Search Results (19,939)

Significant differences in reproductive performance exist between meat-type ducks (e.g., Qiangying Duck, QD) and laying-type ducks (e.g., Shaoxing Duck, SD). The molecular mechanisms underlying these differences, particularly concerning ovarian development and function, remain incompletely understood. This study aimed to comprehensively characterize the ovarian transcriptomes of these two duck types, focusing on differential gene expression and post-transcriptional regulatory events. We performed an integrated full-length transcriptome analysis of ovarian tissues from these two breeds using PacBio SMRT and Illumina sequencing. Bioinformatic analyses, including functional annotation, differential expression analysis, and the identification of APA events, were used. We discovered substantial breed-specific differences in alternative polyadenylation (APA), with SD ducks exhibiting significant 3′UTR shortening in 3799 genes and 3′UTR lengthening in 1626 genes compared to QD. The integrated analysis of differential gene expression and APA events highlighted key genes related to steroid hormone synthesis (HMGCS1, DHCR24), lipid metabolism (SCD), signal transduction (HRAS), and antioxidant defense (SOD1). The functional enrichment implicated critical pathways such as mitochondrial energy metabolism, oxidative phosphorylation, and fatty acid degradation. Our study provides a comprehensive atlas of post-transcriptional regulation in the duck ovary and reveals APA as a crucial process of gene regulation. APA may contribute to the differential ovarian function and egg-laying capacity between meat and laying ducks, thus offering valuable targets for genetic selection. Full article

Mitochondrial genomes play a central role in fungal physiology and adaptation, yet their evolutionary dynamics during domestication remain poorly understood. Here, we performed a comparative mitogenomic and gene-expression analysis of three Pleurotus ostreatus dikaryotic strains differing in origin and degree of adaptation to laboratory conditions: the long-term commercial strain dkN001, the laboratory-maintained wild isolate dkF515, and the recently collected wild strain dkN009. High-throughput Illumina sequencing enabled complete assembly of circular mitochondrial genomes, revealing substantial size variation among strains, where the dkN001 strain exhibited the second smallest mitogenome reported for the genus Pleurotus. Comparative analyses showed >99% sequence identity between wild isolates and ~95% identity relative to the commercial strain. Variations in genome size among strains were associated with intron dynamics in the cox1 and rnl genes, as well as intron loss predominantly in the commercial strain dkN001, consistent with mitochondrial genome streamlining during domestication. Expression profiling of mitochondrial protein-coding genes (PCGs) under multiple culture conditions revealed conserved transcriptional responses in dkN001 and dkF515 that contrasted sharply with those of dkN009. The differences observed, which affected components of the electron transport chain, suggested shifts in energy metabolism associated with long-term laboratory maintenance. Therefore, our results demonstrate that domestication in P. ostreatus involves both structural remodelling of the mitogenome and changes in regulation of mitochondrial PCGs, highlighting the importance of mitonuclear interactions in fungal adaptation to controlled environments. Full article

Mitochondrial dysfunction is a key early pathological process in neurodegenerative diseases (NDs), leading to oxidative stress, impaired energy metabolism, and neuronal apoptosis prior to the onset of clinical symptoms. Although mitochondria represent important therapeutic targets, effective interventions targeting mitochondrial function remain limited. This review summarizes current evidence regarding the mechanisms by which melatonin protects mitochondria and evaluates its therapeutic relevance, with a primary focus on Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease—the major protagonists of NDs—while briefly covering other NDs such as amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. Melatonin selectively accumulates in neuronal mitochondria and exerts neuroprotection through multiple pathways: (1) direct scavenging of reactive oxygen species (ROS); (2) transcriptional activation of antioxidant defenses via the SIRT3 and Nrf2 pathways; (3) regulation of mitochondrial dynamics through DRP1 and OPA1; and (4) promotion of PINK1- and Parkin-mediated mitophagy. Additionally, melatonin exhibits context-dependent pleiotropy: under conditions of mild mitochondrial stress, it restores mitochondrial homeostasis; under conditions of severe mitochondrial damage, it promotes pro-survival autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby conferring stage-specific therapeutic advantages. Overall, melatonin offers a sophisticated mitochondria-targeting strategy for the treatment of NDs. However, successful clinical translation requires clarification of receptor-dependent signaling pathways, development of standardized dosing strategies, and validation in large-scale randomized controlled trials. Full article

The APETALA2/Ethylene Response Factor (AP2/ERF) family of transcription factors (TF) is characterized by their participation in various biological processes related to growth, development, and response to stress. ERFs are ideal candidates for crop improvement because they regulate defense genes like JERF1, JERF3, LeERF2, NtERF5, and Tsil which confer tolerance to drought, salinity, osmotic stress, and pathogen attack, respectively. The ERF subfamily includes the TF Pti4, whose activity is regulated by different signaling pathways, thus providing tolerance response to multiple factors such as drought, salinity, cold, and pathogen attack in tomato. In this work we evaluated the effect of overexpression of TF SlPti4 from Solanum lycopersicum in transgenic tobacco plants when subjected to saline, osmotic, and drought stress. Our results from this study demonstrated that transgenic lines overexpressing Pti4 tolerate abiotic stress during germination and in plants. The transgenic lines showed improvements in photoinhibition, electron transport rate, chlorophyll content, and biomass, as well as a reduction in malondialdehyde content. Full article

The intervertebral disc (IVD) is the largest avascular structure in the human body, and its nucleus pulposus (NP) cells predominantly generate large amounts of lactate through glycolysis, accompanied by an acidic microenvironment—features that represent characteristic metabolic traits of disc cells. In recent years, knowledge of the biological roles of lactate has undergone a conceptual shift. On the one hand, lactate can serve as a context-dependent auxiliary biofuel in specific regions of the IVD, particularly within annulus fibrosus (AF) regions adjacent to the NP. On the other hand, lactate functions in disc cells as a signaling molecule and a metabolic–epigenetic regulator, influencing transcriptional programs through lactylation and modulating multiple molecular pathways associated with cellular stress adaptation and fate determination. This review summarizes current knowledge on lactate production, transport, and clearance in the intervertebral disc, as well as emerging evidence for the roles of lactate in disc health and pathophysiology. In addition, we outline research perspectives and future directions aimed at advancing our understanding of lactate biology and evaluating its potential as a therapeutic target for intervertebral disc degeneration. Full article

Seed coat color in peanut (Arachis hypogaea L.) is a critical agronomic trait that affects both nutritional quality and market appeal. In this study, we identified two bHLH transcription factor genes, AhWSC1a and AhWSC1b, homologues of Arabidopsis TRANSPARENT TESTA 8, as indispensable gatekeepers of basal flavonoid pigmentation. QTL-seq analysis of a recombinant inbred line population derived from a black-testa parent (S3) and a white-testa parent (S2) revealed that recessive loss-of-function mutations in both AhWSC1a/1b abolish proanthocyanidin biosynthesis, resulting in a white testa. Integrated metabolomic and transcriptomic profiling confirmed the absence of proanthocyanidins and a strong repression of late anthocyanin-pathway genes (DFR, LDOX) in the mutants. Molecular assays further demonstrated that AhWSC1 physically interacts with the R2R3-MYB regulator AhTc1 to form a functional MBW complex that activates AhDFR and AhLDOX transcription. In this research, we also found that the black testa phenotype may arise from elevated AhTc1 expression associated with a structural variant (SV); however, in the SV background, the introduction of ahwsc1a/1b mutant leads to a significant suppression of AhTc1 expression. Notably, because AhWSC1 is transcriptionally silent in hairy-root systems, overexpression of AhTc1 alone failed to induce these late-stage anthocyanin biosynthesis genes, highlighting AhWSC1 as an indispensable, rate-limiting hub of anthocyanin biosynthesis pathway regulation. Collectively, our findings establish AhWSC1a and AhWSC1b as master regulators of peanut testa pigmentation, elucidate the molecular basis of classical white testa inheritance, and provide genetic targets for precision-breeding of nutritionally enhanced cultivars. Full article

Inositol is a natural carbocyclic sugar that plays an essential role in regulating the vital cellular functions of plants and animals. Existing research has explored methyl derivatives of inositol, reporting on their various biological activities, including antitumor, anti-inflammatory, and anti-osteoporosis activities. Our previous study demonstrated that L-quebrachitol, a methyl derivative of inositol, enhances osteoblastogenesis and bone formation; however, its effect on osteoclastogenesis remains unclear. Consequently, we aimed to investigate the effect of L-quebrachitol on receptor activator of nuclear factor-κB ligand-induced osteoclastogenesis in pre-osteoclastic RAW 264.7 cells, and bone resorption in an ovariectomized rat model. The results revealed that L-quebrachitol suppressed RANK-mediated signaling, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Fos proto-oncogene (cFOS) pathways, at both the gene and protein levels. Moreover, the critical transcription factor for osteoclastogenesis, nuclear factor of activated T cells c1 (NFATc1), was downregulated. Inhibition of osteoclast-associated marker genes encoding proteolytic enzymes, such as tartrate-resistant acid phosphatase (TRAP), matrix metallopeptidase 9 (MMP-9), and cathepsin K, led to reduced formation of TRAP-positive multinucleated cells and resorption pits. In addition, proteasome subunit alpha type-5 (PSMA5), which is involved in the degradation of the NF-κB inhibitor, was also suppressed. In particular, the animal study clearly supported the bone homeostasis property of the agent by increasing the BV/TV (bone volume/total volume) and Tb.Th (trabecular thickness) in ovariectomized rats. These findings demonstrate the dose-dependent inhibitory effect of L-quebrachitol on osteoclastogenesis through the modulation of RANK-mediated signaling pathways and prevention of bone loss in an animal model. However, further exploration of the potential of L-quebrachitol as an effective approach for osteoporosis is required. Full article

Joint acidosis is increasingly recognized as an important determinant of cellular behavior in osteoarthritis (OA). Declines in extracellular pH (pHe) occur across cartilage, meniscus, synovium, and subchondral bone, where they influence inflammation, matrix turnover, and pain. Among proton-sensing G protein-coupled receptors, GPR68 responds to the acidic pH range characteristic of human OA joints. The receptor is activated between pH 6.8 and 7.0, couples to Gq/PLC-MAPK, cAMP-CREB, G12/13-RhoA-ROCK signaling pathways, and is expressed most prominently in articular cartilage, with additional expression reported in synovium, bone, vasculature, and some neuronal populations. These pathways regulate transcriptional programs relevant to cartilage stress responses, inflammation, and matrix turnover. GPR68 expression is increased in human OA cartilage and aligns with regions of active matrix turnover. We previously reported that pharmacologic activation of GPR68 suppresses IL1β-induced MMP13 expression in human chondrocytes under acidic conditions, indicating that increased GPR68 expression may represent a microenvironment-responsive, potentially adaptive signaling response rather than a driver of cartilage degeneration. Evidence from intestinal, stromal, and vascular models demonstrates that GPR68 integrates pH changes with inflammatory and mechanical cues, providing mechanistic context, although these effects have not been directly established in most joint tissues. Small-molecule modulators, including the positive allosteric agonist Ogerin and the inhibitor Ogremorphin, illustrate the tractability of GPR68 as a drug target, although no GPR68-directed therapies have yet been evaluated in preclinical models of OA. Collectively, current data support GPR68 as a functionally relevant proton sensor within the acidic OA joint microenvironment. Full article

Acute myeloid leukemia (AML) is a highly aggressive malignancy defined by significant biological diversity and variable patient outcomes. A key subset of AML is driven by abnormalities that lead to the overexpression of the oncogenic transcription factors HOXA9 and MEIS1. These abnormalities include KMT2A (formerly MLL) rearrangements and NPM1 mutations, as well as other rare lesions such as NUP98 rearrangements. This review focuses on the biology of the KMT2A, NPM1, and HOX/MEIS1 pathways, dissecting their molecular mechanisms of leukemogenesis. A central theme is the role of the scaffolding protein menin in the epigenetic regulation of this pathway, which ultimately drives malignant transformation. Currently, the clinical landscape is being transformed by the emergence of menin inhibitors as promising therapeutic agents for AML harboring these specific genetic anomalies. We evaluate the latest data on various menin inhibitors—both as monotherapy and in combinations—emphasizing their efficacy and safety profiles. As new evidence continues to accumulate with recent drug approvals and ongoing randomized, phase 3 studies, menin inhibitors are rapidly becoming a component of the AML treatment paradigm for relapsed/refractory and likely newly diagnosed disease. Full article

Osthole is a natural coumarin derivative found in several medicinal plants, including Cnidium monnieri and Angelica pubescens. It has been studied for its various biological properties, such as anti-inflammatory, neuroprotective, osteogenic, cardioprotective, antimicrobial, and antiparasitic effects. Osthole was found to induce Fibroblast growth factor 21 (FGF21) expression. Among the known transcription factors that regulate FGF21 induction, activating transcription factor 4 (ATF4) expression was found to be upregulated by osthole. Additionally, as osthole induced ATF4 downstream gene expression, it was concluded that it activates ATF4 signaling. ATF4 knockdown significantly suppressed osthole-mediated induction of FGF21 expression. These findings suggest that osthole activates FGF21 expression via ATF4 activation. Full article

Cancer stem cells (CSCs) represent a small but highly resilient tumor subpopulation responsible for sustained growth, metastasis, therapeutic resistance, and recurrence. Their survival is supported by aberrant activation of developmental and inflammatory pathways, including Wnt/β-catenin, Notch, Hedgehog, PI3K/Akt/mTOR, STAT3, and NF-κB, as well as epithelial–mesenchymal transition (EMT) programs and niche-driven cues. Increasing evidence shows that phytochemicals, naturally occurring bioactive compounds from medicinal plants, can disrupt these networks through multi-targeted mechanisms. This review synthesizes current findings on prominent phytochemicals such as curcumin, sulforaphane, resveratrol, EGCG, genistein, quercetin, parthenolide, berberine, and withaferin A. Collectively, these compounds suppress CSC self-renewal, reduce sphere-forming capacity, diminish ALDH⁺ and CD44⁺/CD24⁻ fractions, reverse EMT features, and interfere with key transcriptional regulators that maintain stemness. Many phytochemicals also sensitize CSCs to chemotherapeutic agents by downregulating drug-efflux transporters (e.g., ABCB1, ABCG2) and lowering survival thresholds, resulting in enhanced apoptosis and reduced tumor-initiating potential. This review further highlights the translational challenges associated with poor solubility, rapid metabolism, and limited bioavailability of free phytochemicals. Emerging nanotechnology-based delivery systems, including polymeric nanoparticles, lipid carriers, hybrid nanocapsules, and ligand-targeted formulations, show promise in improving stability, tumor accumulation, and CSC-specific targeting. These nanoformulations consistently enhance intracellular uptake and amplify anti-CSC effects in preclinical models. Overall, the consolidated evidence supports phytochemicals as potent modulators of CSC biology and underscores the need for optimized delivery strategies and evidence-based combination regimens to achieve meaningful clinical benefit. Full article

Pigs are a major source of animal protein for humans and serve as valuable biomedical models. Compared to Western commercial pig breeds, Jinhua pigs are characterized by superior meat quality due to dynamic muscle development and fat deposition. However, studies investigating dynamic transcriptional regulation of swine meat quality traits across developmental stages remain limited. In this work, we collected longissimus dorsi muscle tissue from three Jinhua and three Landrace × Yorkshire pigs at 1, 90, and 180 days of age, respectively. We have uncovered differentially expressed genes and transcripts, alternative splicing events, and gene fusion events across development stages utilizing RNA sequencing data. CKM exhibited consistent breed-specific alternative splicing and gene fusion events across all three stages, representing a stable regulator of muscle development in Jinhua pigs. On the other hand, our findings highlight day 90 as a critical “window phase” for muscle development and meat quality differences between Jinhua and Landrace × Yorkshire pigs at this stage, exhibiting the greatest number of inter-breed differences in transcriptomic genetic regulation. Additionally, time series analysis revealed that genes with peak expression at day 90 were significantly enriched in pathways associated with muscle development and function. Finally, we identified PFKM, PRKAG3, and CKM as candidate genes with age-specific expression and post-transcriptional regulation that likely influence muscle development. This study advances understanding of transcriptional regulation in pig muscle with implications for meat quality improvement. Full article

The MATα_HMGbox and HMG-box_ROX1-like domains of the MAT1-1-1 and MAT1-2-1 proteins, respectively, play essential roles in DNA binding and the subsequent regulation of gene transcription, controlling Ophiocordyceps sinensis sexual reproduction. Alternative splicing, differential occurrence and transcription of the MAT1-1-1 and MAT1-2-1 genes have been demonstrated in Hirsutella sinensis (GC-biased Genotype #1 of the 17 O. sinensis genotypes), suggesting self-sterility under heterothallic or hybrid outcrossing. In this study, the MATα_HMGbox domains of MAT1-1-1 proteins in wild-type Cordyceps sinensis isolates were shown to cluster into 5 clades in the Bayesian clustering tree and belong to diverse stereostructure morphs under 19 AlphaFold codes. The HMG-box_ROX1-like domains of MAT1-2-1 proteins, on the other hand, were shown to cluster into 2 branched Bayesian clades and belong to stereostructure morphs under 25 AlphaFold codes. Correlation analysis revealed that 1–3 amino acid substitutions in the DNA-binding domains of the mating proteins resulted in altered hydrophobicity and secondary and tertiary structures of the DNA-binding domains of the proteins, especially altered stereostructures of the hydrophobic cores formed by 3 critical α- helices within the functional domains of the proteins. Fungal origin analysis revealed possible heterospecific fungal sources of mating proteins with stereostructure variations in wild-type C. sinensis isolates, suggesting that alterations in DNA binding function and the subsequent regulation of mating-related gene transcription are involved in ensuring the accuracy and genetic diversity of heterothallic and hybrid reproduction of O. sinensis during the lifecycle of the C. sinensis insect–fungal complex. Full article

Coxsackieviruses possess two proteases that are engaged in cleaving viral polyprotein and hijacking host cell processes such as RNA biosynthesis. Integrator subunit 10 (INTS10), a subunit of the integrator complex, facilitates the processing of small nuclear RNAs (U1 and U2 snRNAs) to regulate cellular transcription. We found that INST10 can be cleaved by Coxsackievirus B (CVB). Hence, we hypothesized that INST10 may play a role in CVB infection. In this study, INTS10 is identified as the substrate of CVB3 protease 3C (3C^pro). The cleavage occurs at the residue Q221 and yields a fragment. Depletion of INTS10 enhanced CVB3 replication and blocked snRNA processing. Overexpression of U1 snRNA inhibited CVB3 infection, whereas its knockdown conversely enhanced it. Similarly, knockdown of U2 snRNA was found to promote CVB3 replication. Taken together, the 3C^pro-mediated cleavage of INTS10 disrupts U snRNA processing, which in turn counteracts the inhibitory effect of snRNA U1 and U2 on virus replication and subverts host defenses. Full article

Delayed harvesting of grapes can alter fruit quality and plays an important role in alleviating the problem of market saturation during peak seasons, as well as in regulating the supply period of grapes. In this study, by conducting a comparative analysis of fruit quality, metabolomics (aroma compounds) and transcriptome sequencing of ‘Shine Muscat’ grapes harvested at six different on-tree ripening stages after maturity, we found that: (1) delayed harvesting led to dramatic variation in berry color change (light green to yellow) with a significant increase in soluble solids (19.5 to 20.89 Brix); (2) A total of 25 volatile aroma compounds was identified in collected berry samples, while trans-2-hexenal and hexanal exhibited the highest concentrations in all samples, marking them as key volatile compounds in ‘Shine Muscat’ grapes. Notable variation in the concentrations of linalool, n-butanol, benzyl alcohol, phenylethanol, β-citronellol, and propionic anhydride were recorded in selected harvest periods. OAV analysis results show that linalool has the largest OAV among the detected compounds, and its OAV proportion increased from 53% to 95% during the six sampling periods of ‘Shine Muscat’; (3) Transcriptome sequencing of selected samples demonstrated a positive correlation between eight terpene-synthesis-related genes and linalool accumulation. Furthermore, genes within the MEP pathway (specifically VvTPS55, VvTPS59) and several transcription factors were associated with terpenoids metabolism. Based on soluble solids and OAV results, T18–T22 period (18–22 weeks post-flowering) can become good quality on-vine storge berries. The gene expression profile and developmental patterns of metabolites in MEP pathway may helpful in functional characterization of candidate genes related to terpenoid metabolism in future studies. Full article