📋 Browse Articles

The natural compound pterostilbene (PTE) has multiple cardiovascular protective effects. However, its effects on pulmonary arterial hypertension (PAH)-associated vascular remodeling remain to be elucidated. This study investigated the effects of PTE on monocrotaline (MCT)-induced PAH in rats Experimental PAH was established by subcutaneous injection of MCT (50 mg/kg) in Sprague-Dawley rats, which were then randomly divided into vehicle or PTE (15 mg/kg via gavage) treatment groups. Endothelial-to-mesenchymal transition (EndMT) was modeled in hPAECs by treating with transforming growth factor-β, tumor necrosis factor-α, and interleukin-1β in combination. In rats with MCT-induced PAH, administration of PTE resulted in a reduction in right ventricular systolic pressure, thereby alleviating right ventricular hypertrophy. This was accompanied by mitigation of the remodeling of pulmonary arteries. PTE mitigates MCT-induced PAH and vascular remodeling in rats, at least in part, by inhibiting HMGA-mediated EndMT, suggesting that PTE may be a useful complementary medicine in the treatment of PAH. Show less

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with tumor progression often driven by dysregulated oncogenic pathways. USP6NL, a known regulator of endocytic trafficking, has recently been implicated in tumorigenesis. However, its precise role in CRC remains unclear, and more studies are still needed to deepen our understanding of underlying mechanisms implicated in its oncogenic role. Therefore, silencing USP6NL could provide a novel therapeutic strategy by concurrently disrupting several oncogenic mechanisms, creating a new avenue for CRC management, particularly in patients who develop resistance against conventional therapies. This study investigates the impact of USP6NL knockdown on CRC cell morphology, proliferation, apoptosis, migration, angiogenesis, and metabolic adaptation, providing mechanistic insights into its oncogenic functions. HCT116 colorectal cancer cells were transfected with USP6NL-specific siRNA. Immunocytochemistry was used to confirm successful silencing, functional assays were performed to assess changes in cell morphology using phase-contrast and scanning electron microscopy, and colony formation and wound healing assays were performed to assess cell clonogenic capacity and migration, respectively, in addition to apoptosis assay via flow cytometry, and RT²-Profiler PCR array to measure variation in gene expression of 84 cancer-related genes. Statistical analyses were performed to evaluate significant differences between control and USP6NL-silenced groups. USP6NL depletion led to profound morphological changes, including membrane blebbing, cell shrinkage, and loss of adhesion, reflecting late apoptotic features of cells. These findings were further supported by flow cytometry, which confirmed increased apoptosis, with a higher proportion of late apoptotic cells (20.99% in USP6NL knockdown vs. 2.69% in control, p = 0.042). Colony formation assays revealed a significant reduction in the clonogenic potential, suggesting a critical role of USP6NL in promoting CRC cell proliferation (p ≤ 0.05). The wound healing assay demonstrated impaired migration in USP6NL-silenced cells, with a marked delay in wound closure (p = 0.0201 at 48 h). Gene expression analysis revealed a significant downregulation of VEGFC (-8.62-fold) and ANGPT2 (-4.03-fold), impairing angiogenesis and suppressing FOXC2, SNAI1, and SNAI2, indicating EMT inhibition. Additionally, CASP9, APAF1, and BCL2L11 were upregulated, confirming the activation of intrinsic apoptosis, while metabolic regulators HIF1A and LDHA were downregulated, suggesting impaired tumor hypoxic adaptation. This study establishes USP6NL as a key modulator of CRC progression, regulating proliferation, apoptosis, migration, angiogenesis, and metabolic pathways. The loss of USP6NL leads to EMT suppression, apoptosis induction, and reduced tumor cell viability, positioning it as a potential therapeutic target in colorectal cancer. Further investigations are warranted to explore USP6NL's interactions in oncogenic signaling networks and its feasibility as a target for CRC therapy. It could serve as a promising therapeutic target in colorectal cancer, potentially enhancing tumor cell death and limiting metastasis. Targeting USP6NL could also provide a novel approach in combination with existing therapies, improving treatment efficacy and reducing side effects. Show less

β-Hydroxybutyrylation (Kbhb) modification regulates protein molecular fates in either physiology or pathology, including cancer. However, the function and regulatory mechanism of Kbhb remain completely unknown in cancer metastasis. Here, we report that β-hydroxybutyrate (BHB) is clinically associated with the progression of pancreatic cancer and functionally promotes pancreatic cancer cell metastasis. Mechanistically, BHB induces Kbhb modification of Snail at lysine 152 to enhance Snail stabilization, which is regulated by Kbhb modification enzyme CREB-binding protein (CBP), and subsequently prevents Snail degradation by blocking recognition of E3 ubiquitin ligases FBXL14. Furthermore, either targeting Snail Kbhb modification or CBP inhibitor decreases cancer metastasis and enhances the therapeutic efficacy of gemcitabine in pancreatic cancer cells. Collectively, our study reveals that Kbhb of Snail is critical to promote metastasis and provides a potential therapeutic strategy. Show less

Accumulation of various genetics and epigenetics alterations are accepted to result in the initiation and progression of hepatocellular carcinoma (HCC), and its high metastasis is viewed as a critical bottleneck leading to its treatment failure. Amongst them, the microRNAs arising from the lack of the antioxidant transcription factor Nrf2 lead to cancer metastasis. However, much less is known about the regulation of microRNAs by Nrf1, even though it acts as an essential determinon of cell homoeostasis by governing the transcriptional expression of those driver genes contributing to the EMT involved in its metastasis. In this study, distinct EMT phenotypes resulted from specific knockouts of Nrf1 and Nrf2 in HepG2 cells, as accompanied by their differential migratory and invasive capabilities. The Show less

In recent years, combination chemotherapy with therapeutic nucleic acids has emerged as a promising strategy to enhance the effectiveness of cancer therapy. However, developing an effective co-delivery system to simultaneously transport both chemotherapeutic drugs and nucleic acids remains challenging. Herein, we fabricated cholesterol-conjugated polyion complex nanoparticles (PCNs) for combination delivery of hydrophobic paclitaxel (PTX) and hydrophilic miR-34a. Cholesterol was conjugated to polyethylenimine (PEI) and hyaluronic acid (HA), producing C-PEI and C-HA, respectively. PTX was initially encapsulated within the hydrophobic core formed by the self-assembly of C-HA and C-PEI, yielding polyion complex nanoparticles (PTX@C-HA/C-PEI PCNs). Subsequently, the negatively charged miR-34a was electrostatically complexed with the cationic C-PEI moieties to generate miR-34a/PTX@C-HA/C-PEI PCNs. These PCNs exhibited a nanoscale structure with a uniform size distribution and demonstrated low cytotoxicity in colon cancer cells. Fluorescence microscopy confirmed efficient cytosolic delivery of C-HA/C-PEI PCNs in colon carcinoma cells. Furthermore, combination delivery of PTX and miR-34a using C-HA/C-PEI PCNs exhibited significantly enhanced transfection efficiency and cellular uptake for human colon cancer cells. Notably, PTX/miR-34a@C-HA/C-PEI PCNs effectively downregulated critical oncogenic targets, including Show less

Myocardial fibrosis (MF) is a key pathological process driving heart failure, characterized by excessive extracellular matrix (ECM) deposition and impaired cardiac function. Although myocyte-specific enhancer factor 2 A (MEF2A) is implicated in cardiac fibroblast activation, its role in MF remains unclear. We manipulated MEF2A expression in cardiac fibroblasts (CFs) through knockdown and overexpression, and assessed fibrosis markers, migration, and RhoA signaling. Binding of MEF2A to the Snail1 promoter was predicted using JASPAR and validated by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. Rescue experiments with Snail1 overexpression and RhoA inhibition were performed. An angiotensin II (Ang II)-induced MF mouse model was used to evaluate cardiac function by echocardiography and to assess collagen deposition through picrosirius red (PSR) staining. MEF2A was significantly upregulated in Ang II-induced fibrotic hearts and CFs. MEF2A knockdown reduced α-SMA and Col1a1 expression, inhibited CF migration, and suppressed activation of the Snail1/RhoA/α-SMA pathway. ChIP and luciferase assays confirmed the direct binding of MEF2A to the Snail1 promoter. Inhibition of RhoA signaling reversed MEF2A-induced myofibroblast activation and migration. Rescue experiments showed that Snail1 overexpression restored the fibrotic phenotype suppressed by MEF2A knockdown. In vivo, MEF2A knockdown improved left ventricular function, reduced collagen deposition (PSR staining), and lowered heart weight/tibia length ratios. MEF2A promotes myocardial fibrosis by directly activating Snail1 and engages the RhoA/α-SMA pathway. Targeting MEF2A offers a promising therapeutic strategy to attenuate MF and improve heart function. Show less

Voghera pepper (VP) extracts were demonstrated to have anti-oxidant ability in several cell types. This study aimed to assess whether VP-extracts could lower oxidative stress and modulate thyroid cancer (TC) cells behavior Extracts were analyzed using the LC-DAD-MS system. Thyroid cell lines, both normal (NHT) and cancerous (TPC-1 and 8505C) were treated with increasing concentrations of Yellow (YVP) and Green (GVP) VP-extracts over time. Viability and proliferation were assessed in all cell types. Changes in Reactive-oxygen-species (ROS) production by TPC-1 and 8505C were assessed by flow-cytometry. The mRNA expression of anti-oxidant mediators ( Treatment with GVP or YVP reduced the viability of TPC-1 and 8505C but not those of NHT, without effects on cells proliferation. GVP and YVP reduced basal and H This is the first demonstration of the potential beneficial effects of VP extracts in TC in terms of reduction of oxidative stress, increase of antioxidant markers, and modulation of markers of metastasis and de-differentiation in TC cells. Show less

This study aimed to investigate the role of SIRT4 in retinal protection, specifically its ability to mitigate excitotoxic damage to Müller glial cells through the regulation of mitochondrial dynamics and glutamate transporters (GLASTs). A model of retinal excitatory neurotoxicity was established in mice. Proteins related to mitochondrial dynamics, GLAST, and SIRT4 were analyzed on days 0, 1, 3, and 5 following toxic injury. The influence of SIRT4 on mitochondrial dynamics-related proteins and GLAST was examined by inducing SIRT4 overexpression through intraperitoneal injection of resveratrol or by using SIRT4 knockout (KO) mice. Additionally, the effects of upregulating and downregulating SIRT4 expression in rat Müller glial cell lines (rMC-1) were explored via lentiviral vector transfection to assess changes in mitochondrial morphology and GLAST expression. After excitotoxic injury to the mouse retina, the retinal thickness and structure were disrupted, the number of retinal ganglion cells (RGCs) decreased, and Müller glial cells were activated by day 1. The levels of OPA1, GLAST, and SIRT4 proteins peaked on the first day after injury and then gradually decreased, indicating a synchronized dynamic trend. The upregulation of SIRT4 expression promoted OPA1 and GLAST protein expression, thereby alleviating retinal excitotoxic injury. Furthermore, the upregulation of SIRT4 expression promoted mitochondrial fusion and increased GLAST expression in rMC-1 cells, reducing cellular excitotoxic damage. Conversely, downregulation of SIRT4 had the opposite effect. SIRT4 plays a significant role in mitigating excitotoxic damage in the retina, modulating Müller glial cell injury by regulating mitochondrial dynamics and glutamate transporter expression, ultimately influencing retinal health. Show less

Despite the known impacts of weaning on animal health, the underlying molecular mechanisms remain unclear, particularly how psychological and nutritional stress differentially affect gut health and immune function over time. This study hypothesized that early weaning exerts distinct short- and long-term effects on lamb stress physiology, immunity, and gut health, mediated by specific molecular pathways. Twelve pairs of full-sibling male Hu sheep lambs were assigned to control (CON) or early-weaned (EW) groups. Plasma stress/immune markers were dynamically monitored, and intestinal morphology, antioxidant capacity, apoptosis, and transcriptomic profiles were analyzed at 5 and 28 days post-weaning. Early weaning triggered transient psychological stress, elevating hypothalamic-pituitary-adrenal (HPA) axis hormones (cortisol, catecholamines) and inflammatory cytokines (TNF-α) within 1 day ( Show less

Mitochondrial dynamics are important for cellular health and include morphology, fusion, fission, vesicle formation, transport and contact formation with other organelles. Myosin XIX (Myo19) is an actin-based motor, which competes with TRAK1/2 adaptors of microtubule-based motors for binding to the outer mitochondrial membrane receptors Mitochondrial Rho GTPases 1/2 (Miro). Currently, it is poorly understood how Myo19 contributes to mitochondrial dynamics. Here, we report on a Myo19-deficient mouse model and the ultrastructure of the mitochondria from cells of Myo19-deficient mice and HEK cells, Miro-deficient HEK cells and TRAK1-deficient HAP1 cells. Myo19-deficient mitochondria in MEFs and HEK cells have morphological alterations in the inner mitochondrial membrane with reduced numbers of malformed cristae. In addition, mitochondria in Myo19-deficient cells showed fewer ER-mitochondria contact sites (ERMCSs). In accordance with the ultrastructural observations, Myo19-deficient MEFs had lower oxygen consumption rates and a reduced abundance of OXPHOS supercomplexes. The simultaneous loss of Miro1 and Miro 2 led to a comparable mitochondria phenotype and reduced ERMCSs as observed upon the loss of Myo19. However, the loss of TRAK1 caused only a reduction in the number of cristae, but not ERMCSs. These results demonstrate that both actin- and microtubule-based motors regulate cristae formation, but only Myo19 and its membrane receptor Miro regulate ERMCSs. Show less

Maternal undernutrition (MUN) causes severe metabolic disruption in the offspring of mammals. Here we determined the role of histone modification in hepatic gene expression in late-gestation fetuses of nutritionally restricted cows, an established model using low-nutrition (LN) and high-nutrition (HN) conditions. The chromatin immunoprecipitation sequencing results show that genes with an altered trimethylation of histone 3 lysine 4 (H3K4me3) are associated with cortisol synthesis and secretion, the PPAR signaling pathway, and aldosterone synthesis and secretion. Genes with the H3K27me3 alteration were associated with glutamatergic synapse and gastric acid secretion. Compared to HN fetuses, promoter H3K4me3 levels in LN fetuses were higher in Show less

Based on the special role of mitochondria in tumour energy metabolism. We hope to explore the pathogenesis and potential therapeutic targets of Hepatocellular carcinoma by analysing the expression of 1136 mitochondrial proteins in hepatocellular carcinoma and their mechanisms in the Human.MitoCarta3.0 database. The expression of 1136 mitochondrial proteins in HCC was analysed by the TCGA database. We selected the top eight mitochondrial proteins among the highly expressed mitochondrial proteins that had not been studied in HCC and were statistically (P < 0.05) significant, according to fold change. Protein expression was verified by real-time quantitative reverse transcription polymerase chain reaction in tumours and adjacent paracancerous tissues of 34 pairs of HCC patients. Further in HCC cells, the expression of FDPS, DNA2 and MYO19 was verified. Clinical correlations of FDPS, DNA2 and MYO19 were analysed by UALCAN and KM-plot databases. Immune correlation of FDPS, DNA2 and MYO19 was analysed by TIMER2.0 and Sangerbox3.0 online databases. Mitochondrial proteins were expressed on all 24 chromosomes. More than 2/3 of the mitochondria were 100-600 bp long, of which 204 were secondary transmembrane proteins. 1136 mitochondrial proteins, of which 202 are not included in the TCGA database. Of the 934 mitochondrial proteins included in the TCGA database, 706 were highly expressed and 228 were poorly expressed in HCC. Further validated by HCC tissues and cells, the study found that significantly high expression of FDPS, DNA2 and MYO19 was negatively correlated with the prognosis of HCC patients. The results of the immune correlation analysis showed that DNA2 and MYO19 may be involved in regulating the infiltration of immune cells. 934 out of 1136 mitochondrial proteins in the Human.MitoCarta3.0 database were differentially expressed in HCC, suggesting that mitochondrial proteins play an important biological role in the development of HCC. Further experimental validation and bioinformatics analyses showed that functional mitochondrial proteins are potential pathophysiological mechanisms for malignant progression of HCC. Mitochondrial proteins, in the future, have the potential to be valuable therapeutic targets for HCC. Show less

Pediatric hypertrophic cardiomyopathy (HCM) is a rare condition, particularly in neonates, and is characterized by rapid and extensive myocardial hypertrophy, often leading to severe clinical outcomes. HCM can arise from variants in sarcomeric genes, which are essential for myocardial contractions, as well as non-sarcomeric gene variants. Although genetic modifiers and oligogenic inheritance have been implicated in congenital heart disease and cardiomyopathy, their complexity in HCM has not been fully elucidated, especially in familial cases with variable phenotypes. Hence, this study aims to investigate the genetic architecture in a family with a history of cardiac disease and neonatal HCM, focusing on oligogenic inheritance of non-sarcomeric variants. Clinical data and blood samples were collected for genetic analysis. Whole genome sequencing (WGS) and bioinformatic analyses identified compound heterozygous variants in the MYO19 gene. Maternally inherited variants were analyzed because the proband's mother was also diagnosed with HCM. WGS was performed on the patient's maternal grandfather and aunt, who have cardiac disease, revealing candidate genetic variants that may contribute to the cardiac phenotype. Compound heterozygous MYO19 variants were identified in the neonatal patient. Missense c.203C > G (p.A68G) and frameshift c.275₂₇₆del (p.E92Vfs*19) variants were identified, which were located in the myosin motor domain, a functionally crucial region of the MYO19 protein. Maternally inherited missense variants were identified in SURF1 and ETFDH. All three genes are associated with mitochondrial function, and in silico prediction tools suggest that these variants are likely damaging. Other candidate genetic variants possibly contributing to the cardiac phenotype were also detected in the extended maternal family. To the best of our knowledge, this study represents the first report proposing MYO19 as a candidate gene for HCM and highlights the potential role of oligogenic inheritance in the etiology of the disease. Furthermore, plausible candidate variants of other mitochondria-related genes, such as MYO19, SURF1, and ETFDH, were identified, and other family members were investigated to support the pathogenesis of HCM further. Given the limited understanding of the genetics of pediatric HCM, these findings contribute valuable insights into its genetic basis in pediatric patients. Show less

Breast cancer is considered to be the most common cancer that affects women worldwide, where it accounts for approximately 38.8% of all cancer cases among females. Luminal subtypes are the most prevalent in Egypt. Small noncoding RNAs also called microRNAs (miRNAs) influence gene expression posttranscriptionally. Since they regulate the epithelial-mesenchymal transition process, which is vital for tumor invasion and metastasis, microRNAs play a critical role in the progression of cancer. This study has investigated the expression profiles of four microRNAs (miR-101-3p, miR-106a-5p, miR-106b-5p, and miR-130b-5p) and their impacts on genes associated with epithelial-mesenchymal transition (EMT) in luminal breast cancer. Tissue samples from 43 luminal breast cancer patients and 18 controls have been studied via real-time PCR (RT-qPCR). The association between the expression levels was evaluated using the Pearson correlation test. The correlation between the measured variables and numerous clinicopathological characteristics was assessed using the linear regression test. The results demonstrated that miR-101-3p, miR-106a-5p, and miR-106b-5p were significantly dysregulated, highlighting their possible role as oncogenes or tumor suppressors in the development of breast cancer. EMT markers, especially Twist, SNAI1, and E-cadherin, show significant alterations, indicating the activation of EMT pathways in luminal breast cancer. Correlation analysis showed interactions between miRNAs and EMT-related genes, showing a negative correlation between miR-101-3p and SNAI1, as well as a positive correlation between Twist and miR-106a-5p. Moreover, logistic regression analysis associated expression levels of those miRNAs with clinicopathological characteristics, such as body weight, age, and tumor laterality. These findings highlight the leading role of miR-101-3p and miR-106b-5p in the progression of luminal breast cancer via interacting with the EMT process and their potential as diagnostic, prognostic, and therapeutic targets. Show less

Acute respiratory distress syndrome (ARDS) is a common respiratory emergency, but current clinical treatment remains at the level of symptomatic support and there is a lack of effective targeted treatment measures. Our previous study confirmed that inhalation of hydrogen gas can reduce the acute lung injury of ARDS, but the application of hydrogen has flammable and explosive safety concerns. Drinking hydrogen-rich liquid or inhaling hydrogen gas has been shown to play an important role in scavenging reactive oxygen species and maintaining mitochondrial quality control balance, thus improving ARDS in patients and animal models. Coral calcium hydrogenation (CCH) is a new solid molecular hydrogen carrier prepared from coral calcium (CC). Whether and how CCH affects acute lung injury in ARDS remains unstudied. In this study, we observed the therapeutic effect of CCH on lipopolysaccharide (LPS) induced acute lung injury in ARDS mice. The survival rate of mice treated with CCH and hydrogen inhalation was found to be comparable, demonstrating a significant improvement compared to the untreated ARDS model group. CCH treatment significantly reduced pulmonary hemorrhage and edema, and improved pulmonary function and local microcirculation in ARDS mice. CCH promoted mitochondrial peripheral division in the early course of ARDS by activating mitochondrial thioredoxin 2 (Trx2), improved lung mitochondrial dysfunction induced by LPS, and reduced oxidative stress damage. The results indicate that CCH is a highly efficient hydrogen-rich agent that can attenuate acute lung injury of ARDS by improving the mitochondrial function through Trx2 activation. Show less

The dysregulation of hepatic lipid metabolism is closely associated with dyslipidemia. Previous research suggested that Hepatic Data regarding circulating lipid traits and hepatic Hepatic This study identifies Show less

Local metabolic demand within cells varies widely, and the extent to which individual mitochondria can be specialized to meet these functional needs is unclear. We examined the subcellular distribution of the mitochondrial contact site and cristae organizing system (MICOS) complex, a spatial and functional organizer of mitochondria, and discovered that it dynamically enriches at the tip of a minor population of mitochondria in the cell periphery. Based on their appearance, we term these mitochondria "METEORs". METEORs have a unique composition, and MICOS enrichment sites are depleted of mtDNA and matrix proteins and contain high levels of the Ca Show less

The actin-based motor myosin-19 (Myo19) exerts force on mitochondrial membrane receptors Miro1/2, influencing endoplasmic reticulum (ER)-mitochondria contact sites and mitochondrial cristae structure. The mitochondrial intermembrane bridging (MIB) complex connects the outer and inner mitochondrial membranes at the cristae junction through the mitochondrial contact site and cristae organization system (MICOS). However, the interaction between Myo19, Miro1 and Miro2 (hereafter Miro1/2), and the MIB-MICOS complex in cristae regulation remains unclear. This study investigates the roles of Miro1/2 and metaxin 3 (Mtx3), a MIB complex component, in linking Myo19 to MIB-MICOS. We show that Miro1/2 interact with Myo19 and the MIB complex but not with Mtx3. Their mitochondrial membrane anchors are not essential for MIB interaction or cristae structure. However, Mtx3 is crucial for the connection between MIB-MICOS and the Myo19 and Miro1/2 proteins. Deleting Miro1/2 mimics the effects of Myo19 deficiency on ER-mitochondria contacts and cristae structure, whereas Mtx3 deletion does not. Notably, the loss of Myo19 and Miro1/2 alters mitochondrial lipid composition, reducing cardiolipin and its precursors, suggesting Myo19 and Miro1/2 influence cristae indirectly via lipid transfer at ER-mitochondria contact sites. Show less

During mammalian spermatogenesis, the cytoskeleton system plays a significant role in morphological changes. Male infertility such as non-obstructive azoospermia (NOA) might be explained by studies of the cytoskeletal system during spermatogenesis. The cytoskeleton, scaffold, and actin-binding genes were analyzed by microarray and bioinformatics (771 spermatogenic cellsgenes and 774 Sertoli cell genes). To validate these findings, we cross-referenced our results with data from a single-cell genomics database. In the microarray analyses of three human cases with different NOA spermatogenic cells, the expression of TBL3, MAGEA8, KRTAP3-2, KRT35, VCAN, MYO19, FBLN2, SH3RF1, ACTR3B, STRC, THBS4, and CTNND2 were upregulated, while expression of NTN1, ITGA1, GJB1, CAPZA1, SEPTIN8, and GOLGA6L6 were downregulated. There was an increase in KIRREL3, TTLL9, GJA1, ASB1, and RGPD5 expression in the Sertoli cells of three human cases with NOA, whereas expression of DES, EPB41L2, KCTD13, KLHL8, TRIOBP, ECM2, DVL3, ARMC10, KIF23, SNX4, KLHL12, PACSIN2, ANLN, WDR90, STMN1, CYTSA, and LTBP3 were downregulated. A combined analysis of Gene Ontology (GO) and STRING, were used to predict proteins' molecular interactions and then to recognize master pathways. Functional enrichment analysis showed that the biological process (BP) mitotic cytokinesis, cytoskeleton-dependent cytokinesis, and positive regulation of cell-substrate adhesion were significantly associated with differentially expressed genes (DEGs) in spermatogenic cells. Moleculare function (MF) of DEGs that were up/down regulated, it was found that tubulin bindings, gap junction channels, and tripeptide transmembrane transport were more significant in our analysis. An analysis of GO enrichment findings of Sertoli cells showed BP and MF to be common DEGs. Cell-cell junction assembly, cell-matrix adhesion, and regulation of SNARE complex assembly were significantly correlated with common DEGs for BP. In the study of MF, U3 snoRNA binding, and cadherin binding were significantly associated with common DEGs. Our analysis, leveraging single-cell data, substantiated our findings, demonstrating significant alterations in gene expression patterns. Show less

First-line immune checkpoint inhibitor (ICI) combinations show responses in subsets of hepatocellular carcinoma (HCC) patients. Nearly half of HCCs are Wnt-active with mutations in CTNNB1 (encoding for β-catenin), AXIN1/2, or APC, and demonstrate heterogeneous and limited benefit to ICI due to an immune excluded tumor microenvironment. We show significant tumor responses in multiple β-catenin-mutated immunocompetent HCC models to a novel siRNA encapsulated in lipid nanoparticle targeting CTNNB1 (LNP-CTNNB1). Both single-cell and spatial transcriptomics reveal cellular and zonal reprogramming, along with activation of immune regulatory transcription factors IRF2 and POU2F1, re-engaged type I/II interferon signaling, and alterations in both innate and adaptive immunity upon β-catenin suppression with LNP-CTNNB1 at early- and advanced-stage disease. Moreover, ICI enhances response to LNP-CTNNB1 in advanced-stage disease by preventing T cell exhaustion and through formation of lymphoid aggregates (LA). In fact, expression of an LA-like gene signature prognosticates survival for patients receiving atezolizumab plus bevacizumab in the IMbrave150 phase III trial and inversely correlates with CTNNB1-mutatational status in this patient cohort. In conclusion, LNP-CTNNB1 is efficacious as monotherapy and in combination with ICI in CTNNB1-mutated HCCs through impacting tumor cell-intrinsic signaling and remodeling global immune surveillance, providing rationale for clinical investigations. Show less

Clubfoot, medically termed congenital talipes equinovarus (CTEV), is a prevalent musculoskeletal birth defect, affecting approximately 0.3% of all live births. This serious congenital anomaly results from structural abnormalities in the foot and lower leg, leading to abnormal positioning of the ankle and foot joints. This review provides a comprehensive overview of the causative factors associated with CTEV and evaluates current therapeutic approaches. Although variations in genes encoding contractile proteins of skeletal myofibers have been proposed as contributors to the etiology of CTEV, no definitive candidate genes have been conclusively linked to increased risk. However, genes such as Show less

Neuroinflammation is central to Alzheimer's disease (AD) pathogenesis, yet its contribution to region-specific brain atrophy remains unclear. We examined whether cerebrospinal fluid (CSF) biomarkers predict longitudinal atrophy in the hippocampus and basal forebrain and mediate the impact of AD pathology. Data from 227 DELCODE participants with baseline CSF measures and longitudinal structural MRI were analyzed. Four latent factors (synaptic, microglia, chemokine/cytokine, complement) were derived to capture shared variance across biomarkers. Latent factors represent unobserved biological domains inferred from related CSF markers. In addition, four single biomarkers (neurogranin, sTREM2, YKL-40, ferritin) were tested separately. Regional atrophy rates were estimated using linear mixed-effects models including biomarker × time, A/T classification, diagnosis, and covariates (age, sex, education, ApoE-ε4). Individual slopes were then entered into mediation models. Higher synaptic latent factor (β = - 0.019, pFDR = 0.021) and YKL-40 (β = - 0.020, pFDR = 0.025) significantly predicted hippocampal atrophy. Only these two markers remained significant after correction for multiple comparisons. Mediation analyses revealed significant indirect effects of the synaptic latent factor and YKL-40 on hippocampal atrophy across all A/T groups. No biomarker was associated with basal forebrain atrophy (pFDR > 0.05). Latent factors captured shared biological variance across related biomarkers and provided a more robust representation of underlying biological domains than single biomarkers. This approach identified synaptic dysfunction and astroglial activation as key links between AD pathology and hippocampal neurodegeneration. These findings highlight synaptic and glial pathways as promising targets for disease-modifying interventions. Show less

Current research lacks comprehensive investigations into the potential causal link between mitochondrial-related genes and the risk of neurodegenerative diseases (NDDs). We aimed to identify potential causative genes for five NDDs through an examination of mitochondrial-related gene expression levels. Through the integration of summary statistics from expression quantitative trait loci (eQTL) datasets (human blood and brain tissue), mitochondrial DNA copy number (mtDNA-CN), and genome-wide association studies (GWAS) datasets of five NDDs from European ancestry, we conducted a Mendelian randomization (MR) analysis to explore the potential causal relationship between mitochondrial-related genes and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Lewy body dementia (LBD). Sensitivity analysis and Bayesian colocalization were employed to validate this causal relationship. Through MR analysis, we have identified potential causal relationships between 12 mitochondria-related genes and AD, PD, ALS, and FTD overlapping with motor neuron disease (FTD_MND) in human blood or brain tissue. Bayesian colocalization analysis further confirms 9 causal genes, including NDUFS2, EARS2, and MRPL41 for AD; NDUFAF2, MALSU1, and METTL8 for PD; MYO19 and MRM1 for ALS; and FASTKD1 for FTD_MND. Importantly, in both human blood and brain tissue, NDUFS2 exhibits a significant pathogenic effect on AD, while NDUFAF2 demonstrates a robust protective effect on PD. Additionally, the mtDNA-CN plays a protected role in LBD (OR = 0.62, p = 0.031). This study presents evidence establishing a causal relationship between mitochondrial dysfunction and NDDs. Furthermore, the identified candidate genes may serve as potential targets for drug development aimed at preventing NDDs. Show less

Aberrant activation of fibroblast growth factor receptors (FGFRs) plays a critical role in tumorigenesis across multiple cancer types, driving the development of various FGFR inhibitors. Despite clinical advances, therapeutic efficacy remains limited by the emergence of drug resistance, primarily mediated by gatekeeper mutations in FGFRs. To overcome this challenge, we designed and synthesized a novel series of 7-(1-methyl-1 Show less

Products encoded by approximately 30% of the mammalian genome exit the endoplasmic reticulum via the coat complex II (COPII) system en route to their functional destination. Among these cargoes, APOB-containing lipoproteins stand out as abundant and bulky secretory particles with profound implications for human health and diseases. Recent insights into the specialized intracellular itinerary of lipoprotein metabolism and transport not only shed light on longstanding questions of lipid dynamics, but also highlight challenges faced by the COPII machinery in accommodating these complex, unconventional cargoes. Emerging evidence supports that tightly-regulated COPII condensation enables maximal capacity of cargo transport, providing a potential solution tailored for efficient lipoprotein delivery without affecting general protein secretion. This distinction suggests that targeting COPII condensation may provide new therapeutic strategies for lipid-associated diseases. Indeed, recent studies have identified manganese as a key modulator of this process, offering novel insights into its physiological relevance and potential translations. Show less

Apolipoprotein E (ApoE) affects lipid metabolism and was associated with type 2 diabetes mellitus (T2DM) complications, including diabetic peripheral neuropathy (DPN). Despite improved glycemic control, DPN prevalence continues to rise, indicating mechanisms beyond hyperglycemia. We assessed the association between The case-control study included 908 Lebanese patients with T2DM (382 with DPN, 526 without) and 695 healthy controls who underwent multimodal DPN assessment (NCS, QST, and MNSI). T2DM patients showed significantly higher frequencies of Show less

Malignant gliomas (MGs) are the most common primary brain malignancies and are considered universally fatal. Oncolytic herpes simplex viruses (oHSVs) are promising immunotherapeutics capable of selectively lysing cancer cells, eliciting antitumor immunity, and providing local delivery of immune-activating transgenes. Interleukin 27 (IL-27) is a pleiotropic cytokine capable of enhancing tumor-reactive cytotoxic T lymphocyte (CTL) function while also possessing neuroprotective properties. We hypothesized that IL-27 expression by oHSV would enhance CTL function and improve antiglioma therapeutic activity. We developed an oHSV that expresses IL-27 (C027). The antiglioma efficacy of C027 was tested in three syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (SB28, KR158) glioma lines. Spectral flow cytometry was used to assess immunophenotypic and functional changes in the tumor infiltrates and systemically. To further investigate the C027-related CTL activity, we employed in vivo cell-specific depletion and IL-27 blockade alongside in vitro T cell stimulation assays. Local and systemic antitumor memory was evaluated by both orthotopic and flank tumor rechallenge of C027-treated long-term survivors. C027 significantly prolonged survival in syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (KR158, SB28) glioma lines. In the CT-2A model, IL-27-expressing oHSV treatment was associated with increased intratumoral multifunctional effector CTLs and functional T cell populations systemically. Mechanistically, both CD8 T cells and IL-27 were required for the C027 survival benefit in vivo and IL-27 enhanced CTL function in vitro. C027-treated mice that survived their initial tumors had local and systemic antiglioma memory rejecting tumors on rechallenge. Our findings demonstrate that IL-27 expression by oHSV significantly improves antiglioma therapeutic efficacy, enhances CTL effector function, and induces durable immune memory. Thus, IL-27-oHSV may provide a promising therapeutic approach for MGs. Show less

This study isolated a high-molecular-weight Morchella esculenta polysaccharide (MEP-1), mainly composed of glucose with a triple-helix structure. MEP-1 alleviated high-fat diet (HFD)-induced hepatic lipid metabolic disorders and inflammation by significantly reducing the levels of TC, TG, LDL-C, TNF-α, IL-6, and IL-1β, especially at the high dose. Transcriptomic analysis revealed that arginine biosynthesis was the most significantly enriched pathway after MEP-1 intervention. Specifically, MEP-1 upregulated Ass1 and Cps1 expression to promote L-arginine biosynthesis, which subsequently activated the AMPK/Sirt1/PGC-1α signaling axis, thereby enhancing fatty acid oxidation (FAO) and ameliorating lipid metabolism disorders. This study further delineates a novel protective mechanism for MEP-1 ameliorating HFD-induced lipid metabolism disorders and providing a theoretical foundation for its application in functional food. Show less