Search Results (1,586)

Perturbations in the tightly regulated processes of VLDL biosynthesis and secretion can directly impact both liver and cardiovascular health. Patients with metabolic disorders have an increased risk of developing hepatic steatosis, which can lead to cirrhosis. These associated metabolic risks underscore the importance of discerning the role of different cellular proteins involved in VLDL biogenesis, transport, and secretion. Small VCP-Interacting Protein (SVIP) has been identified as a component of VLDL transport vesicles and VLDL secretion. This study evaluates the cellular effects stemming from the CRISPR-Cas9-mediated depletion of SVIP in rat hepatocytes. The SVIP-knockout (KO) cells display an increased VLDL retention with elevated intracellular levels of ApoB100 and neutral lipid staining. RNA sequencing studies reveal an impaired PPARα and Nrf2 signaling in the SVIP KO cells, implying a state of metabolic reprograming, with a shift from fatty acid uptake, synthesis, and oxidation to cells favoring the activation of glucose by impaired glycogen storage and increased glucose release. Additionally, SVIP KO cells exhibit a transcriptional profile indicative of acute phase response (APR) in hepatocytes. Many inflammatory markers and genes associated with APR are upregulated in the SVIP KO hepatocytes. In accordance with an APR-like response, the cells also demonstrate an increase in mRNA expression of genes associated with protein synthesis. Together, our data demonstrate that SVIP is critical in maintaining hepatic lipid homeostasis and metabolic balance by regulating key pathways such as PPARα, Nrf2, and APR. Full article

The apicoplast is a highly specialized organelle in the biosynthesis of essential metabolites in most of the apicomplexan protozoa. This organelle is surrounded by four layers of membranes. However, the molecular mechanisms mediating transmembrane transport are not yet fully understood. In this study, we conducted a phenotypic analysis to investigate the role of a major facilitator superfamily transporter (TgApMFS1) in the survival of the parasite. The results indicated that TgApMFS1 is critical for the survival of Toxoplasma gondii in cell culture conditions. Further analysis indicated that these transporters are crucial for the biogenesis of organelles and the metabolic processes of parasite. Full article

Sarcopenia, characterized by progressive skeletal muscle loss and functional decline, represents a major public heath challenge in aging populations. Despite increasing awareness, current management strategies—primarily resistance exercise and nutritional support—remain limited by accessibility, adherence, and inconsistent outcomes. This underscores the urgent need for novel, effective, and scalable therapeutics. Flavonoids, a diverse class of plant-derived polyphenolic compounds, have attracted attention for their muti-targeted biological activities, including anti-inflammatory, antioxidant, metabolic, and myogenic effects. This review aims to evaluate the anti-sarcopenic potential of selected flavonoids—quercetin, rutin, kaempferol glycosides, baicalin, genkwanin, isoschaftoside, naringin, eriocitrin, and puerarin—based on recent preclinical findings and mechanistic insights. These compounds modulate key pathways involved in muscle homeostasis, such as NF-κB and Nrf2 signaling, AMPK and PI3K/Akt activation, mitochondrial biogenesis, proteosomal degradation, and satellite cell function. Importantly, since muscle wasting also features prominently in cancer cachexia—a distinct but overlapping syndrome—understanding flavonoid action may offer broader therapeutic relevance. By targeting shared molecular axes, flavonoids may provide a promising, biologically grounded approach to mitigating sarcopenia and the related muscle-wasting conditions. Further translational studies and clinical trials are warranted to assess their efficacy and safety in human populations. Full article

Background: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold transformative potential for cardiovascular regenerative medicine, yet their clinical application is hindered by suboptimal mitochondrial maturation and metabolic inefficiencies. This systematic review evaluates targeted strategies for optimizing mitochondrial function, integrating metabolic preconditioning, substrate selection, and pathway modulation to enhance energy production and cellular resilience. Additionally, we examine the role of extracellular matrix stiffness and mechanical stimulation in mitochondrial adaptation, given their influence on metabolism and maturation. Methods: A comprehensive analysis of recent advancements in iPSC-CM maturation was conducted, focusing on metabolic interventions that enhance mitochondrial structure and function. Studies employing metabolic preconditioning, lipid and amino acid supplementation, and modulation of key signaling pathways, including PGC-1α, AMPK, and mTOR, were reviewed. Computational modeling approaches predicting optimal metabolic shifts were assessed, alongside insights into reactive oxygen species (ROS) signaling, calcium handling, and the impact of electrical pacing on energy metabolism. Results: Evidence indicates that metabolic preconditioning with fatty acids and oxidative phosphorylation enhancers improves mitochondrial architecture, cristae density, and ATP production. Substrate manipulation fosters a shift toward adult-like metabolism, while pathway modulation refines mitochondrial biogenesis. Computational models enhance precision, predicting interventions that best align iPSC-CM metabolism with native cardiomyocytes. The synergy between metabolic and biomechanical cues offers new avenues for accelerating maturation, bridging the gap between in vitro models and functional cardiac tissues. Conclusions: Strategic metabolic optimization is essential for overcoming mitochondrial immaturity in iPSC-CMs. By integrating biochemical engineering, predictive modeling, and biomechanical conditioning, a robust framework emerges for advancing iPSC-CM applications in regenerative therapy and disease modeling. These findings pave the way for more physiologically relevant cell models, addressing key translational challenges in cardiovascular medicine. Full article

T cells play a vital role in resisting pathogen invasion and maintaining immune homeostasis. However, T cells gradually become exhausted under chronic antigenic stimulation, and this exhaustion is closely related to mitochondrial dysfunction in T cells. Mitochondria play a crucial role in the metabolic reprogramming of T cells to achieve the desired immune response. Here, we compiled the latest research on how mitochondrial metabolism determines T cell function and differentiation, with the mechanisms mainly including mitochondrial biogenesis, fission, fusion, mitophagy, and mitochondrial transfer. In addition, the alterations in mitochondrial metabolism in T-cell exhaustion were also reviewed. Furthermore, we discussed intervention strategies targeting mitochondrial metabolism to reverse T cell exhaustion in detail, including inducing PGC-1α expression, alleviating reactive oxygen species (ROS) production or hypoxia, enhancing ATP production, and utilizing mitochondrial transfer. Targeting mitochondrial metabolism in exhausted T cells may achieve the goal of reversing and preventing T cell exhaustion. Full article

The expanding distribution and geographic range of mosquitoes have potentially contributed to increased flaviviral dissemination and transmission. Despite the growing burden of flaviviral infections, there are no effective antiviral treatments or vaccines, highlighting the need for novel therapeutic targets. Tetraspanins, a superfamily of transmembrane domain glycoproteins involved in cellular organization, signaling, and protein–protein interactions have been recognized as potential mediators of flaviviral infection and transmission. While their roles in vertebrate hosts have been explored, their involvement in flaviviral replication and dissemination within medically important vectors remains poorly understood. In this study, we investigated the role of arthropod tetraspanins in mosquito cells and extracellular vesicles (EVs) derived from cells infected with Zika virus (ZIKV) and dengue virus (serotype 2; DENV2). Among several of the tetraspanins analyzed, only CD151 was significantly upregulated in both mosquito cells and in EVs derived from ZIKV/DENV2-infected cells. RNAi-mediated silencing of CD151 led to a marked reduction in viral burden, suggesting its crucial role in flavivirus replication. Inhibition of EV biogenesis using GW4869 further demonstrated that EV-mediated viral transmission contributes to flavivirus propagation. Additionally, co-immunoprecipitation and immunofluorescence analyses revealed direct interactions between CD151 and ZIKV NS2B and DENV2 capsid proteins. Overall, our findings highlight the functional importance of mosquito CD151 in the replication and transmission of ZIKV and DENV2. This study provides new insights into the molecular mechanisms of flaviviral infection in mosquitoes and suggests that targeting vector tetraspanins may offer a potential approach to controlling mosquito-borne flaviviruses. Full article

Lymphoma continues to pose a serious challenge to global health, underscoring the urgent need for new therapeutic strategies. Recently, the gut microbiome has been shown to play a potential role in regulating immune responses and influencing cancer progression. However, its molecular mechanisms of action in lymphoma remain poorly understood. This study investigates the antiproliferative and apoptotic activities of gut microbiota-derived metabolites, specifically nisin (N) and urolithin B (UB), individually and in combination 7:3 (5750 μM), against the human lymphoma cell line HKB-11. Comprehensive evaluations were performed using Alamar Blue viability assays, combination index (CI) analyses, reactive oxygen species (ROS) quantification, flow cytometry for apoptosis detection, and advanced bottom-up proteomics analyses. N and UB exhibited potent antiproliferative activity, with the 7:3 combination demonstrating strong synergistic effects (CI < 1), significantly enhancing apoptosis (p < 0.01) and ROS production (p < 0.0001) compared to the untreated control. Proteomics analyses revealed substantial alterations in proteins crucial to ribosomal biogenesis, mitochondrial function, cell cycle control, and apoptosis regulation, including a marked downregulation of ribosomal proteins (RPS27; Log₂FC = −3.47) and UBE2N (Log₂FC = −0.60). These findings highlight the potential of N and UB combinations as a novel and practical therapeutic approach for lymphoma treatment, warranting further in vivo exploration and clinical validation. Full article

The enterovirus Coxsackievirus B3 causes a range of serious health problems, including aseptic meningitis, myocarditis, and pancreatitis. Currently, Coxsackievirus B3 has no targeted antiviral treatments or vaccines, leaving supportive care as the primary management option. Understanding how Coxsackievirus B3 interacts with and alters the blood–brain barrier may help identify new therapies to combat this often-devastating infection. We reanalyzed a previously published RNA sequencing dataset for Coxsackievirus B3-infected human-induced pluripotent stem-cell-derived brain endothelial cells (iBECs) to examine how Coxsackievirus B3 altered mRNA expression. By integrating GSEA, EnrichR, and iLINCs-based perturbagen analysis, we present a novel, systems-level approach to uncover potential drug repurposing candidates for CVB3 infection. We found dynamic changes in host transcriptomic response to Coxsackievirus B3 infection at 2- and 5-day infection time points. Downregulated pathways included ribosomal biogenesis and protein synthesis, while upregulated pathways included a defense response to viruses, and interferon production. Using iLINCs transcriptomic analysis, MEK, PDGFR, and VEGF inhibitors were identified as possible novel antiviral therapeutics. Our findings further elucidate Coxsackievirus B3-associated pathways in (iBECs) and highlight potential drug repurposing candidates, including pelitinib and neratinib, which may disrupt Coxsackievirus B3 pathology at the blood–brain barrier (BBB). Full article

Plant-derived vesicle-like nanoparticles (PDVLNs) are bioactive nanovesicles secreted by plant cells, emerging as a novel therapeutic tool for tissue repair and regeneration due to their low immunogenicity, intrinsic bioactivity, and potential as drug delivery carriers. This review examines PDVLNs’ biogenesis mechanisms, isolation techniques, and compositional diversity, emphasizing their roles in promoting essential regenerative processes—cell proliferation, differentiation, migration, immune modulation, and angiogenesis. We explore their therapeutic applications across multiple tissue types, including skin, bone, neural, liver, gastrointestinal, cardiovascular, and dental tissues, using both natural and engineered PDVLNs in various disease models. Compared to mammalian exosomes, PDVLNs offer advantages such as reduced immune rejection and ethical concerns, enhancing their sustainability and appeal for regenerative medicine. However, challenges in clinical translation, including scalability, standardization, and safety remain. This paper consolidates current knowledge on PDVLNs, highlighting their versatility and providing insights into engineering strategies to optimize efficacy, ultimately outlining future research directions to advance their clinical potential. Plant vesicle-like nanoparticles (PDVLNs) may become a new avenue for the treatment of tissue injury, promoting tissue repair and regeneration through their intrinsic bioactivity or as drug delivery carriers. In addition, PDVLNs can be engineered and modified to achieve better results. Full article

Sorghum is a versatile crop that serves as a major source of food, feed, fodder and biofuel globally. Lignin content in sorghum affects multiple important traits, including lodging resistance, forage digestibility and the efficiency of bioenergy production. However, the genetic regulation of lignin content in sorghum remains poorly understood. In this study, we combined transcriptomic and comparative genomic approaches to uncover the genetic network underlying lignin biosynthesis in sorghum. Through comparative genomic analysis, we identified 104 candidate genes involved in lignin biosynthesis. Transcriptome analysis of four sorghum accessions with contrasting lignin contents identified 6132 differentially expressed genes with an enrichment of genes related to phenylpropanoid biosynthesis and cell wall biogenesis. The 104 lignin biosynthesis candidates were significantly enriched (p-value < 0.01) in these differentially expressed genes, with most differentially expressed candidate genes related to monolignol biosynthesis and polymerization being up-regulated in high-lignin accessions. These up-regulated genes are related to all key enzymes involved in lignin biosynthesis, suggesting that the elevated lignin content in these accessions results from a collective increase in enzyme activity. Sequence analysis revealed a significant reduction in genetic diversity across lignin biosynthesis genes in cultivated sorghum compared to wild sorghum. Moreover, selection signals during domestication were identified in 30 lignin biosynthesis genes, 22 of which were differentially expressed, further supporting the functional relevance of these differentially expressed genes in lignin biosynthesis. Overall, our findings uncover the lignin biosynthesis gene network in sorghum and offer potential targets for future functional studies and trait manipulation. Full article

The mitochondrial regulator MNRR1 is reduced in several pathologies, including the mitochondrial heteroplasmic disease MELAS, and genetic restoration of its level normalizes the pathological phenotype. Here, we investigate the upstream mechanism that reduces MNRR1 levels. We have identified the hypoxic regulator HIF2α to bind the MNRR1 promoter and inhibit transcription by competing with RBPJκ. In MELAS cells, there is a pseudohypoxic state that transcriptionally induces HIF2α and stabilizes HIF2α protein. MELAS cybrids harboring the m.3243A > G mutation display reduced levels of prolyl hydroxylase 3 (PHD3), which contributes to the HIF2α stabilization. These results prompted a search for compounds that could increase MNRR1 levels pharmacologically. The screening of a 2400-compound library uncovered the antifungal drug nitazoxanide and its metabolite tizoxanide as enhancers of MNRR1 transcription. We show that treating MELAS cybrids with tizoxanide restores cellular respiration, enhances mitophagy, and, importantly, shifts heteroplasmy toward wild-type mtDNA. Furthermore, in fibroblasts from MELAS patients, the compound improves mitochondrial biogenesis, enhances autophagy, and protects from LPS-induced inflammation. Mechanistically, nitazoxanide reduces HIF2α levels by increasing PHD3. Chemical activation of MNRR1 is thus a potential strategy to improve mitochondrial deficits seen in MELAS. Finally, our data suggests a broader physiological pathway wherein two proteins, induced under severe (1% O2; HIF2α) and moderate (4% O2; MNRR1) hypoxic conditions, regulate each other inversely. Full article

Sarcopenia, the age-related loss of skeletal muscle mass and function, is associated with inflammation, mitochondrial dysfunction, and gut barrier impairment. This study investigates the postbiotic effects of heat-killed Lactiplantibacillus plantarum HY7715 (HY7715) and its extracellular vesicles (EVs) on muscle health and intestinal integrity. In C2C12 myotubes, both treatments enhanced myogenic differentiation by upregulating Myf5 and MYOG, and improved mitochondrial activity and biogenesis via increased PGC1α and mTOR expression. Under TNFα-induced muscle atrophy, they suppressed expression of atrophy-related markers (Fbox32, MuRF1, and myostatin). EVs showed stronger anti-inflammatory effects by reducing IL6 expression in muscle cells. In intestinal Caco-2 cells, HY7715-derived EVs improved barrier function by upregulating tight junction proteins (ZO-1, occludin, and claudins), and effectively reduced LPS-induced inflammation. These findings suggest that heat-killed HY7715 and its EVs may alleviate sarcopenia by enhancing muscle regeneration and maintaining intestinal homeostasis, highlighting their potential as safe, gut–muscle axis-targeting postbiotic interventions for healthy aging. Full article

Multidrug resistance (MDR) significantly contributes to colon cancer recurrence, making it essential to understand its molecular basis for improved therapies. This study aimed to identify genes and pathways involved in resistance to standard chemotherapeutics by comparing transcriptome profiles of sensitive and paclitaxel-induced MDR colonospheres. Cell viability and growth were assessed following treatment with 5-fluorouracil, oxaliplatin, irinotecan, bevacizumab, and cetuximab. Drug concentrations in culture media posttreatment were measured using high-performance liquid chromatography (HPLC). RNA sequencing (RNA-seq) of untreated sensitive and resistant colonospheres identified differentially expressed genes linked to baseline resistance. Our results confirmed cross-resistance in the resistant model, showing highest oxaliplatin tolerance may involve mechanisms beyond efflux. Transcriptome analysis highlighted upregulation of PIGR and activation of the ribosomal signaling pathway as potential resistance mediators. Notably, AKR1B10, a gene linked to chemotherapeutic detoxification, was overexpressed, whereas genes related to adhesion and membrane transport were downregulated. The overexpression of ribosomal protein genes suggests ribosome biogenesis plays a key role in acquired resistance. These findings suggest that targeting ribosome biogenesis and specific deregulated genes such as PIGR and AKR1B10 may offer promising strategies to overcome MDR in colon cancer. Full article

This manuscript assesses the critical role of exosomal PD-L1 (ExoPD-L1) in immune suppression, tumor progression, and resistance to therapy. ExoPD-L1 has been identified as a key mediator of tumor immune evasion, contributing to systemic immunosuppression beyond the tumor microenvironment (TME) due to its capacity to travel to distant anatomical sites. In this context, the review aims to elaborate on the mechanisms by which exosomal PD-L1 interacts with T cell receptors and modulates both the tumor microenvironment and immune responses, impacting patient outcomes. We further explore emerging therapeutic strategies that target ExoPD-L1 to enhance the effectiveness of immunotherapy. Blocking ExoPD-L1 offers a novel approach to counteracting immune escape in cancer. Promising strategies include inhibiting exosome biogenesis with GW4869 or Rab inhibitors, neutralizing ExoPD-L1 with targeted antibodies, and silencing PD-L1 expression through RNA interference (RNAi) or CRISPR-based methods. While each approach presents certain limitations, their integration into combination therapies holds significant potential to improve the efficacy of immune checkpoint inhibitors. Future research should focus on optimizing these strategies for clinical application, with particular attention to improving delivery specificity and minimizing off-target effects. Full article

Helicobacter pylori, which colonizes the human gastric mucosa, uses a cluster of polar, sheathed flagella to swim across the mucous layer of the stomach. The function and biogenesis of the H. pylori flagellar sheath are poorly understood. Cardiolipin is a phospholipid that accumulates in regions of the membrane that have negative curvature, such as the cell pole, cell septum, and flagellar sheath. The final step in cardiolipin biosynthesis is catalyzed by cardiolipin synthase. H. pylori has at least two cardiolipin synthases, one of which is cardiolipin synthase C (ClsC). Bioinformatic analysis revealed that homologs of H. pylori ClsC are restricted to Helicobacter species that have sheathed flagella and the ClsC homologs are predicted lipoproteins. Fluorescence microscopy revealed that a ClsC super-folder green fluorescent protein localized to the cell pole and cell septum in H. pylori G27. Comparing the proteomes of isolated sheathed flagella from the H. pylori B128 wild type and a clsC::cat mutant, we identified five proteins that were absent in the mutant flagellum preparations. One of the proteins was FaaA, an autotransporter that localizes to the flagellar sheath. These findings suggest that the localization of FaaA and possibly other proteins to the flagellar sheath is dependent on ClsC. Full article