD susceptibility and traits were tested using log-additive regression with adaptive permutation. Loci underwent functional annotation. The C allele of BAG1 rs706121 was associated with increased CAD risk overall (OR = 1.24, p_perm = 0.019), in males (OR = 1.39, p_perm = 0.002), and in smokers (OR = 1.39, p_perm = 0.020). BAG3 rs196329 was associated with lower risk in males (A allele: OR = 0.82, p_perm = 0.040), whereas HSPA6 rs753856 was associated with reduced risk in physically active individuals (G allele: OR = 0.61, p_perm = 0.008). Additional associations involved clinical or biochemical traits. Functional annotation identified potential regulatory effects, including eQTL associations, overlap with histone marks, and allele-dependent changes in transcription factor binding. HSP70 and BAG variants may contribute to CAD susceptibility and support sex- and lifestyle-informed risk assessment. Full article

Chile is a global leader in the fruit industry; however, the sector faces significant yield losses due to phytopathogens and an urgent need to reduce reliance on chemical fungicides. Induction of plant defenses and priming offer sustainable alternatives by activating the plant’s innate immune system. This study aimed to evaluate the ability of native Pseudomonas protegens strains and their formulations to trigger plant defense responses in five agronomically important fruit crops: kiwifruit (Actinidia chinensis var. deliciosa), walnut (Juglans regia), cherry (Prunus avium), blueberry (Vaccinium corymbosum), and grapevine (Vitis vinifera). Under controlled conditions, a randomized block design was implemented with four treatments, including P. protegens strains and their formulations, as well as a chemical elicitor (acibenzolar-S-methyl) as a positive control. Foliar treatments were applied, and leaf tissues were sampled at 1 day, 7 days, and 14 days post-inoculation. Transcriptional responses were quantified via qPCR using the ΔΔC_t method, targeting key defense-related genes, including pathogenesis-related proteins (pr1, pr2, pr3, pr5, pr10) and enzymes of the phenylpropanoid and signaling pathways (pal, chs, ppo, lox9, glc). This study provides a molecular framework for understanding how biological inducers modulate defense-related gene expression in perennial crops. The results highlight the potential of native bacteria to be integrated into sustainable integrated pest management programs, offering an alternative strategy to trigger defense-related transcriptional activation in fruit perennial crops. Full article

Background: Osteoarthritis (OA) is a prevalent degenerative joint disease with a complex molecular basis. This study aims to identify key molecules involved in OA pathogenesis, focusing on the role of acetylation-related gene expression. Methods: Public microarray datasets GSE82107 and GSE169077 were integrated to construct a differential expression landscape between OA patients and healthy controls. Acetylation-linked differentially expressed genes (acetylation-DEGs, ARDEGs) were extracted by intersecting DEGs with a curated set of acetyltransferases, deacetylases and acetylation substrates. A protein–protein interaction (PPI) network was built and subjected to LASSO-penalized regression to prioritise hub genes. Gene Ontology (GO), Kyoto Encyclopaedia of Genes and Genomes (KEGG) and Gene Set Variation Analysis (GSVA) were performed to characterize biological themes. Immune infiltration was quantified with CIBERSORTx and single-sample Gene Set Enrichment Analysis (ssGSEA). Single-cell RNA-seq data (GSE216651) were employed for orthogonal validation. For experimental corroboration, synovial tissue was collected from OA patients undergoing arthroplasty; mRNA and protein levels of hub genes were determined by qRT-PCR, Western blot and immunofluorescence. The destabilisation of the medial meniscus (DMM) mouse model was used for in vivo verification. Results: Twenty-one high-confidence ARDEGs were identified. Analysis of the PPI network yielded ten hub nodes, six of which (EGR1, PFKFB3, HDAC4, MMP13, PDK4 and ACADL) retained non-zero coefficients in the least absolute shrinkage and selection operator (LASSO) model. Enrichment analyses implicated these genes in embryonic development, collagen-containing extracellular matrix remodeling and PI3K–Akt signaling. Immune infiltration analysis showed potential differences in immune cell abundance between OA and healthy controls. Single-cell dataset analysis verified the expression patterns of key genes in different cell types. Concordant dysregulation of EGR1, PFKFB3, HDAC4, MMP13 and PDK4 was observed at both mRNA and protein levels in human OA synovium and DMM mouse joints. Conclusion: This comprehensive analysis identified acetylation-related genes and analyzed their potential biological roles in OA. The identified ARDEGs may provide new insights into OA diagnosis and treatment. Full article

Kaposi’s Sarcoma Herpesvirus (KSHV), an enveloped double-stranded DNA virus, is the etiological agent of Kaposi’s Sarcoma (KS), an endothelial cell-based tumor. KSHV is a leading cause of infection-related cancers in sub-Saharan Africa and immunocompromised individuals worldwide. Therefore, it is vital to identify the underlying mechanisms of viral infection and transmission to effectively identify specific therapeutic strategies and combat the disease. Here, we demonstrate that KSHV rewires the host cell lipidome during lytic infection. Bulk lipidomic analysis shows significant changes in the abundance of neutral lipids and phospholipids during lytic infection. We further investigated fatty acid binding proteins (FABPs) to understand the underlying mechanisms that support KSHV pathogenesis. Using the doxycycline-inducible iSLK.BAC16 cell line, we find that FABP genes are differentially regulated by lytic KSHV infection compared to latent infection. We report that FABP4 is significantly upregulated during lytic infection. FABP4 knockdown using siRNA or inhibition of the FABP4 protein via treatment with a competitive inhibitor during lytic infection significantly reduces extracellular viral titers, indicating that FABP4 supports maximal infectious virion production. This study highlights the role of FABP4 as a host target that facilitates KSHV infection and pathogenesis. Full article

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide despite advances in screening, surgical techniques, and systemic therapies. In recent years, exosomes—nanoscale extracellular vesicles involved in intercellular communication—have emerged as critical regulators of CRC biology. Exosomes mediate tumor progression, metastatic dissemination, immune evasion, and therapeutic resistance through the transfer of bioactive molecules including proteins, lipids, and non-coding RNAs. Moreover, exosomes have gained increasing attention as promising liquid biopsy tools and therapeutic platforms due to their stability, biocompatibility, and ability to reflect tumor molecular dynamics. This review provides a comprehensive overview of exosome biogenesis, molecular composition, and their functional roles in CRC pathogenesis. We further discuss their diagnostic and prognostic value, involvement in therapeutic resistance, and emerging therapeutic applications, with particular emphasis on translational and surgical oncology implications. Finally, we highlight current limitations and future perspectives for clinical integration of exosome-based strategies in CRC management. Full article

Wheat is a globally important staple crop, whose growth and yield formation rely on the precise regulation of phytohormone signaling. The PR10/Bet v 1 (Pathogenesis-related protein 10/Betula verrucosa 1) family consists of conserved small-molecule ligand-binding proteins that participate in phytohormone signaling and plant development; however, systematic investigations of this family in wheat remain limited. Here, we performed a genome-wide identification of 75 PR10/Bet v 1 members in wheat, which were phylogenetically classified into three subfamilies: 21 known members belonging to the PYL (Pyrabactin resistance 1-like) subfamily, and 54 members assigned to two previously uncharacterized subfamilies. Bioinformatic analyses revealed that whole-genome/segmental duplication has driven the expansion of this gene family, which has evolved under strong purifying selection. Expression profiling and promoter analysis revealed differential expression patterns, along with abundant cis-acting elements responsive to multiple hormones. Quantitative RT-PCR (qRT-PCR) of 12 representative genes revealed marked transcriptional changes in several members within 1 h of treatment with BR (Brassinosteroid), ABA (Abscisic acid), CK (Cytokinin), or SA (Salicylic acid) suggesting that these genes may be directly involved in hormone-regulated processes. This study provides a fundamental framework for exploring the regulatory functions of the wheat PR10/Bet v 1 family, and valuable hormone-responsive candidate genes for the genetic improvement of wheat agronomic traits. Full article

This review examines the viral quasispecies concept and its implications for understanding viral evolution, pathogenesis, and the development of effective antiviral therapies. Quasispecies are dynamic populations of closely related but genetically distinct viral genomes, which evolve under mutation and Darwinian selection. Notably, minority variants, often dismissed as “genetic noise”, may harbor significant biological differences—such as drug resistance—and become dominant under changing selective pressures. Next-generation sequencing (NGS) has become an indispensable tool for characterizing genetic diversity within quasispecies, enabling detection and quantitative analysis of minority variants often missed by conventional Sanger sequencing, as well as the calculation of diversity indices. We highlight two NGS-based studies of hepatitis B virus quasispecies as illustrative examples of the relevance of minority variants in antiviral resistance and clinical outcomes. These studies also exemplify transcomplementation, whereby defective viral genomes can be replicated and packaged through functional proteins provided by co-infecting variants. Finally, we discuss how the quasispecies concept may extend beyond viruses, with parallels in biological systems such as the adaptive immune system and tumor cell populations. Recognizing quasispecies as dynamic evolving populations rather than static entities is crucial for developing successful strategies to address infectious diseases and other complex biological challenges. Full article

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide and remains a major therapeutic challenge due to its marked inter- and intratumoral heterogeneity, diverse etiologies, and high propensity for therapeutic resistance. This review summarizes the biological complexity of HCC and current therapeutic challenges, with a particular focus on the RNA-binding protein human antigen R (HuR) as an emerging therapeutic target. Methods: A comprehensive narrative review of peer-reviewed literature was conducted, focusing on HCC pathogenesis, molecular heterogeneity, tumor microenvironment, mechanisms of therapeutic resistance, and recent advances in treatment. Emphasis was placed on studies investigating the biological functions of HuR and its therapeutic potential in HCC. Results: HCC progression is driven by complex interactions among genetic, epigenetic, metabolic, and environmental factors, resulting in substantial tumor heterogeneity and variable therapeutic responses. Dysregulated oncogenic signaling and immunosuppressive tumor microenvironment collectively contribute to resistance against current therapies, including multikinase inhibitors and immune checkpoint inhibitors. Although emerging strategies, such as combination immunotherapy, metabolic targeting, epigenetic modulation, and precision medicine, have shown encouraging preclinical and clinical results, their efficacy remains limited by tumor complexity and adaptive resistance. HuR functions as a master post-transcriptional regulator that stabilizes and promotes the translation of numerous mRNAs encoding oncogenic, inflammatory, and pro-survival factors. Accumulating preclinical evidence demonstrates that pharmacological inhibition of HuR suppresses multiple tumor-promoting pathways and enhances therapeutic sensitivity, supporting its potential as a novel therapeutic strategy for HCC. Conclusions: The biological complexity of HCC necessitates multifaceted, precision-based therapeutic approaches. Although additional HCC-specific mechanistic and translational studies are needed, targeting HuR represents a promising strategy to overcome tumor heterogeneity, therapeutic resistance, and disease progression. Continued integration of molecular profiling, advanced omics technologies, and rational combination therapies will be essential for translating these advances into improved clinical outcomes for patients with HCC. Full article

Extracellular vesicles (EVs) have emerged as fundamental pillars of intercellular communication, acting as primary mediators of the bidirectional biochemical crosstalk within the integrated bone–muscle unit. This review provides a comprehensive synthesis of EV-mediated signaling across the bone–muscle axis, offering a side-by-side mapping of vesicular biogenesis, cargo composition, and functional roles in both tissues. Under physiological conditions, skeletal muscle- and bone-derived EVs orchestrate tissue homeostasis, adaptations to physical exercise, myogenesis, and bone remodeling by transferring unique molecular cargos of proteins and specific microRNAs. However, aging induces a profound remodeling of the EV secretome toward a senescent profile characterized by harmful vesicular factors. This dysfunctional vesicular signaling impairs both muscle regeneration and osteogenesis, directly contributing to the pathogenesis of interconnected age-related disorders like sarcopenia, osteoporosis, and osteosarcopenia. Concurrently, circulating EVs represent valuable, minimally invasive biomarkers for early diagnosis. On the therapeutic front, this review critically evaluates emerging EV-based approaches, utilizing mesenchymal stem cell-derived, bioengineered, or biomaterial-incorporated EVs, offering promising, low-immunogenic alternatives to cell transplantation to enhance musculoskeletal tissue repair and restore bone–muscle homeostasis. Despite persisting technical challenges regarding large-scale production and standardization, targeting or leveraging EV-mediated communication represents one of the most innovative and revolutionary strategies to counteract age-related musculoskeletal decline. By unifying physiological mechanisms, age-related molecular reprogramming, and therapeutic engineering across both muscle and bone into a single narrative, this review provides a comprehensive framework to guide future research and clinical translation in musculoskeletal health. Full article

Cellular senescence may affect the post-mitotic cells of the brain. We examined the expression of senescence markers, including p16, p21, γH2Ax and H3K9me3, in the frontal cortex of brain donations from the Cognitive Function and Ageing Study to assess their relationship to Alzheimer’s disease neuropathological change (ADNC) and dementia. p21, γH2Ax and H3K9me3 were expressed in pyramidal neurons and glia, whilst p16 was confined to glial cells. p21 and γH2Ax were correlated in neurons, and with p16 in glia. They did not increase with ADNC, tending to be higher at early Braak neurofibrillary tangle stages. Transcriptomic profiling of pyramidal neuron-enriched samples at low Braak stages showed that higher neuronal p21 expression was associated with altered pathways for neuronal function, neurodegeneration, protein homeostasis, mitochondrial dysfunction and synaptic signalling. In conclusion, the different expression profile of senescence markers in neurons and glia suggest possible differences in senescence-related mechanisms. Expression at lower ADNC stages suggests senescence may be important at earlier stages of Alzheimer’s pathogenesis, whilst transcriptomic changes suggest an impact on neuronal function. The lack of association of senescence markers with dementia status indicates that more work is needed to determine the value of senescence as a therapeutic target for dementia. Full article

To delineate the serum proteomic profile of persistent subclinical hypocalcemia (pSCH) in periparturient dairy cows, elucidate its molecular pathogenesis, and provide a theoretical basis for early warning and precision prevention and control, we selected 12 Holstein dairy cows of similar age (2.92 ± 0.12 years), parity (1.56 ± 0.21), body condition score (BCS) (2.84 ± 0.04), milk yield (26.81 ± 0.22 kg/d), and day in milk (DIM) (6.60 ± 0.24 d) and no significant between-group differences as experimental animals. Based on serum calcium concentrations on postpartum days 1 to 4 and clinical presentation, the cows were divided into a healthy control group (serum calcium > 1.77 mmol/L on day 1 and >2.20 mmol/L on day 4 postpartum, n = 6) and a persistent subclinical hypocalcemia group (serum calcium ≤ 1.77 mmol/L on day 1 and ≤2.20 mmol/L on day 4 postpartum, n = 6). Serum samples were collected on postpartum days 1, 2, and 4 and analyzed using 4D-DIA quantitative proteomics. A total of 178 significantly differentially expressed proteins were identified (fold change > 1.2, p < 0.05), including 59 up-regulated and 119 down-regulated proteins. These differentially expressed proteins were mainly enriched in pathways involving endocrine and other factor-regulated calcium reabsorption, regulation of actin cytoskeleton, the tricarboxylic acid cycle (TCA cycle), and lipoic acid metabolism. The results indicate that the pathological state of pSCH is closely associated with abnormalities in calcium reabsorption regulation, actin cytoskeleton maintenance, and mitochondrial energy metabolism-related signaling pathways. The key proteins and pathways identified in this study provide a theoretical foundation for future in-depth research on the pathogenesis, prevention, and treatment of pSCH. Full article