Search Results (757)

Treatment for acute liver failure (ALF) is constrained by shortages of liver transplant donors and immune rejection. Porcine bone marrow mesenchymal stem cells (pBMSCs) demonstrate clinical potential in xenotransplantation due to their abundant availability, low immunogenicity, and strong proliferative activity. This study is the first to investigate the reparative effects and mechanisms of pBMSCs derived from Luopan Mountain pigs in a D-galactosamine (D-GalN)-induced ALF rat model. The results demonstrated that tail-vein transplantation of pBMSCs significantly improved survival rates in ALF rats; reduced serum ALT, AST, and TBIL levels; enhanced hepatic glycogen metabolism; and mitigated histopathological liver damage. Additionally, pBMSC transplantation upregulated serum HGF, IGF-1, and VEGF levels while inhibiting hepatocyte apoptosis. Mechanistic studies indicate that pBMSCs promote liver function recovery and regeneration by activating the PI3K/Akt/mTOR signaling pathway and suppressing its key negative regulator, PTEN, by regulating the expression of key genes involved in inflammation, fibrosis, proliferation, and apoptosis. This study provides crucial experimental evidence for the use of pBMSCs in treating acute liver failure (ALF) and lays the groundwork for its clinical translation in the field of xenotransplantation. Full article

Background and Clinical Significance: In hepatocellular carcinoma (HCC), numerous signaling pathways become aberrantly regulated, resulting in sustained cellular proliferation and enhanced metastatic potential. Tumors that lack PYGO2 may not show the same types of tissue remodeling or regenerative features driven by the Wnt/β-catenin pathway, which could make the tumor behave differently from others that are Wnt-positive. PIK3CA-positive tumors are often associated with worse prognosis due to the aggressive nature of the PI3K/AKT pathway activation. This is linked to higher chances of metastasis, recurrence, and resistance to therapies that do not target this pathway. Case presentation: In this paper we present a rare case of hepatocellular carcinoma with PIK3CA-positive and PYGO2-negative signaling pathways, several key aspects of the tumor’s behavior, prognosis, and treatment options. Although alpha-fetoprotein (AFP) levels were significantly elevated, the CT and MRI examination showed characteristics of malignancy, HCC with secondary hepatic lesions and associated perfusion disturbances. The case particularities and immunohistochemistry features are highlighted in the context of literature review, the PIK3CA mutation suggesting the activation of the PI3K/AKT/mTOR pathway, a critical signaling pathway involved in cell survival, proliferation, and metabolism. Conclusions: Due to the aggressive nature of PIK3CA mutations, close monitoring and consideration of immunotherapy and targeted treatments are of crucial importance. Full article

Adipose tissue renewal requires precise coordination of stem/progenitor cell proliferation, preadipocyte commitment, and terminal adipocyte differentiation. T-cadherin (CDH13), an atypical GPI-anchored cadherin, is expressed in adipose tissue and functions as a receptor for high-molecular-weight (HMW) adiponectin—a key adipokine produced by adipose tissue and involved in metabolic regulation. While T-cadherin is implicated in cardiovascular and metabolic homeostasis, its role in adipogenesis still remains poorly understood. In this study, we used the 3T3-L1 preadipocyte model to investigate the function of T-cadherin in adipocyte differentiation. We analyzed T-cadherin expression dynamics during differentiation and assessed how T-cadherin overexpression or knockdown affects lipid accumulation, expression of adipogenic markers, and key signaling pathways including ERK, PI3K–AKT, AMPK, and mTOR. Our findings demonstrate that T-cadherin acts as a negative regulator of adipogenesis. T-cadherin overexpression ensured a proliferative, undifferentiated cell state, delaying early adipogenic differentiation and suppressing both lipid droplet accumulation and the expression of adipogenic markers. In contrast, T-cadherin downregulation accelerated differentiation, enhanced lipid accumulation, and increased insulin responsiveness, as indicated by PI3K–AKT pathway activation at specific stages of adipogenesis. These results position T-cadherin as a key modulator of adipose tissue plasticity, regulating the balance between progenitor expansion and terminal differentiation, with potential relevance to obesity and metabolic disease. Full article

Background/Objectives: Cancer progression is characterized by the suppression of apoptosis, activation of metastatic processes, and dysregulation of cell proliferation. The proper functioning of these mechanisms relies on critical signaling pathways, including Phosphoinositide 3-kinase/Protein kinase B/mammalian Target of Rapamycin (PI3K/Akt/mTOR), Mitogen-Activated Protein Kinase (MAPK), and Signal Transducer and Activator of Transcription 3 (STAT3). Although curcumin and resveratrol exhibit anticancer properties and affect these pathways, their pharmacokinetic limitations, including poor bioavailability and low solubility, restrict their clinical application. The aim of our study was to evaluate the synergistic anticancer potential of curcumin and resveratrol through hybrid molecules rationally designed from these compounds to mitigate their pharmacokinetic limitations. Furthermore, we analyzed the multi-target anticancer effects of these hybrids on the AKT serine/threonine kinase 1 (AKT1), MAPK, and STAT3 pathways using in silico molecular modeling approaches. Methods: Three hybrid molecules, including a long-chain (ELRC-LC) and a short-chain (ELRC-SC) hybrid, an ester-linked hybrid, and an ether-linked hybrid (EtLRC), were designed using the Avogadro software (v1.2.0), and their geometry optimization was carried out using Density Functional Theory (DFT). The electronic properties of the structures were characterized through Frontier Molecular Orbital (FMO), Molecular Electrostatic Potential (MEP), and Fourier Transform Infrared (FTIR) analyses. The binding energies of the hybrid molecules, curcumin, resveratrol, their analogs, and the reference inhibitor were calculated against the AKT1, MAPK, and STAT3 receptors using molecular docking. The stabilities of the best-fitting complexes were evaluated through 100 ns molecular dynamics (MD) simulations, and their binding free energies were estimated using the Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) method. Results: DFT analyses demonstrated stable electronic characteristics for the hybrids. Molecular docking analyses revealed that the hybrids exhibited stronger binding compared to curcumin and resveratrol. The binding energy of −11.4 kcal/mol obtained for the ELRC-LC hybrid against AKT1 was particularly remarkable. Analysis of 100 ns MD simulations confirmed the conformational stability of the hybrids. Conclusions: Hybrid molecules have been shown to exert multi-target mechanisms of action on the AKT1, MAPK, and STAT3 pathways, and to represent potential anticancer candidates capable of overcoming pharmacokinetic limitations. Our in silico-based study provides data that will guide future in vitro and in vivo studies. These rationally designed hybrid molecules, owing to their receptor affinity, may serve as de novo hybrid inhibitors. Full article

Background: Ivermectin has recently garnered significant scientific attention for its potential anticancer properties. Objective: This research aims a comprehensive literature review to evaluate IVM’s chemical characteristics and assess its applicability as an alternative therapeutic strategy in oncology. Methods: The methodology involved a systematic search and critical appraisal of data from peer-reviewed scientific databases, focusing on structural analyses, such as nuclear magnetic resonance (NMR), crystallography, and in silico modeling, as well as preclinical experimental studies. Results: The review highlights IVM’s distinct physicochemical profile, including high lipophilicity, poor aqueous solubility, and moderate acid stability, which collectively affect its bioavailability and pharmacokinetic behavior. Mechanistically, IVM has been shown to modulate multiple oncogenic signaling pathways, including Wnt/β-catenin, PI3K/Akt/mTOR, and STAT3. These interactions contribute to the induction of apoptosis, inhibition of tumor cell proliferation, and modulation of the tumor microenvironment across a range of malignancies. Despite encouraging preclinical evidence, clinical validation remains limited. Conclusions: Further investigation is needed to optimize IVM’s formulation for enhanced solubility and targeted delivery, as well as to design robust clinical trials assessing its safety and efficacy in oncology settings. This review provides a foundational framework for future interdisciplinary research on drug repurposing and highlights the potential of IVM as a cost-effective and accessible adjunct or alternative to modern cancer therapy. Full article

Reactive oxygen species (ROS) function as critical signaling molecules in cancer biology, promoting proliferation, angiogenesis, and metastasis at controlled levels while inducing lethal damage when exceeding the cell’s buffering capacity. To survive under this state of chronic oxidative stress, cancer cells become dependent on a hyperactive antioxidant shield, primarily orchestrated by the Nrf2, glutathione (GSH), and thioredoxin (Trx) systems. These defenses maintain redox homeostasis and sustain oncogenic signaling, notably through the oxidative inactivation of tumor-suppressor phosphatases, such as PTEN, which drives the PI3K/AKT/mTOR pathway. Targeting this addiction to a rewired redox state has emerged as a compelling therapeutic strategy. Pro-oxidant therapies aim to overwhelm cellular defenses, with agents like high-dose vitamin C and arsenic trioxide (ATO) showing significant tumor-selective toxicity. Inhibiting the master regulator Nrf2 with compounds such as Brusatol or ML385 disrupts the core antioxidant response. Disruption of the GSH system by inhibiting cysteine uptake with sulfasalazine or erastin potently induces ferroptosis, a non-apoptotic cell death driven by lipid peroxidation. Furthermore, the thioredoxin system is targeted by the repurposed drug auranofin, which irreversibly inhibits thioredoxin reductase (TrxR). Extensive preclinical data and ongoing clinical trials support the concept that this reliance on redox adaptation is a cancer-selective vulnerability. Moreover, novel therapeutic strategies, including the expanding field of redox-active metal complexes, such as manganese porphyrins, which strategically leverage the differential redox state of normal versus cancer cells through both pro-oxidant and indirect Nrf2-mediated antioxidative mechanisms (triggered by Keap1 oxidation), with several agents currently in advanced clinical trials, have also been discussed. Essentially, pharmacologically tipping the redox balance beyond the threshold of tolerance offers a rational and powerful approach to eliminate malignant cells, defining a novel frontier for targeted cancer therapy. Full article

Background: Acute myeloid leukemia (AML) remains a hematopoietic clonal malignancy that is characterized by a poor prognosis, largely attributable to chemotherapy resistance and a high incidence of post-chemotherapy relapse. Therefore, the identification of novel molecular markers is crucial for optimizing treatment regimens and improving outcomes for this disease. Methods: We first investigated the expression levels of poly(ADP-ribose)polymerase 3(PARP3) mRNA in data from our center and the Gene Expression Omnibus (GEO), then explored the role of PARP3 in AML through cell experiments. Results: Our results demonstrated that the expression levels of PARP3 were significantly elevated in AML samples compared to controls (p < 0.05). Based on the median expression of PARP3, 151 cases of AML from TCGA data were divided into two groups. The results showed that PARP3-high group had markedly shorter overall survival (OS) than the PARP3-low group (OS: median: 1.18 vs. 3.88 years; p < 0.001). The overexpression of PARP3 was correlated with older age and high-risk stratification in the AML from TCGA data (p < 0.05). Finally, we confirmed that specifically down-regulating PARP3 expression impaired AML cell proliferation, disrupted cell cycle process, inhibited migration, accelerated apoptosis, and impaired the PI3K/AKT/mTOR signaling pathway in vitro. Conclusions: PARP3-mediated activation of the PI3K/AKT/mTOR signaling pathway enhances AML cell proliferation and migration, identifying it as a potential therapeutic target for poor-prognosis AML. Full article

Background: Intermittent fasting (IF) is emerging as a promising non-pharmacological intervention in oncology, with the potential to modulate key biological processes including metabolic reprogramming, inflammation, autophagy, and immune function, particularly through the PI3K/AKT/mTOR pathway. However, translating IF into clinical practice requires robust tools to monitor its biological impact and therapeutic effectiveness. Objective: This narrative review aims to present and critically evaluate current diagnostic and monitoring strategies that can support the safe and effective integration of IF into oncological care. Methods: A comprehensive literature search was conducted across PubMed/Medline, Science Direct, Scopus, Wiley Online Library, and Google Scholar using a combination of free-text and MeSH terms related to intermittent fasting, oncology, biomarkers, immunophenotyping, metabolic pathways, gut microbiome, and diagnostic imaging. Results: Two principal categories of monitoring objectives were identified. The first—mechanistic monitoring—focuses on elucidating IF-induced biological effects, including modulation of insulin/IGF-1 signaling, oxidative stress reduction, autophagy activation, immune reprogramming, and microbiome alterations. Advanced research tools such as single-cell RNA sequencing, proteomics, metabolomics, and circulating tumor DNA (ctDNA) assays offer high-resolution insights but currently remain limited to preclinical or translational settings due to cost and complexity. The second—clinical response monitoring—assesses IF’s impact on treatment outcomes, including chemotherapy and immunotherapy response, toxicity reduction, tumor dynamics, and maintenance of nutritional and functional status. This requires clinically validated, accessible, and interpretable diagnostic tools. Conclusions: A dual-layered monitoring framework that integrates both mechanistic insights and clinical applicability is essential for the personalized implementation of IF in oncology. Although preliminary findings are promising, large-scale randomized trials with standardized protocols are necessary to confirm the efficacy, safety, and feasibility of IF in routine oncological care. The integration of IF with modern diagnostics may ultimately contribute to a more individualized, biologically informed cancer treatment paradigm. Full article

Fibromyalgia (FM) is characterized by widespread musculoskeletal pain and tenderness, cognitive dysfunction, fatigue, and insomnia. Electroacupuncture (EA) has documented efficacy against FM-associated pain, while cannabinoid receptor 1 (CB1) plays a critical role in endogenous analgesia. Herein, we examined whether pain relief initiated by EA was linked with differing cerebellar CB1 levels and signaling in an intermittent cold stress (ICS) mouse model of FM. FM-like hyperalgesia and recovery were assessed by measuring mechanical and thermal nociceptive thresholds. Compared to control mice, ICS-induced FM-model mice exhibited a significantly reduced mechanical withdrawal threshold (2.3 ± 0.1 g) and shorter thermal withdrawal latency (4.0 ± 0.5 s), indicative of mechanical and thermal hyperalgesia. Both conditions were reversed by 2 Hz EA but not sham EA. Hyperalgesia was associated with reduced CB1 receptor expression and the enhanced activity of multiple nociceptive signaling pathways (PKA, PI3K, Akt, mTOR, ERK, and NF-kB) in the mouse cerebellum. The 2 Hz EA treatment reliably reversed these abnormalities, while the sham EA treatment did not. Intracerebroventricular injection of the CB1 agonist anandamide (AEA) recapitulated the effects of EA on pain thresholds, while the analgesic effects of EA were blocked by the CB1 antagonist AM251. Precise chemogenetic stimulation at the paraventricular nucleus (PVN) of the hypothalamus reliably induced FM pain. Chemogenetic inhibition at the PVN diminished FM through the CB1 pathway in the cerebellum. Our findings suggest that dysregulation of CB1 expression and aberrant hyperactivity of nociceptive signaling pathways in the cerebellum contribute to the etiology of FM and that the upregulation of CB1 signaling mediates the analgesic efficacy of EA. Full article

The utilization of saline–alkali water resources presents a promising approach for freshwater aquaculture. Red tilapia (Oreochromis spp.) exhibits moderate salinity tolerance, but its adaptation mechanism to alkaline conditions remains poorly understood. In the current study, five alkaline carbonate concentrations in a 60-day chronic stress experiment on red tilapia were evaluated. The experimental design included a control group (CA0, 0 mmol/L) and three treatment groups (CA10, 20 mmol/L; CA30, 30 mmol/L; and CA40 40 mmol/L). The results indicated that at alkaline carbonate concentrations exceeding 20 mmol/L, the gill filaments exhibited curling and deformation, the hepatocytes displayed migration, and tissue damage increased significantly. The gill’s antioxidant capacity initially decreased and then increased, with severe gill injury in the CA40 group, leading to significantly reduced levels of SOD, CAT, and GSH-PX compared to the CA40 group (p < 0.05). Conversely, the enzymatic activities related to energy metabolism showed an opposite trend under alkaline carbonate stress. The transcriptome analyses of gill tissues across five groups identified significant alterations in key pathways, including the metabolic process (endocytosis, focal adhesion, PI3K−Akt signaling pathway, MAPK signaling pathway, and Citrate cycle (TCA cycle)), and immune responses (mTOR signaling and NOD−like receptor signaling pathways). Additionally, we screened 13 differentially expressed genes (DEGs) as potential regulators of alkaline stress and validated their expression levels using quantitative real-time PCR (qPCR). This study preliminarily elucidated the molecular mechanism of red tilapia in the physiological regulation process under chronic alkaline stress, and offers a theoretical foundation for breeding programs aimed at developing alkali-tolerant strains for aquaculture in alkaline water environments. Full article

Background: Prior work established that about a third of ASD-derived LCLs show excessive mitochondrial respiration and stress vulnerability—features divergent from both controls and classical mitochondrial disease. This study explores how mRNA and microRNA (miRNA) expression profiles distinguish subtypes of autism spectrum disorder (ASD) defined by mitochondrial function. Methods: Lymphoblastoid cell lines (LCLs) from boys with ASD were classified into two groups: those with abnormal (AD-A) and normal (AD-N) mitochondrial function. RNA-seq compared mRNA and miRNA expression differences. Results: 24 mRNA differentially expressed genes (DEGs) (14 downregulated, 10 upregulated in AD-N vs. AD-A) were identified, implicating processes such as mRNA processing, immune response, cancer biology, and crucially, mitochondrial and nuclear activities. Notably, genes such as DEPTOR (an mTOR modulator) were upregulated in AD-A, highlighting dysregulation in the mTOR pathway—a central regulator of cellular metabolism, protein synthesis, autophagy, and mitochondrial function. miRNA analysis revealed 18 differentially expressed miRNAs (DEMs) upregulated and one downregulated in AD-N compared to AD-A. Several miRNAs (including hsa-miR-1273h-3p, hsa-miR-197-3p, and hsa-miR-199a-5p) targeted both the differentially expressed genes and pathways previously linked to ASD, such as mTOR, Calmodulin Kinase II, and mitochondrial regulation. Enrichment analyses indicated involvement regulation of cell growth and division, gene expression, immune regulation and cellular stress as well as mTOR signaling. Conclusions: These molecular signatures support the idea that mitochondrial dysfunction in ASD is tied to specific disruptions in the mTOR and PI3K/AKT signaling axes, influencing cell growth, autophagy, oxidative stress handling, and neuronal metabolism. The findings highlight a miRNA-mRNA regulatory network that may underpin mitochondrial dysfunction and ASD heterogeneity, suggesting avenues for subtype-specific biomarkers and targeted therapies that address energy metabolism and cellular stress in ASD. Full article

Background and Objectives: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with few effective treatments. In its pathogenesis, damage-associated molecular patterns are released and recognized by Toll-like receptors (TLRs); all TLRs except TLR3 transduce signals through MyD88. Research has shown that autophagy participates in the progression of pulmonary fibrosis, and MyD88 is closely associated with autophagy. However, whether targeting MyD88 can affect fibrosis progression by regulating autophagy during lung fibrosis remains unclear. Materials and Methods: TJ-M2010-5 (TJ-5) is a small molecular derivative of aminothiazole that inhibits MyD88 homodimerization. A bleomycin-induced pulmonary fibrosis model in mice was established, and a human lung fibroblast cell line MRC-5 was cultured, and the mechanism of fibrosis induced by TGF-β1 was studied. TJ-5 and the autophagy inhibitor 3-MA were used to intervene. Results: Our study indicated that TJ-5 suppressed fibrosis foci formation and collagen deposition in fibrotic lungs, effectively increased the survival rate of bleomycin-stimulated mice from 40.0% to 80.0%, and repressed lung fibroblast activation in vitro. Subsequently, TJ-5 could trigger autophagy, as indicated by increased autophagosomes, LC3B-II and Beclin-1 promotion, and p62 degradation. Moreover, inhibition of TJ-5-induced autophagy by 3-MA reversed the anti-fibrosis effect of TJ-5. Furthermore, the autophagy-related pathways PI3K/AKT/mTOR and MAPK/mTOR were inhibited under TJ-5 intervention. Conclusions: Our findings demonstrated that the mechanism of TJ-5 in alleviating lung fibrosis was through triggering MyD88-related autophagy, and TJ-5 may be therapeutically useful for the clinical treatment of IPF. Full article

The ERK1/2 and PI3K signaling pathways play important roles in cellular proliferation, survival, differentiation, and metabolism. In cancer, these pathways are frequently dysregulated and overactivated, resulting in poor patient prognosis and resistance to treatment. These pathways are activated by receptor tyrosine kinases and send downstream signals to effectors such as RAS, RAF, MEK, AKT, and mTOR. In this review, we highlight the key components of the ERK1/2 and PI3K pathways, the roles they play in tumor progression, and the development of inhibitors and combination therapies designed to enhance therapeutic outcomes and address treatment resistance. Our review demonstrates the need and promise for future research and clinical trials for inhibitors and combination therapies for the ERK1/2 and PI3K pathways in cancer. Full article

Curcumin has been extensively investigated as an anticancer agent, yet its clinical application remains constrained by low bioavailability, incomplete mechanistic understanding, and limited therapeutic optimization. In light of growing resistance to conventional chemotherapies and the demand for safer, multi-targeted agents, this review revisits curcumin with a contemporary lens. We critically evaluate the literature published since 2020, focusing on newly elucidated molecular mechanisms by which curcumin regulates tumor progression, including modulation of oncogenic signaling pathways (Wnt/β-catenin, PI3K/Akt/mTOR, JAK/STAT, and MAPK), induction of ferroptosis, and epigenetic reprogramming. A particular emphasis is placed on recent advances in nanoformulation strategies that enhance curcumin’s pharmacokinetic profile and target-specific delivery. Furthermore, the emerging paradigm of combination therapy is explored, where curcumin acts synergistically with chemotherapeutics and phytochemicals to overcome drug resistance and potentiate anticancer efficacy. This review identifies key knowledge gaps, such as inconsistent clinical translation and the underexplored interplay between nanocurcumin systems and immune modulation, outlining directions for future translational research. Full article

Histiocytic sarcoma (HS) is an ultra-rare hematopoietic neoplasm that frequently occurs in extranodal sites of adults. Clinically, HS demonstrates aggressive behavior and can arise de novo or in association with other hematological neoplasms. The median overall survival from the time of diagnosis is approximately six months. Histologically, HS is composed of sheets of large, round to oval cells with abundant eosinophilic cytoplasm and can be confused with a variety of benign and malignant conditions. Immunohistochemistry plays a crucial role in the diagnosis of HS, showing expression of CD163, CD68, lysozyme, and PU.1 and negative staining with follicular dendritic cell markers and myeloid cell markers. Recent studies have demonstrated a high rate of PD-L1 expression, suggesting a potential therapeutic target. Several genomic alterations have been identified in HS, including mutations involving the RAS/MAPK and PI3K/AKT/mTOR signaling pathways, CDKN2A mutations/deletions, and TP53 mutations. There is no standard protocol for the management of HS. Surgical resection with or without radiotherapy is the most common first-line treatment for unifocal/localized disease. The systemic treatment options for multifocal/disseminated disease are very limited. This review provides an overview of the current knowledge on the clinicoradiological features, histopathology, pathogenesis, and management of HS. Full article