Search Results (262)

Embryos being treated using assisted reproductive technology (ART) are unavoidably exposed to physical stressors, thus producing reactive oxygen species (ROS) which trigger mitophagy to support embryonic development. However, the mechanisms underlying the regulation of mitophagy in early embryonic development remain largely unexplored. Here, we found that Mucin 1 (MUC1) exhibited a uniform distribution in both mouse and human oocytes, and its expression peaked at the blastocyst stage. Further analysis revealed that Muc1 knockout impairs blastocyst formation in vitro. Correspondingly, Muc1 knockout led to the accumulation of mitochondrial reactive oxygen species (mtROS) and a reduction in phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)/Parkinson protein 2 (PARK2/Parkin)-dependent mitophagy. Stimulation of mitophagy via low-dose carbonyl cyanide 3-chlorophenylhydrazone (CCCP) treatment rescued the blastocyst formation defect in Muc1-null embryos. Vitamin C supplementation effectively scavenged mtROS and restored developmental competence. Together, our findings establish that MUC1 safeguards early embryonic development by promoting mitophagy to decrease mtROS levels in vitro. Moreover, vitamin C could compensate for Muc1 deficiency by eliminating mtROS. This study not only identified a new function of MUC1 in protecting early embryonic development in vitro, but also revealed a novel mechanism of mitophagy regulation in early embryos, which has potential applications for ART. Full article

Ubiquitin-specific protease 13 (USP13) is a deubiquitinating enzyme that stabilizes phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a well-established tumor suppressor involved in PI3K/AKT signaling. This study aimed to evaluate the relationship between USP13 immunohistochemical staining intensity and clinicopathological factors associated with prostate cancer progression. USP13 staining was scored as grade 0 (negative), 1 (weak), 2 (moderate), or 3 (strong) in 242 prostate cancer tissues and 22 adjacent non-neoplastic control tissues. Higher USP13 grades were exhibited by adjacent non-neoplastic tissues than prostate carcinoma. In comparison, lower USP13 grades were observed in 88.6% of the neoplastic regions (p < 0.001). No differences in PSA level, Gleason’s score, disease stage, involvement of either the seminal vesicle or lymph nodes, surgical margin positivity, biochemical or clinical recurrence rates, or overall survival statistics were found. Cox proportional hazards modeling showed no significant association between USP13 expression and biochemical recurrence-free survival or overall survival. Kaplan–Meier analysis demonstrated no statistically significant differences in survival outcomes according to USP13 expression, although a descriptive trend was observed. USP13 immunohistochemical staining distinguished malignant prostate tissue from adjacent non-neoplastic tissue in tissue microarrays. However, USP13 expression was not independently associated with pathological aggressiveness or survival outcomes in this cohort. Full article

Oligodendroglial cells are the myelinating glial cells of the central nervous system (CNS), and their morphological differentiation is a prerequisite for efficient myelin formation, which is essential for proper neuronal function. While oligodendroglial morphological changes normally proceed through tightly regulated developmental transitions, disruption of the underlying molecular mechanisms can lead to aberrant cellular phenotypes characterized by either premature, insufficient, or excessive differentiation. Although the phosphatidylinositol 3-kinase (PI3K) and its downstream Akt kinase signaling are well established as major drivers of oligodendrocyte morphological differentiation, myelination, and CNS white matter formation, how its negative regulator, phosphatase and tensin homolog (PTEN), is involved in the regulation of oligodendroglial morphogenesis remains incompletely understood. Recent genetic studies have highlighted a spectrum of disorders caused by PTEN dysfunction, conceptually established but currently evolving as PTENopathy, which has been partially associated with white matter abnormalities. Here, we report that, in an experimental model using the FBD-102b cell line, a well-established model of oligodendroglial cell differentiation, chemical inhibition of PTEN enhances pronounced morphological changes characterized by widespread membranes, accompanied by increased expression of differentiation and/or myelin marker proteins. We then focused on Rho family small GTPases, central regulators of cell morphogenesis, and examined their potential involvement downstream of this signaling. Expression of the RhoG-binding domain (RBD) of engulfment and cell motility 1 (ELMO1) attenuated the increased morphological changes. Similarly, inhibition of downstream Akt signaling also reversed these changes. Taken together, these results provide insight into how balanced regulation between PTEN and downstream signaling molecules governs oligodendroglial cell differentiation and suggest that dysregulation of this signaling equilibrium may contribute to cellular phenotypes relevant to disease-associated cellular alterations. Full article

Deletion of the tumor suppressor gene phosphatase and tensin homolog (PTEN) in hepatocellular carcinoma (HCC) is associated with a poor response to therapy and reduced survival. In mice, the deletion of PTEN in hepatocytes generates steatosis; however, on the background of steatosis not all emerging HCC cells lack PTEN, suggesting that steatosis confers a metabolic liability to proliferating PTEN-deficient hepatocytes. Here, we show that PTEN-deficient HepG2 cells develop terminal stress in the endoplasmic reticulum (ER) and profound apoptosis when exposed to a mixture of oleic and palmitic acids, while control cells do not. Lipidomic analyses before and after the treatment indicate a higher increase in triglycerides in PTEN KO cells, as well as profound differences in phospholipid concentrations. Although the triglyceride content increases, the coalescence into lipid droplets was impaired in the KO cells, together with a reduction in β-oxidation. Xenograft studies showed that PTEN KO HCC tumors progressed faster than did the control tumors when mice were fed with normal chow and slower under a high-fat diet. We suggest that while the health risks of a fatty acid-rich diet to liver function and the increased propensity to develop HCC are prominent, once a PTEN-deficient HCC has been established, it exposes vulnerability to lipid overload that can be exploited through diet and pharmacological interventions. Full article

Oncometabolites and hypoxia-regulated exosomes orchestrate hypoxia-inducible factor (HIF)–driven macrophage reprogramming across chronic cardiometabolic and oncologic conditions. In type 2 diabetes (T2D) and obesity, regional hypoxia in expanding white adipose tissue (WAT) reconfigures macrophage immunometabolism and chemokine signaling, recruits C-C chemokine receptor 2 (CCR2⁺) monocytes, and skews adipose-tissue macrophages toward M1-like programs that sustain low-grade inflammation and blunt the physiological M1-to-M2 transition during wound repair. In atherosclerotic plaques, lipid-core hypoxia stabilizes HIF-1α, amplifies nuclear factor kappa-light-chain-enhancer of activated B cells/reactive oxygen species (NF-κB/ROS) signaling, increases matrix metalloproteinase-2/-9 (MMP-2/-9) release, and reduces ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux, weakening the fibrous cap. In tumors, poorly perfused niches accumulate lactate and succinate, which act as paracrine cues. Lactate activates PKA/cAMP pathways and promotes immunosuppressive tumor-associated macrophages (TAMs), whereas succinate signals through succinate receptor 1 (SUCNR1) to reinforce HIF-1α–dependent transcription and M2-like programming. In parallel, hypoxia-regulated exosomes deliver microRNAs such as miR-301a-3p, which suppress phosphatase and tensin homolog (PTEN) and activate PI3Kγ, thereby augmenting immunosuppression and programmed death-ligand 1 (PD-L1) expression. Clinically, this hypoxia–oncometabolite–exosome triad links oxygen debt with macrophage state, plaque destabilization, impaired wound repair, and tumor immune escape. Translational entry points include selective HIF-2α inhibition, phosphoinositide 3-kinase gamma (PI3Kγ) blockade, SUCNR1 targeting, and exosome-based miRNA modulation, while a biomarker panel comprising HIF-1α, vascular endothelial growth factor A (VEGF-A), and MMP-9 offers a pragmatic readout of hypoxia burden, macrophage programming, and therapeutic response. We conducted a focused narrative review (PubMed, Scopus, Web of Science; English; 2003–2025), prioritizing mechanistic and translational studies on hypoxia–HIF, lactate/succinate, and hypoxia-regulated exosomes across T2D, atherosclerosis, and cancer. Full article

Phosphatase and Tensin Homolog (PTEN) functions in numerous biological processes, encompassing cell proliferation, growth, self-renewal, and differentiation. This study examined the modulatory function of the PTEN inhibitor in periodontal ligament stem cells (PDLSCs). PDLSCs were treated with VO-OHpic at a concentration range from 0.625 to 5 μM. MTT assay and Coomassie Blue staining were conducted to determine cell viability and colony-forming unit ability, respectively. The scratch assay was employed to examine cell migration. Mineral deposition and intracellular lipid accumulation were assessed. The qRT-PCR and immunofluorescence were used to evaluate mRNA and protein expression, respectively. RNA sequencing was employed for transcriptomic analysis. VO-OHpic exposure showed no cytotoxic effects in PDLSCs; however, at 5 μM, it markedly decreased colony-forming efficiency and impaired cell migration. Under osteogenic induction conditions, 5 μM VO-OHpic markedly attenuated mineralisation and downregulated the osteogenic marker gene expression partly through ERK signalling. Indeed, VO-OHpic impaired intracellular lipid accumulation during adipogenic differentiation, as evidenced by reduced expression of adipogenic marker genes. RNA sequencing analysis revealed that VO-OHpic treatment upregulated genes in the TGF-β and calcium signalling pathways, suggesting a regulatory role in PDLSC differentiation. In conclusion, PTEN regulates PDLSC colony formation, migration, and differentiation, suggesting a pivotal role for PTEN in maintaining periodontal tissue homeostasis. Full article

Extracellular vesicles (EVs) have garnered significant attention in cancer research, as they enable the regulation of the occurrence, progression, and metastasis of tumors. This narrative review summarizes studies published between 2020 and 2025 from PubMed, focusing on nasopharyngeal carcinoma and extracellular vesicles. We analyze the function and mechanism of EVs in the tumor microenvironment, biomarkers, and treatment. Numerous studies have attempted to explain the mechanism of NPC-EVs affecting tumor microenvironments through the transmission of its cargo. And liquid-biopsy technology using EVs as biomarkers, such as exosomal cyclophilin A, the phosphatase and tensin homolog, and EVs-miR-30a-5p, has been studied for diagnosis and prognostic evaluation. In the therapy aspect, researchers are attempting to explore the role of EVs in the resistance process of NPC treatment, with the aim of clinical translation. Current limitations include biological distribution of EVs and so on. Future research should focus on establishing the standardized production system and more convenient separation and purification techniques for EVs. This review provides a comprehensive overview of the nasopharyngeal carcinoma-related EVs. Full article

MicroRNA-221 (miR-221), a conserved small non-coding RNA, acts as a pivotal modulator of biological processes across multiple organ systems, the dysregulation of which is closely linked to the pathogenesis of various human diseases. This review systematically summarizes its multifaceted roles in cancer, cardiovascular diseases (CVDs), neurological disorders, digestive system diseases, respiratory conditions, and adipose-endocrine dysfunction. In cancer, miR-221 exerts context-dependent oncogenic/tumor-suppressive effects by targeting phosphatase and tensin homolog (PTEN), cyclin-dependent kinase inhibitor 1c (CDKN1C/p57), and BCL2 modifying factor (Bmf), thereby regulating cell proliferation, invasion, stemness, and resistance to cancer therapy; it also serves as a non-invasive biomarker for glioma, papillary thyroid carcinoma, and colorectal cancer. In the cardiovascular system, it balances antiviral defense in viral myocarditis, modulates ventricular fibrotic remodeling in heart failure, and regulates endothelial function in atherosclerosis, with cell-type/ventricle-specific effects. In neurological disorders, it protects dopaminergic neurons in Parkinson’s disease and modulates microglial activation in epilepsy. It also regulates hepatic pathogen defense and intestinal mucosal immunity. Mechanistically, miR-221 alters cellular phenotypes by targeting tumor suppressors or signaling components (e.g., PI3K/AKT, TGF-β/suppressor of mothers against decapentaplegic homolog(SMAD), Wnt/β-catenin). Therapeutically, miR-221-targeting strategies show preclinical promise in cancer and CVDs. Despite this progress, further studies are needed to resolve context-dependent functional discrepancies, validate biomarker utility, and develop cell-specific delivery systems. This review provides a framework to understand its pathophysiologcial roles and potential application as a biomarker and therapeutic target. Full article

Biliary tract carcinoma (BTC) is a group of highly heterogeneous malignancies arising from the biliary epithelium. Anatomically, BTC is categorized into gallbladder cancer (GBC) and cholangiocarcinoma (CCA), with the latter further subdivided into intrahepatic (iCCA), perihilar (pCCA), and distal cholangiocarcinoma (dCCA). Epidemiological studies reveal a dismal five-year survival rate of less than 20% for BTC patients, with limited responses to current chemotherapy regimens, underscoring the urgent need to unravel its complex molecular pathogenesis. Recent research has increasingly focused on the regulatory networks of post-translational modifications, particularly the ubiquitin-proteasome system (UPS), in tumorigenesis. As the largest subfamily of deubiquitinating enzymes (DUBs), ubiquitin-specific proteases (USPs) regulate the stability of key oncoproteins such as phosphatase and tensin homolog (PTEN) and c-Myc, playing pivotal roles in tumor cell proliferation, apoptosis evasion, invasion, and metastasis. This review systematically summarizes the differential expression profiles of USP family members (e.g., USP1, USP3, USP7, USP8, USP9X, USP21, and USP22) in BTC and their clinical significance, with a focus on elucidating how specific USPs regulate tumor progression through key substrates, including poly(ADP-ribose) polymerase 1 (PARP1), dynamin-1-like protein (DNM1L), and O-GlcNAc transferase (OGT). Furthermore, based on recent advances, we discuss the therapeutic potential of small-molecule USP inhibitors in BTC targeted therapy, providing a theoretical foundation for developing novel precision treatment strategies. Full article

microRNAs (miRNAs) are known to play critical roles in the regulation of gene expression during neurodegenerative diseases and neurotropic viral infections. However, their specific contribution to the pathogenesis of Powassan virus (POWV) infection in the brain remains poorly understood. Understanding miRNA dynamics in the brain during POWV infection may reveal novel insights into viral neuropathogenesis and host antiviral responses. Therefore, in the present study, we analyzed miRNA expression profiles in the mouse brain at different time points following a peripheral POWV infection. A total of 599 miRNAs were examined at day 3, 6, and 9 post-infection. Infection with POWV resulted in the modulation of several miRNAs in the brain at all time points. There was a progressive increase in the number of dysregulated miRNAs over the course of infection. This correlated with POWV dissemination into the brain with a progressive increase in viral RNA levels that peaked at day 9 post-infection. There was an early upregulation of miR-1983, miR-19a, and miR-216b that persisted until day 9 post-infection. POWV infection also resulted in the downregulation of miR-500 at all examined time points. Using IPA, we determined the significant canonical pathways affected by miRNA dysregulation. POWV infection modulated the activation of the thyroid hormone receptor and retinoid X receptor (TR/RXR) and the regulation of the phosphatase and tensin homolog (PTEN). Additionally, macrophage classical activation and growth arrest and DNA damage-inducible 45 (GADD45) signaling were activated as early as day 3 post-infection and persisted until day 9 post-infection. Furthermore, our analysis revealed the activation of cell death pathways such as necrosis and apoptosis and the inhibition of cell cycle progression, as well as leukopoiesis. To our knowledge, this is the first study to evaluate the modulation of miRNAs in the brain following POWV infection. Full article

The regulation of T cell-mediated immune responses is essential for maintaining immune homeostasis and preventing autoimmune diseases. In multiple sclerosis (MS), impaired immunoregulatory control allows autoreactive T cells to persist, as effector T cells (Teff) display reduced susceptibility to regulatory T cells (Treg). This resistance to Treg-mediated tolerance is linked to altered IL-6 signaling and hyperactivation of protein kinase B (PKB/c-Akt). However, the mechanisms leading to increased PKB phosphorylation remain poorly understood. Here, we examined the expression of phosphatase and tensin homolog PTEN, a key phosphatase that negatively regulates PKB/c-Akt activation. We found that PTEN protein expression rapidly declines in activated Teff from MS patients. To clarify whether PTEN downregulation contributes to Treg resistance, we used PTEN-specific siRNA to modulate PTEN expression in Teff from healthy donors. PTEN knockdown resulted in accelerated IL-6 production, enhanced PKB phosphorylation, and reduced responsiveness to Treg-mediated suppression, similar to Treg resistance observed in MS. This study reports disrupted PTEN expression in activated Teff from MS patients. Our findings highlight that PTEN is critical for effective immune regulation of T cells, and suggest its dysregulation contributes to impaired immune tolerance in MS. Full article

Background/Objectives: Twin and family studies suggest that 90% of the risk for autism spectrum disorder (ASD) is due to genetic factors, with 800 genes recognized as playing a role. An important gene is phosphatase and tensin homolog (PTEN), which plays a significant role in cancer as a tumor suppressor best known for causing overgrowth and PTEN hamartoma tumor syndromes (PHTS). Less well known are PTEN germline mutations with adverse neurodevelopmental impacts of macrocephaly, intellectual disability, and ASD, as well as other behavioral and psychiatric disturbances. There remains a limited understanding of whether these gene variants are associated with differing manifestations of PTEN-associated neurodevelopmental disorders. Methods: This review utilized comprehensive literature searches such as PubMed, OMIM, and Gene Reviews with keywords of PTEN, genetic factors, autism, and human studies and by searching genomic-protein functional networks with STRING computer-based programs for functional and genetic mechanisms. Results: This review explored the genetic underpinnings of PTEN gene variants causing altered interactive proteins and their mechanisms, biological processes, molecular functions, pathways, and disease–gene associations. We characterized specific gene–gene or protein–protein interactions and their functions relating to neurodevelopment, psychiatric disorders, and ASD that were found to be increased with PTEN gene variants. Conclusions: PTEN gene defects are among the most recognized genetic causes of ASD. PTEN gene variants and altered protein interactions and mechanisms described in our study are associated with an increased risk for tissue and organ overgrowth, macrocephaly, and distinct brain anomalies, specifically newly identified abnormal CSF dynamics. These genetic underpinnings and impacts on neurodevelopment are discussed. The genetic and protein findings identified may offer clues to effective treatment interventions, particularly when instituted at a young age, to improve long-term outcomes. Full article

Glioblastoma multiforme (GBM), the most aggressive primary brain tumor in adults, has a poor prognosis due to rapid recurrence and treatment resistance. This review examines the evolution of radiotherapy (RT) for GBM management, from whole-brain RT to modern techniques like intensity-modulated RT (IMRT) and volumetric modulated arc therapy (VMAT), guided by 2023 European Society for Radiotherapy and Oncology (ESTRO)-European Association of Neuro-Oncology (EANO) and 2025 American Society for Radiation Oncology (ASTRO) recommendations. The standard Stupp protocol (60 Gy/30 fractions with temozolomide [TMZ]) improves overall survival (OS) to 14.6 months, with greater benefits in O6-methylguanine-DNA methyltransferase (MGMT)-methylated tumors (21.7 months). Tumor Treating Fields (TTFields) extend median overall survival (mOS) to 31.6 months in MGMT-methylated patients and 20.9 months overall in supratentorial GBM (EF-14 trial). However, 80–90% of recurrences occur within 2 cm of the irradiated field due to tumor infiltration and radioresistance driven by epidermal growth factor receptor (EGFR) amplification, phosphatase and tensin homolog (PTEN) mutations, cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions, tumor hypoxia, and tumor stem cells. Pseudoprogression, distinguished using Response Assessment in Neuro-Oncology (RANO) criteria and positron emission tomography (PET), complicates response evaluation. Targeted therapies (e.g., bevacizumab; PARP inhibitors) and immunotherapies (e.g., pembrolizumab; oncolytic viruses), alongside advanced imaging (multiparametric magnetic resonance imaging [MRI], amino acid PET), support personalized RT. Ongoing trials evaluating reirradiation, hypofractionation, stereotactic radiosurgery, neoadjuvant therapies, proton therapy (PT), boron neutron capture therapy (BNCT), and AI-driven planning aim to enhance efficacy for GBM IDH-wildtype, but phase III trials are needed to improve survival and quality of life. Full article