Mol. Cell. Biochem. [JOURNAL]
Sun
200 papers
Olaparib alleviates diclofenac-induced toxicity in HepG2 cells via modulation of oxidative stress and mitochondrial functions.
Maki M, Vantus VB, Koszegi B … +6 more , Szabo A, Fekete K, Ali O, Ali MA, Janosi TZ, Gallyas F
Mol Cell Biochem · 2026 Jun · PMID 42228267 · Publisher ↗
Non-steroidal anti-inflammatory agents are widely used for their analgesic, anti-inflammatory, and antipyretic effects, and a prominent representative of the drug family, diclofenac has recently been proposed for cancer...
Non-steroidal anti-inflammatory agents are widely used for their analgesic, anti-inflammatory, and antipyretic effects, and a prominent representative of the drug family, diclofenac has recently been proposed for cancer therapy. However, overdose of diclofenac has also been reported to cause liver toxicity, whereas olaparib, a widely used antineoplastic poly (ADP-ribose) polymerase inhibitor, is known for its mitochondria-mediated cytoprotective properties. In this study, we used HepG2 human hepatocellular carcinoma cells, which retain various characteristics of hepatocytes, to study the interaction between these two drugs. We found that diclofenac caused a 20-50% decrease in the viability and invasive growth of the cells, which olaparib ameliorated by approximately 50%. Additionally, olaparib reversed diclofenac-induced mitochondrial depolarization as demonstrated by JC-1 fluorescence microscopy and flow cytometry. Furthermore, although not possessing significant free-radical scavenging properties according to the cell-free Fenton reaction system, olaparib also mitigated diclofenac-induced reactive oxygen species production and apoptosis-inducing factor-mediated parthanatos. Using the Seahorse cellular respirometer, we showed that diclofenac shifted the energy production of HepG2 cells toward oxidative phosphorylation by approximately 40%, whereas olaparib reversed this effect, suggesting that the two drugs may have opposite effects on the metabolic reprogramming of cancer cells. Therefore, further studies are needed before considering their combined use for oncological applications. Additionally, we demonstrated that complex I inhibition and preservation of cellular NAD pool are unlikely to be involved among the mechanisms of olaparib's protective effect.
NEFL⁺NEFM⁺ myeloid-reprogrammed cells promote ccRCC progression through CX3CL1-CX3CR1-mediated Tregs chemotaxis.
Zi S, Yu Z, Zhao Z … +2 more , Lv X, Zhang J
Mol Cell Biochem · 2026 May · PMID 42189461 · Publisher ↗
Tumor-associated myeloid cells (TAMCs) fuel immune evasion and progression, yet their roles in clear cell renal cell carcinoma (ccRCC) remain unclear. Single-cell transcriptomic analyses have suggested the emergence of m...
Tumor-associated myeloid cells (TAMCs) fuel immune evasion and progression, yet their roles in clear cell renal cell carcinoma (ccRCC) remain unclear. Single-cell transcriptomic analyses have suggested the emergence of myeloid cells expressing neuronal structural genes such as NEFL and NEFM, implying a neuron-like reprogrammed state. In addition, CX3CL1, a chemokine involved in immune-cell recruitment, has been implicated in tumor immune regulation. However, the existence and function of NEFL/NEFM-associated neuron-like myeloid cells and their potential link to CX3CL1 signaling in ccRCC remain unclear. We analyzed a publicly available single-cell RNA sequencing dataset of human ccRCC tumors and identified a distinct subpopulation of myeloid cells co-expressing canonical myeloid markers and neuronal structural genes, NEFL and NEFM. Functional assays were conducted using ccRCC-conditioned THP-1 cells with or without NEFL/NEFM knockdown or CX3CL1 neutralization. T cell co-culture, ELISA, Transwell assays, and tumor cell phenotyping were applied to investigate immunomodulatory and pro-tumorigenic functions. Single-cell results showed that NEFL⁺NEFM⁺ neuron-like myeloid cells emerged as a reprogrammed TAMC state in ccRCC and were characterized by elevated CX3CL1 expression without CX3CR1 co-expression. Conditioned medium from 786-O ccRCC cells induced THP-1 cells to acquire NEFL⁺NEFM⁺CD68⁺ phenotype and secrete CX3CL1. Genetic silencing of NEFL/NEFM suppressed CX3CL1 secretion. Functionally, NEFL/NEFM-induced reprogrammed cells suppressed T cell proliferation, activation, and cytokine secretion, while enhancing Tregs recruitment via the CX3CL1-CX3CR1 axis. Furthermore, these reprogrammed cells promoted ccRCC cell proliferation, migration, invasion, and EMT, which were mitigated by NEFL/NEFM knockdown or CX3CL1 blockade. Our study identifies NEFL/NEFM-driven myeloid reprogramming in ccRCC, producing neuron-like cells that secrete CX3CL1 to recruit Tregs and foster tumor progression.
Unveiling muscle fatigue: identifying key gene biomarkers and therapeutic targets.
Zhang Y, Zhang Z, Chen X … +4 more , Dai M, Zheng Y, Zhang W, Li F
Mol Cell Biochem · 2026 May · PMID 42183984 · Publisher ↗
Muscle fatigue, a potential risk factor for athlete injuries, lacks specific therapeutic targets and diagnostic biomarkers. This study aimed to identify biomarkers or targets for muscle fatigue to develop new diagnostic...
Muscle fatigue, a potential risk factor for athlete injuries, lacks specific therapeutic targets and diagnostic biomarkers. This study aimed to identify biomarkers or targets for muscle fatigue to develop new diagnostic and treatment approaches. We utilized skeletal muscle and blood expression Quantitative Trait Loci data, employing the methods of Summary-data-based Mendelian Randomization (SMR) and Bayesian colocalization to identify genes that exhibit significant association with fatigue. DSigDB database and molecular docking method were used to predict potential drug candidates for the identified target genes and validated their interactions. Finally, the transcription levels of candidate genes were assessed in a muscle fatigue rat model using RT-qPCR. Using SMR and Bayesian colocalization analyses, we ultimately identified 24 genes stably associated with fatigue in skeletal muscle and 24 fatigue-related genes in blood, among which 6 common genes (ISYNA1, PABPC4, ZDHHC5, KATNAL1, UBOX5, and ATP11B) were found to serve as potential intervention targets for muscle fatigue and peripheral blood gene biomarkers. Several drugs associated with fatigue symptoms, including valproic acid, hesperidin, and cannabidiol were explored through DSigDB database and validated by molecular docking. RT-qPCR results confirmed that the transcriptional levels of Isyna1, Pabpc4, Zdhhc5, Katnal1, Ubox5, and Atp11b in the skeletal muscle of fatigue model rats were significantly altered compared to the control group (p = 0.020, p = 0.028, p = 0.001, p = 0.006, p = 0.027, p = 0.041). Our findings identified potential biomarkers or therapeutic targets for the diagnosis and treatment of fatigue, particularly muscle fatigue.
Deciphering the anticancer potential of an entomopathogenic fungus, Cordyceps militaris in Dalton's Lymphoma transplanted murine model: a multidimensional approach involving computational methods and in vivo validation.
Dutta D, Verma AK, Singh NS … +2 more , Gogoi D, Dutta PP
Mol Cell Biochem · 2026 May · PMID 42183983 · Publisher ↗
Cordyceps militaris, a medicinal mushroom in traditional Chinese medicine, emerged as a promising source of bioactive compounds, exhibiting potent antioxidant, anti-inflammatory, anticancer, antiviral and immunomodulator...
Cordyceps militaris, a medicinal mushroom in traditional Chinese medicine, emerged as a promising source of bioactive compounds, exhibiting potent antioxidant, anti-inflammatory, anticancer, antiviral and immunomodulatory properties. Despite documenting in vitro cytotoxicity against various cancer cell lines, in vivo efficacy against Dalton's Lymphoma (DL) remains underexplored. This study investigates the anticancer efficacy of methanolic Cordyceps militaris extract (CME) against DL-bearing mice, and validate its molecular mechanism via in-silico approaches. DL-bearing Swiss albino mice treated with varying doses of CME showed significant tumor volume reduction and improved survival rates and cytotoxicity. Apoptosis induction, cell cycle progression, mitochondrial membrane potential and DNA fragmentation were analyzed using AO/EB dual staining, flow cytometry, Rhodamine-123 and comet assay, respectively. Molecular docking and dynamics simulations were performed to validate the interactions of CME's potent bioactive compound, cordycepin with anti-apoptotic target proteins, BCL-2, BCL-xL and BFL-1. CME treatment (24-96 h) led to dose- and time-dependent apoptosis supported by scanning electron microscopy, G2/M phase arrest, mitochondrial membrane depolarization and substantial DNA damage characterized by increased tail length, % tail DNA and olive tail moment in comet assay. Docking and MD simulations established strong and stable binding affinity of cordycepin to BFL-1 throughout 100ns simulation time, corroborating in vivo apoptotic outcomes. CME induces mitochondria-mediated apoptosis, DNA damage and cell cycle arrest in DL cells. This highlights the potential of C. militaris as a natural anticancer drug against lymphoma, thereby warranting further clinical validation for phytotherapeutic applications.
Integrative multi-omics and machine learning reveal glycolysis-related biomarkers driving vascular remodeling in pulmonary arterial hypertension.
Tian H, Liu Z, He J … +3 more , Wei R, Bai X, Liu K
Mol Cell Biochem · 2026 Jun · PMID 42176135 · Publisher ↗
Metabolic reprogramming toward aerobic glycolysis, a phenomenon analogous to the Warburg effect, is increasingly recognized as a hallmark of pulmonary arterial hypertension (PAH). However, how glycolytic activation orche...
Metabolic reprogramming toward aerobic glycolysis, a phenomenon analogous to the Warburg effect, is increasingly recognized as a hallmark of pulmonary arterial hypertension (PAH). However, how glycolytic activation orchestrates pulmonary vascular remodeling and endothelial-mesenchymal transition (EndMT) remains poorly understood. To delineate the molecular determinants of glycolytic remodeling, we integrated bulk and single-cell transcriptomic datasets from hypoxia-induced (SuHx) PAH rat models. A multi-algorithm machine-learning pipeline combining LASSO, BORUTA, and SVM-RFE was employed to identify glycolysis-related hub genes. Diagnostic performance was validated in independent rat and human datasets, followed by single-cell communication and pseudotime trajectory analyses to infer cellular dynamics. Experimental verification was performed using SuHx/MCT rat models and hypoxia-treated HUVECs. Five glycolysis-related biomarkers-Cxcr4, Pfkfb3, Rgcc, MGC105649, and Mt2A-were identified, exhibiting consistent differential expression across datasets. PFKFB3 and MT2A emerged as core regulators that link glycolytic activation with endothelial-fibroblast crosstalk and EndMT. Single-cell and pseudotime analyses revealed that endothelial cells progressively transition toward mesenchymal-like phenotypes under hypoxia, accompanied by enhanced glycolytic signaling. Functional validation confirmed increased expression of PFKFB3 and MT2A in vivo and demonstrated that hypoxia and lactate synergistically promote endothelial proliferation in vitro. This integrative framework combining multi-omics and machine learning uncovers a glycolysis-driven EndMT axis that underlies pulmonary vascular remodeling. The identified biomarkers provide mechanistic insight into metabolic-structural coupling in PAH and highlight PFKFB3 and MT2A as promising molecular targets for future glycolysis-based therapeutic interventions.
Netrin-1 protects against doxorubicin-induced cardiotoxicity by suppressing ferroptosis via the UNC5B-LKB1/CaMKKβ-AMPK-NRF2 axis.
Lu W, Wu H, Wang Y … +4 more , Duan Y, Gao P, Li H, Du R
Mol Cell Biochem · 2026 Jun · PMID 42171941 · Publisher ↗
Doxorubicin (DOX)-induced cardiotoxicity is strongly associated with ferroptosis and oxidative stress, yet the endogenous protective mechanisms remain incompletely understood. This study aimed to determine whether Netrin...
Doxorubicin (DOX)-induced cardiotoxicity is strongly associated with ferroptosis and oxidative stress, yet the endogenous protective mechanisms remain incompletely understood. This study aimed to determine whether Netrin-1 protects against DOX-induced cardiomyocyte and myocardial injury and to elucidate the underlying signaling pathway. H9C2 cardiomyocytes and DOX-treated mice were used to evaluate the effects of Netrin-1 on ferroptosis, oxidative stress, and cardiac function. Ferroptosis markers, antioxidant proteins, and signaling molecules were assessed by biochemical assays, immunofluorescence, and Western blotting. Loss-of-function experiments were conducted using si-UNC5B, si-LKB1, si-CaMKKβ, Compound C, and AAV-shUNC5B to dissect pathway dependence. Netrin-1 significantly restored DOX-impaired cell viability, reduced membrane damage, and suppressed ferroptosis by decreasing Fe²⁺, MDA, and ROS while replenishing GSH. It normalized GPX4, ACSL4, ferritin, and TFR1 expression, uniquely activated AMPK, suppressed BACH1, enhanced HO-1, and promoted robust NRF2 nuclear translocation. UNC5B knockdown abolished these effects, indicating its essential role. Mechanistically, Netrin-1 activated AMPK through both LKB1 and CaMKKβ pathways, with dual knockdown producing additive suppression. In DOX-treated mice, Netrin-1 markedly improved cardiac function, lowered serum injury markers, alleviated histological damage, reduced apoptosis, and inhibited ferroptosis; these benefits were negated by AMPK inhibition or UNC5B depletion. Netrin-1 mitigated DOX-induced cardiotoxicity by suppressing ferroptosis and restoring antioxidant defenses through the UNC5B-LKB1/CaMKKβ-AMPK-NRF2 axis, highlighting Netrin-1 as a promising therapeutic candidate for preventing chemotherapy-induced cardiac injury.
Mechanistic insights into mesenchymal stem cell therapy for cognitive impairments in Alzheimer's disease models: a systematic review and meta-analysis.
Kariminejad-Farsangi H, Kariminejad-Farsangi H, Mir Y … +2 more , Sheibani V, Joushi S
Mol Cell Biochem · 2026 May · PMID 42166005 · Publisher ↗
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options that primarily offer symptomatic relief. Mesenchymal stem cells (MSCs) have shown promise in preclinical studies due to...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options that primarily offer symptomatic relief. Mesenchymal stem cells (MSCs) have shown promise in preclinical studies due to their neuroprotective, immunomodulatory, and regenerative properties. This systematic review and meta-analysis aimed to assess the effects of MSC therapy on cognitive performance and molecular pathology in animal models of AD.A systematic search was conducted in PubMed, Web of Science, Scopus, Embase, ProQuest, and gray literature sources. This study included in vivo interventional animal studies that evaluated the effects of MSCs on cognitive outcomes in Alzheimer's disease models using the Morris Water Maze test. The standardized mean difference (SMD) was used as the effect size, and data were synthesized using a random-effects model. Study quality was assessed using the SYRCLE risk of bias tool. Publication bias was evaluated through funnel plots, Egger's test, and the trim-and-fill method. Sensitivity analysis was performed using the leave-one-out method and further supported by a risk-of-bias-based approach.A total of 51 studies met the inclusion criteria, of which 37 were included in the meta-analysis. The findings indicated that MSC therapy significantly reduced escape latency (SMD = -1.18, 95% CI -1.46 to-0.89, I = 56.81%, P = 0.00) and increased time spent in the target quadrant (SMD = 1.93, 95% CI 1.46 to 2.40, I = 78.63%, P = 0.00). MSC treatment also led to an increase in hippocampal BDNF levels and a reduction in Aβ deposition and pro-inflammatory cytokines such as IL-1β and TNF-α. However, the effect on IL-6 levels was not statistically significant.MSCs Improve cognitive function and modulate pathological features in AD animal models. Further high-quality studies with standardized protocols and broader literature inclusion are needed to support clinical translation.
Single-cell transcriptomics reveals glycolytic heterogeneity and identifies STC2 as a key regulator of metabolic reprogramming in osteosarcoma.
Hu X, Wang Q, Lin S
Mol Cell Biochem · 2026 May · PMID 42166004 · Publisher ↗
Osteosarcoma (OS) exhibits profound metabolic reprogramming, yet the specific cellular subpopulations and regulatory networks governing glycolysis within the tumor microenvironment remain elusive. We integrated single-ce...
Osteosarcoma (OS) exhibits profound metabolic reprogramming, yet the specific cellular subpopulations and regulatory networks governing glycolysis within the tumor microenvironment remain elusive. We integrated single-cell RNA sequencing (scRNA-seq) data from 12 OS samples with bulk transcriptomics and high-dimensional Weighted Gene Co-expression Network Analysis (hdWGCNA). The identified core metabolic regulator was comprehensively validated in vitro using functional assays and Seahorse extracellular flux analysis in MG-63 and U2OS cells. Our single-cell analysis revealed marked metabolic heterogeneity, identifying a dedifferentiated "Chondroblastic" subpopulation characterized by high glycolytic flux and stem-like features. Multi-omics screening pinpointed Stanniocalcin-2 (STC2) as a core prognostic regulator of this phenotype. In vitro validation demonstrated that STC2 knockdown significantly suppressed OS cell proliferation, invasion, and the expression of key glycolytic enzymes (PGK1, LDHA, and GLUT1). Crucially, extracellular flux analysis revealed that STC2 depletion induced a profound metabolic shift, substantially attenuating glycolysis (decreased ECAR) while concomitantly enhancing mitochondrial oxidative phosphorylation (increased OCR). We present a high-resolution single-cell metabolic map of OS, identifying STC2 as a critical regulator of glycolysis-associated tumor progression. Targeting STC2 effectively reverses metabolic reprogramming-shifting energy metabolism from glycolysis toward oxidative phosphorylation-offering a promising therapeutic strategy for osteosarcoma.
UCHL1-mediated deubiquitination of GLOD4 regulates mitochondrial homeostasis and PTC malignant progression via GLO1.
Cai L, Qian LY, Wu W … +3 more , Ding BN, Luo ZR, Du J
Mol Cell Biochem · 2026 May · PMID 42166003 · Publisher ↗
Papillary thyroid carcinoma (PTC) is prone to metastasis, and patients with metastatic PTC have a poor prognosis. This study aimed to investigate the function of GLOD4 in PTC. Cancerous and paracancerous tissues were col...
Papillary thyroid carcinoma (PTC) is prone to metastasis, and patients with metastatic PTC have a poor prognosis. This study aimed to investigate the function of GLOD4 in PTC. Cancerous and paracancerous tissues were collected from patients with PTC. CO-IP was performed to detect the level of GLOD4 or ubiquitination modification, as well as to verify protein interactions of GLOD4 with UCHL1 or GLO1. Cell proliferation was detected by CCK-8 or EdU staining, cell migration and invasion by transwell assay, GLO1 enzyme activity by ELISA, total and mitochondrial methylglyoxal levels by commercial kits, mitochondrial ROS levels by flow cytometry, and oxygen consumption rate and ATP levels by seahorse energy metabolism analyzer. GLOD4 knockdown subcutaneous xenograft model was constructed in nude mice, HE staining was used to detect the histopathological condition of the tumor, and IHC was used to detect Ki67 and GLOD4 expression. GLOD4 levels were significantly upregulated in PTC tissues and cells, and overexpression of GLOD4 enhanced PTC cell proliferation, migration, and invasion. Mechanistically, UCHL1 could directly bind to GLOD4 and enhance its protein stability by promoting K48-linked deubiquitination, whereas the ability of GLOD4 to promote invasion and migration in PTC cells depends on this regulatory function of UCHL1. Furthermore, GLOD4 regulated GLO1 to detoxify methylglyoxal, a toxic by-product of glycolysis, to maintain mitochondrial homeostasis. GLOD4 knockdown inhibited PTC tumor growth in vivo. UCHL1 enhances the protein stability of GLOD4 through deubiquitination, promoting its interaction with GLO1 to cooperatively detoxify methylglyoxal, maintain mitochondrial homeostasis, and ultimately drive PTC progression.
N-glycosylation of ERLIN2 promotes hepatocellular carcinoma progression by enhancing CCNB1 stability.
Li S, Huang H, Feng J … +2 more , Gu Q, Sun D
Mol Cell Biochem · 2026 May · PMID 42166002 · Publisher ↗
Hepatocellular carcinoma (HCC) ranks among the most lethal cancers, and its dismal prognosis underscores the urgent need to elucidate the underlying carcinogenic mechanisms. Endoplasmic reticulum lipid rafts associated p...
Hepatocellular carcinoma (HCC) ranks among the most lethal cancers, and its dismal prognosis underscores the urgent need to elucidate the underlying carcinogenic mechanisms. Endoplasmic reticulum lipid rafts associated protein 2 (ERLIN2), an endoplasmic reticulum protein, has been implicated in various malignant tumors. However, its functional role in HCC remains poorly understood. Here, we found elevated ERLIN2 expression and N-glycosylation modification at asparagine 106 (N106) in HCC. We identify site-specific N-glycosylation as a crucial advantage of ERLIN2 that may result in aberrant cancer cell growth. Overexpression of either N-glycosylated ERLIN2 (wild-type, WT) or an asparagine-to-glutamine mutant (N106Q) in HCC cell lines indicated that N106 N-glycosylation of ERLIN2 acts as an important advantage in the tumorigenesis and triggers aberrant cell proliferation, migration, and invasion. Furthermore, we found that E3 ubiquitin ligase membrane-associated ring-CH-type finger protein 6 (MARCHF6) can mediate the ubiquitination degradation of ERLIN2, and this effect is more significant after the N-glycosylation at the N106 site is inhibited. In addition, excessive N-glycosylation at this site enhanced the interaction between ERLIN2 and cyclin B1 (CCNB1), leading to dysregulated CCNB1 expression and further accelerating the progression of HCC. Comprehensive studies confirm that N-glycosylation is a significant post-translational modification of ERLIN2 in HCC, and elucidating this mechanism may pave the way for the development of novel therapeutic strategies in the future.
Flavonoids as functional food-derived modulators of the gut microbiota-NF-κB axis in metabolic dysfunction-associated steatotic liver disease.
Saikia L, Dutta PP, Law D … +3 more , Sen S, Gautam MK, Gogoi D
Mol Cell Biochem · 2026 Jun · PMID 42166001 · Publisher ↗
Metabolically Dysfunctional-Associated Steatotic Liver Disease (MASLD) is increasingly recognised as a gut-liver axis disorder driven by sustained activation of pro-inflammatory signalling networks, particularly the NF-κ...
Metabolically Dysfunctional-Associated Steatotic Liver Disease (MASLD) is increasingly recognised as a gut-liver axis disorder driven by sustained activation of pro-inflammatory signalling networks, particularly the NF-κB pathway. Flavonoids, a diverse class of dietary polyphenols, have emerged as promising modulators of NF-κB-mediated gut-liver crosstalk due to their capacity to restore intestinal homeostasis and suppress hepatic inflammation. This review synthesises recent preclinical evidence identifying NF-κB as a central mechanistic target underlying flavonoid actions in MASLD. A structured literature search was conducted in PubMed, Scopus, Web of Science, and ScienceDirect to identify studies published between 2020 and February 2026. Accumulating evidence indicates that flavonoids remodel the gut microbiota toward beneficial taxa. Several flavonoids also modulate upstream regulators, thereby converging on NF-κB to mitigate MASLD. To improve translational interpretation, animal experimental doses were contextualised using established human-equivalent dose conversion methods, alongside reported dietary sources and estimated achievable intake levels. Although the present work highlights the considerable potential of flavonoids as functional food-derived modulators of the gut microbiota NF-κB axis in MASLD, their clinical translation remains constrained by limited bioavailability and heterogeneity across experimental models, highlighting the need for standardised dosing strategies, integrated host microbiota analyses, and well-designed human studies to substantiate clinical applicability.
Chronic bisphenol A exposure activates the cGAS-STING-NLRP3 axis driving persistent hippocampal neuroinflammation and cognitive impairment.
Tom VV, Mallick S, Sasidharan A … +4 more , Biswas T, Bose B, Somayaji Y, Fernandes R
Mol Cell Biochem · 2026 May · PMID 42166000 · Publisher ↗
Bisphenol A (BPA), a main component of polycarbonate plastics and epoxy resins, has been reported to cause chronic neuroinflammation and cognitive impairment in animal models. However, the precise molecular mechanisms of...
Bisphenol A (BPA), a main component of polycarbonate plastics and epoxy resins, has been reported to cause chronic neuroinflammation and cognitive impairment in animal models. However, the precise molecular mechanisms of BPA-induced chronic neuroinflammation remain unknown. In this study, male C57BL/6 mice were administered BPA at different doses for one month, followed by a one-month washout period. We then conducted behavioral tests, oxidative stress assays, and immunohistochemistry to quantify neuronal density and the activation of microglia and astrocytes in the central nervous system. We also carried out RT-qPCR gene expression analysis of the hippocampus for the cGAS-STING-NLRP3 pathway, cytokine assays, and microglial markers to decipher the immune responses in the hippocampus following BPA exposure. BPA induced dose-dependent behavioral deficits, which were most pronounced at 50 mg/kg. These findings suggest that cGAS-STING signaling acts as a key upstream mediator of BPA-induced hippocampal neuroinflammation and cognitive dysfunction.
Renoprotective effects of vitamin D and thymoquinone, alone and in combination, in a rat co-treatment model of gentamicin-induced acute kidney injury.
Refaat B, El-Sebaey AM, Khan A … +8 more , Albukhari TA, Rajab B, Alqurashi S, Filimban W, Sembawa H, Megahed A, Sindi G, El-Boshy ME
Mol Cell Biochem · 2026 May · PMID 42165999 · Publisher ↗
To investigate the prophylactic (co-treatment) effects of vitamin D (VD), thymoquinone (TQ), and their combination against gentamicin (GM)-induced acute kidney injury (AKI). Forty male Wistar rats were divided into five...
To investigate the prophylactic (co-treatment) effects of vitamin D (VD), thymoquinone (TQ), and their combination against gentamicin (GM)-induced acute kidney injury (AKI). Forty male Wistar rats were divided into five groups: negative control, GM-treated positive control (PC; 100 mg/kg/day), and three groups receiving GM simultaneously with VD (210 IU/kg/day), TQ (12.5 mg/kg/day), or both. The GM-treated rats developed classical AKI symptoms, including elevated serum creatinine and urea, altered urine parameters, abnormal renal histology, and increased renal cell apoptosis. Moreover, renal tissues from PC rats showed a marked increase of oxidative stress markers (MDA/HO/protein carbonyls) and pro-inflammatory cytokines (TNF-α/IL-1β/IL-6/IL-18/TLR2), with inhibition of antioxidants (GSH/GPx1/SOD/CAT) and interleukin-10. The expression of pathogenic mediators (NFκB-p50/iNOS/TGF-β1) was significantly upregulated, while renoprotective molecules (Nrf2/AMPK-α/AKT1/survivin) were inhibited. Both VD and TQ provided partial renal protection, with TQ showing relatively greater efficacy under the tested conditions. However, their co-administration demonstrated superior efficacy relative to both monotherapies, reflected by better restoration of renal function and histology alongside stronger reductions in oxidative stress and inflammation. This combination also resulted in a more effective downregulation of pathogenic molecules alongside enhanced expression of the renoprotective pathways. This is the first study to report a relative advantage of TQ over VD under the tested conditions and demonstrate that VD and TQ co-therapy exerted enhanced renoprotection in GM-induced AKI. These ameliorations were potentially mediated through enhanced modulation of renal oxidative stress and inflammation. However, further studies should explore VD and TQ co-therapy effects on additional pathogenic mechanisms underlying aminoglycoside-induced nephropathy.
Inhibition of the mitochondrial pyruvate carrier attenuates the integrated stress response activation in a cellular model of Huntington's disease.
Oliveira Â, Almeida LM, Oliveira JMA … +1 more , Pinho BR
Mol Cell Biochem · 2026 May · PMID 42165998 · Publisher ↗
Mitochondrial pyruvate carrier (MPC) inhibition was found protective in models of neurodegenerative diseases, such as Alzheimer's and Parkinson's. However, little is known about MPC as a potential therapeutic target in H...
Mitochondrial pyruvate carrier (MPC) inhibition was found protective in models of neurodegenerative diseases, such as Alzheimer's and Parkinson's. However, little is known about MPC as a potential therapeutic target in Huntington's disease (HD), a neurodegenerative disorder with dysregulation of the pro-survival pathway integrated stress response (ISR). Here, we investigate if MPC inhibition modulates the ISR and mitigates mutant huntingtin (mut-Htt) proteotoxicity in a cellular HD model. We treated cells expressing N-terminal fragments of wild-type- (wt-) or mut-Htt with two MPC inhibitors (mitoglitazone and UK5099) or solvent control. Metabolism was assessed analysing resazurin reduction, oxygen consumption, extracellular acidification, and ATP levels. ISR activation and huntingtin proteostasis were assessed using western-blot and filter-trap assays. Mut-Htt-expressing cells showed decreased resazurin reduction and ATP levels, and increased eIF2α phosphorylation, indicating metabolic stress and ISR activation. MPC inhibitors (100 µM) increased resazurin reduction and decreased respiration. The latter was rescued by the membrane-permeant methyl pyruvate, which bypasses MPC inhibition. In wt-Htt-expressing cells, MPC inhibitors increased levels of ATP and ISR markers, suggesting metabolic adaptation and ISR activation. In mut-Htt-expressing cells, MPC inhibitors preserved ATP levels and attenuated mut-Htt-induced eIF2α phosphorylation but without changing soluble or aggregated mut-Htt levels. This work showed that MPC inhibition differentially modulates the ISR: it activates ISR in control cells and attenuates overactive ISR in mut-Htt-expressing cells. However, MPC inhibition did not impact the proteostasis of N-terminal fragment mut-Htt. Further studies are essential to explore MPC inhibition in less severe full-length mut-Htt-expressing models to better understand its therapeutic potential in HD.
TMED2 regulates macrophage polarization through MEK/ERK signaling pathway for osteosarcoma progression promotion.
Zou P, Tao Z, Yang Z … +3 more , Xiong J, Zhong B, Yang D
Mol Cell Biochem · 2026 May · PMID 42165997 · Publisher ↗
Osteosarcoma (OS) is the most prevalent malignant tumor among adolescents, characterized by high recurrence rates and poor prognosis. Identifying novel prognostic biomarkers and therapeutic targets has become an urgent c...
Osteosarcoma (OS) is the most prevalent malignant tumor among adolescents, characterized by high recurrence rates and poor prognosis. Identifying novel prognostic biomarkers and therapeutic targets has become an urgent clinical need. We analyzed the GSE99671 dataset and identified TMED2, STC2, and GAL as high-risk genes for OS through LASSO regression and multivariate Cox proportional hazards modeling. Further examination of the expression levels of these genes in paired tumor and adjacent non-tumor tissue samples from OS patients ultimately pinpointed TMED2 as a key candidate gene. Preliminary analysis based on TCGA data suggested that TMED2 might influence osteosarcoma progression by regulating immune cell infiltration. Functional experiments demonstrated that shRNA-mediated knockdown of TMED2 significantly suppressed the proliferation, migration, and invasive capacity of osteosarcoma cells, while promoting the polarization of M0 macrophages toward the M1 phenotype. KEGG enrichment analysis indicated that TMED2's function is closely associated with the MAPK signaling pathway, and Western blot experiments further validated TMED2's role in activating this pathway. Mechanistic studies revealed that CKAP4 may serve as a downstream effector molecule of TMED2, with CKAP4 knockdown significantly affecting macrophage polarization and the activation status of the MAPK pathway. To further validate these findings, we established a xenograft mouse model, and the in vivo experimental results were consistent with those of the in vitro cell experiments, confirming that the TMED2/CKAP4 axis may promote osteosarcoma progression by regulating the MEK/ERK signaling pathway and macrophage polarization.
Semaglutide ameliorates neuroinflammation and cognitive impairment in APP/PS1 mice.
Yuan Y, Zhang J, Zhang Z … +6 more , Zhai Y, Cheng XJ, Xue L, Zhao F, Cao L, Wang H
Mol Cell Biochem · 2026 May · PMID 42126676 · Publisher ↗
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown neuroprotective potential, but the mechanisms under...
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown neuroprotective potential, but the mechanisms underlying these effects remain incompletely understood. This study investigated whether semaglutide, a long-acting GLP-1RA, ameliorates AD-like phenotypes in APP/PS1 mice and explored associated changes in neuroinflammatory signaling and blood-brain barrier (BBB) integrity. Eight-month-old amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice were treated with semaglutide for 8 weeks. Cognitive performance was evaluated using the Morris water maze (MWM). AD-related neuropathology, neuroinflammation-associated protein markers, BBB integrity-related measures, and microglial ultrastructure were assessed using histological, ultrastructural, and molecular approaches. Fecal microbiota composition was profiled by 16 S rRNA amplicon sequencing. Semaglutide improved cognitive performance in APP/PS1 mice and was associated with attenuation of neuronal loss-related changes, reduced Aβ deposition, and improved synaptic ultrastructure. Semaglutide also reduced the AD-associated upregulation of inflammasome-/pyroptosis-associated proteins (including NLRP3-related and caspase-11-related markers) and TLR4/NF-κB-related inflammatory signaling proteins, accompanied by attenuation of microglial mitochondrial ultrastructural abnormalities. In addition, semaglutide improved markers of BBB integrity (tight junction proteins and brain albumin levels) and increased BBB-related Aβ clearance proteins (LRP-1 and P-gp). Gut microbiota profiling revealed genus-level differences between WT and APP/PS1 mice without significant changes in α- or β-diversity. Semaglutide was associated with improved cognition and attenuation of AD-like pathology and neuroinflammatory signaling in APP/PS1 mice, accompanied by partial preservation of BBB integrity.
Genetic regulation of insulin resistance surrogate index (TyG) and susceptibility to common diseases based on phenome-wide association study.
Wu JX, Bu LH, He P … +4 more , Xia MH, Bo L, Deng FY, Lei SF
Mol Cell Biochem · 2026 May · PMID 42126675 · Publisher ↗
Insulin resistance (IR) is a crucial driver of numerous metabolic and non-metabolic diseases, yet the associations between the triglyceride-glucose (TyG) index-a marker for IR-and a broad spectrum of health conditions re...
Insulin resistance (IR) is a crucial driver of numerous metabolic and non-metabolic diseases, yet the associations between the triglyceride-glucose (TyG) index-a marker for IR-and a broad spectrum of health conditions remain poorly understood. A large-scale genome-wide association study (GWAS) of triglyceride-glucose (TyG) was performed based on over 320,000 Europeans in the UK Biobank. Then we used Mendelian randomization (MR) within the framework of a phenome-wide association study (PheWAS) and Multivariable Mendelian Randomization (MVMR) to investigate potential causal associations between TyG and clinical diseases and to explore genetic mechanisms through complex genetic approaches. GWAS identified a total of 166 independent single nucleotide polymorphisms (SNPs) with known functions in the regulation of adipogenesis and glucose energy metabolism, which are enriched in liver metabolic pathways. The MR-PheWAS study found causal associations between TyG and 9 clinical diseases. MVMR reveals a causal association between TyG and Hypertensive Heart Disease. Linkage disequilibrium score regression (LDSC) analysis further revealed genetic correlations between TyG and these diseases. PLACO analysis provided valuable insights into the potential mechanisms connecting TyG and common diseases. These findings enhance understanding of genetic determinants of TyG, clarify the underlying molecular mechanisms and causal relationships between TyG and common diseases, and guide future research toward potential interventions based on existing biomarkers and genetic insights.
TangShenKang decoction plays an anti-inflammatory and anti-fibrotic role in diabetic nephropathy by activating AT2R/ATIP1/SHP1 axis and antagonizing angiotensin II.
Wei R, Ma J, Yu Z … +2 more , Zou W, Zhao N
Mol Cell Biochem · 2026 Jun · PMID 42126674 · Publisher ↗
Diabetic nephropathy (DN) is the most prevalent microvascular complication of diabetes, where a hyperglycemic environment can induce chronic damage to renal vessels and parenchyma, severely endangering patients' health....
Diabetic nephropathy (DN) is the most prevalent microvascular complication of diabetes, where a hyperglycemic environment can induce chronic damage to renal vessels and parenchyma, severely endangering patients' health. TangShenKang decoction (TSK) is a traditional Chinese medicine formula developed based on the clinical and pathological characteristics of DN. In this study, through transcriptomic data analysis of a rat DN model and a TSK intervention group, the key regulatory gene AT2R was identified. Molecular mechanisms underlying TSK's effects on inflammation and fibrosis in DN were investigated using Western blot, quantitative polymerase chain reaction (qPCR), and immunofluorescence staining experiments, with further in vivo validation of TSK's therapeutic effects on DN. The results showed that TSK can activate AT2R in the DN model and promote SHP1 phosphorylation, thereby inhibiting the phosphorylation of IκBα, an important protein in the NFκB signaling pathway, reducing the secretion of inflammatory cytokines such as TNF-α, IL-1β, and IL-6, and suppressing the progression of inflammation. Meanwhile, after activating AT2R, TSK can effectively inhibit the epithelial-mesenchymal transition (EMT) process in DN, downregulate the expression of p-Smad2/3 in the TGF-β signaling axis, and decrease the expression levels of fibrosis phenotype molecules such as connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), and fibronectin 1 (FN1), thereby alleviating renal fibrosis in DN. In conclusion, the therapeutic effect of TSK on DN may be mediated through the activation of the AT2R/ATIP1/SHP1 axis, which subsequently inhibits inflammation- and fibrosis-related signaling pathways.
Dose- and time-dependent cardioprotection of liproxstatin-1 via sequential modulation of ferroptosis pathways after myocardial ischemia-reperfusion.
Huang Z, Chen X, Ren J … +5 more , Wan L, Li M, Ma X, Dong J, Ran H
Mol Cell Biochem · 2026 Jun · PMID 42126673 · Publisher ↗
Myocardial ischemia-reperfusion (MI/R) injury significantly limits the clinical benefits of coronary reperfusion therapy. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has been...
Myocardial ischemia-reperfusion (MI/R) injury significantly limits the clinical benefits of coronary reperfusion therapy. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has been implicated in myocardial ischemia-reperfusion (I/R) injury. Liproxstatin-1 (Lip-1) is a potent ferroptosis inhibitor, but its dynamic, dose-dependent effects on key molecular pathways and pathological hallmarks in the heart remain incompletely characterized. To systematically investigate the dose- and time-dependent cardioprotective effects of Lip-1 against myocardial I/R injury, with a focus on the NRF2/GPX4 pathway, iron deposition, and lysosomal integrity. Ninety Wistar rats were randomly allocated to 15 experimental groups (n = 6 per group): Normal (no surgery), Sham (thoracotomy without ischemia), I/R model, and I/R + Lip-1 treatment groups. Lip-1 was administered intravenously at doses of 1, 3, or 5 mg/kg at 0, 24, 48, and 72 h post-reperfusion initiation, with myocardial tissue and blood samples harvested 6 h after each injection. Cardiac function was assessed by echocardiography. Myocardial infarct size was determined by Evans Blue/TTC double staining. Serum levels of CK-MB and LDH were measured as markers of myocardial injury. Analyses included Western blot for NRF2 and GPX4 expression, Prussian blue staining for iron deposition quantification, and immunofluorescence for LAMP1 localization and intensity. Statistical analysis was performed using two-way ANOVA with Tukey's post hoc test for Lip-1 treatment groups, and t-tests or one-way ANOVA for model validation comparisons. Compared to Sham, I/R injury significantly decreased LVEF, increased infarct size, and elevated CK-MB and LDH levels (all P < 0.0001), confirming successful model establishment. It also downregulated GPX4 expression, induced severe iron deposition, and reduced LAMP1 levels, while triggering an adaptive upregulation of NRF2. Lip-1 treatment produced dose- and time-dependent protection across all measured endpoints. It improved cardiac function, reduced infarct size, and attenuated CK-MB and LDH release, with significant dose×time interactions for infarct size (F(6,60) = 8.338, P < 0.0001), CK-MB (F(6,60) = 6.467, P < 0.0001), and LDH (F(6,60) = 9.021, P < 0.0001). It dynamically modulated the NRF2/GPX4 axis, with peak GPX4 expression observed following the 48-hour administration (sampled at 54 h post-reperfusion). Lip-1 progressively reduced iron deposition, with maximal effect observed after the 72-hour administration (sampled at 78 h post-reperfusion), and rescued LAMP1 downregulation in later sampling points. Statistical analysis revealed significant dose×time interactions for NRF2 (F(6,60) = 200.8, p < 0.0001), GPX4 (F(6,60) = 34.84, p < 0.0001), and iron deposition. High-dose Lip-1 (5 mg/kg) demonstrated superior and sustained efficacy across all parameters. Lip-1 confers multi-faceted cardioprotection against I/R injury through sequential mechanisms involving early potentiation of the NRF2/GPX4 antioxidant defense, progressive attenuation of pathological iron accumulation, and restoration of lysosomal membrane integrity. The strict dose and temporal dependency of these effects provide critical insights for optimizing ferroptosis-targeted therapeutic strategies in ischemic heart disease.
Innovative valsartan-loaded self-nanoemulsifying drug delivery system combat liver inflammation and oxidative stress in streptozotocin-induced diabetic rats.
Elimam H, Hussein J, El-Banna M … +5 more , El-Khayat Z, Zaki MB, Alamri SH, Ahmed TA, El-Say KM
Mol Cell Biochem · 2026 Jun · PMID 42118427 · Publisher ↗
Diabetes-induced liver damage is a significant complication of hyperglycemia, which results in oxidative stress, inflammation, and fibrosis. Conventional treatment strategies remain limited, necessitating novel therapeut...
Diabetes-induced liver damage is a significant complication of hyperglycemia, which results in oxidative stress, inflammation, and fibrosis. Conventional treatment strategies remain limited, necessitating novel therapeutic approaches. This study evaluates the hepatoprotective effects of valsartan-loaded self-nanoemulsifying drug delivery system (SNEDDS) in streptozotocin (STZ)-induced hyperglycemic rats, focusing on oxidative stress modulation, suppression of inflammatory cytokines, and metabolic regulation. Male Sprague-Dawley rats were divided into six groups: control, STZ-induced diabetic model, and treatment diabetic groups receiving valsartan (Val) or valsartan/hydrochlorothiazide (Val/HCT) in either SNEDDS-loaded liquisolid tablets or directly compressed tablets. Liver function, oxidative stress biomarkers, lipid profiles, histopathological changes, and gene expression levels of NF-κB, TGF-β, and Nrf2 were assessed. Val and Val/HCT-loaded-SNEDDS significantly reduced fasting blood glucose to ~ 95 mg/dl, serum ALT levels (34-50%), and pro-inflammatory cytokines (NF-κB and IL-1) (21% and 40%, respectively). They also enhanced antioxidant defenses by increasing hepatic glutathione levels (34-39%) while reducing malondialdehyde (36-39%) and nitric oxide (50%). Histopathological analysis confirmed improved liver architecture with diminished inflammatory cell infiltration and fibrosis. Gene expression analysis revealed a downregulation of TGF-β and NF-κB, alongside upregulation of Nrf2, indicating reduced fibrogenesis and an oxidative stress response. In conclusion, Val-loaded SNEDDS effectively mitigates STZ-induced hepatotoxicity. This hepatoprotective effect is due to blocking the angiotensin II type 1 receptor (AT1R), leading to inhibition of TGF-β and other TGF-β-mediated inflammatory markers, such as NF-κB and IL-1. This nanoformulation offers a promising therapeutic strategy for diabetes-associated liver injury and warrants further investigation for clinical applications.
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