Mol. Cell. Biochem. [JOURNAL]
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200 papers
L-carnitine mitigates urographin-induced nephrotoxicity via modulation of inflammatory, oxidative, and apoptotic pathways in rat kidney.
Erbaş M, Gündüz D, Sarman E … +4 more , İlhan İ, Tepebaşı MY, Arlıoğlu M, Savran M
Mol Cell Biochem · 2026 Feb · PMID 41261345 · Publisher ↗
Contrast-induced nephropathy (CIN) remains a significant clinical challenge, particularly following the administration of iodinated agents such as urographin. L-carnitine (LC) is a substance known for its anti-inflammato...
Contrast-induced nephropathy (CIN) remains a significant clinical challenge, particularly following the administration of iodinated agents such as urographin. L-carnitine (LC) is a substance known for its anti-inflammatory and antiapoptotic effects. This study investigates the nephroprotective potential of LC through its regulatory effects on inflammation, oxidative stress, and apoptosis in a rat model of CIN. Thirty-two Wistar albino rats were assigned to four groups: Control, urographin (URO, 10 mL/kg i.p.), URO-LC (200 mg/kg L-carnitine i.p. for 10 days), and LC alone. Renal function markers (urea, creatinine), oxidative stress indicators as total oxidans status (TOS), total antioxidant status (TAS), oxidative stress (OSI), and histopathological features were evaluated. The immunohistochemical expression of tumor necrosis factor alpha (TNF-α) and Caspase-3 (Cas-3), along with the mRNA expression levels of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and Caspase-9 (Cas-9), were assessed. URO significantly increased serum urea and creatinine levels, TOS and OSI values. TNF-α and Cas-3 immunoreactivity, along with Bax and Cas-9 gene expression, were markedly elevated in the URO group, while anti-apoptotic Bcl-2 expression was suppressed. URO also induced severe histological damage. LC treatment reversed these effects, preserving tissue integrity and restoring molecular markers toward baseline levels. LC exerts potent nephroprotective effects against URO-induced renal injury by attenuating oxidative stress, suppressing pro-inflammatory and apoptotic signaling, and promoting anti-apoptotic gene expression. These findings support its potential clinical use in the prevention of contrast-induced renal damage.
H as a potential redox homeostasis modulator: a review of mechanisms targeting key elements of cardiovascular pathogenesis-related pathways.
Wang W, Yang F, Geng B … +5 more , Song H, Gao Y, Shi J, Wang G, Cui C
Mol Cell Biochem · 2026 Feb · PMID 41254431 · Publisher ↗
Cardiovascular diseases (CVDs) are among the leading causes of death worldwide, and their pathogenesis is closely associated with the imbalance of the oxidative stress microenvironment. Hydrogen (H) has attracted attenti...
Cardiovascular diseases (CVDs) are among the leading causes of death worldwide, and their pathogenesis is closely associated with the imbalance of the oxidative stress microenvironment. Hydrogen (H) has attracted attention in the field of CVDs treatment due to its property of selectively scavenging reactive oxygen species (ROS) and regulating redox homeostasis. This article systematically reviews the multi-level regulatory mechanisms of H in CVDs, including the activation of the Nrf2-Keap1 pathway, the regulation of AMPK/mTOR and JAK-STAT networks, as well as the inhibition of key pathways such as miR-124-3p-calpain, NOX4/NLRP3, Wnt/CX3CR1, and LOX-1/NF-κB, thereby participating in the remodeling of cellular redox balance. In addition to scavenging ROS, H also exhibits certain anti-inflammatory effects, differing functionally from traditional antioxidants. This article explores the role of H in reconstructing oxidative stress regulation, analyzes the heterogeneity of the oxidative stress microenvironment in CVDs, and provides a basis for its therapeutic potential. Integrating preclinical research and translational medicine evidence, this article proposes a "precision H medicine" framework, aiming to provide theoretical references for targeted therapy of CVDs and explore potential pathways for precision treatment.
Mechanistic toxicity profiling of nicotine-rich e-liquids: mitochondrial and oxidative stress responses in ALI-exposed bronchial cells.
Emma R, Distefano A, Zuccarello P … +10 more , Copat C, Ferrante M, Oliveri Conti GM, Pulvirenti R, Carota G, Campagna D, Polosa R, Rust S, Caruso M, Li Volti G
Mol Cell Biochem · 2026 Feb · PMID 41254430 · Full text
Combustion byproducts contained in cigarette smoke are considered the main responsible for the occurring of serious chronic diseases. Aerosols from electronic cigarettes contain substantially fewer of these dangerous byp...
Combustion byproducts contained in cigarette smoke are considered the main responsible for the occurring of serious chronic diseases. Aerosols from electronic cigarettes contain substantially fewer of these dangerous byproducts, potentially reducing health risks. This study examined the potential of four different commercial nicotine-rich e-liquids to induce cytotoxicity and mitochondrial dysfunction and oxidative stress in human bronchial epithelial cells (H292), using air-liquid interface (ALI) exposure. In addition to a qualitative control of the e-liquids, by dosing contaminants, we assessed cell viability, apoptosis, mitochondrial membrane potential, and reactive oxygen species (ROS) generation, by comparing e-cig aerosols to 1R6F reference cigarette smoke. All tested e-liquids showed very low levels of trace metals and microplastics, with contaminant concentrations below WHO drinking water limits. Furthermore, e-liquid aerosol induced significantly reduced cytotoxicity compared to 1R6F regular cigarette smoke, and mitochondrial integrity was preserved. Furthermore, no ROS generation was observed when using flavored e-cigarette aerosol. These results provide evidence of the lower potential toxicity of e-cigarettes compared to tobacco cigarettes in an in vitro model simulating real-world smoke exposure.
Empagliflozin alleviates lipid deposition and inflammation in diabetic kidney disease by downregulating C1QC.
Shi S, Li W, Yang L … +2 more , Zhang J, Wu X
Mol Cell Biochem · 2026 Feb · PMID 41252098 · Publisher ↗
Our previous study has identified C1QC as a potential mediator through which obesity accelerates the progression of diabetic kidney disease (DKD). Emerging evidence suggests that empagliflozin, a sodium-glucose cotranspo...
Our previous study has identified C1QC as a potential mediator through which obesity accelerates the progression of diabetic kidney disease (DKD). Emerging evidence suggests that empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, mitigates renal injury by downregulating C1QC expression. This study systematically investigated the mechanistic role of C1QC in DKD pathogenesis and validated empagliflozin's therapeutic effects through C1QC modulation, thereby establishing a novel target for DKD management. Human proximal tubular (HK-2) cells were challenged with high glucose (HG) (30 mM) and palmitate (PA) (300 µM) to establish metabolic injury models. Subsequent interventions included: (1) siRNA-mediated C1QC silencing; (2) C1QC overexpression via plasmid transfection; (3) empagliflozin (500 nM) co-treatment. For in vivo validation, 8-week-old male db/db mice (n = 12) and db/m controls (n = 12) were randomized into four cohorts (n = 6 per group): (1) db/m + vehicle; (2) db/db + vehicle; (3) db/m + empagliflozin (10 mg/kg/d); (4) db/db + empagliflozin (10 mg/kg/d). HG/PA treatment induced C1QC overexpression in HK-2 cells (P < 0.05). C1QC knockdown or empagliflozin treatment attenuated lipid accumulation and inflammation, whereas C1QC overexpression exacerbated these pathological changes (P < 0.05). Rescue experiments revealed that C1QC overexpression partially reversed the protective effects of empagliflozin (P < 0.05). In db/db mice, empagliflozin treatment significantly reduced renal C1QC expression, lipid deposition, and inflammation compared with untreated db/db mice (P < 0.05). This study established C1QC as a critical molecular node linking tubular metabolic stress with renal inflammation in DKD. The SGLT2 inhibitor empagliflozin confers renoprotection through partial C1QC downregulation, suggesting combinatorial therapies targeting C1QC may enhance therapeutic efficacy.
Do microplastics play a role in the pathogenesis of neurodegenerative diseases? Shared pathophysiological pathways for Alzheimer's and Parkinson's disease.
Siu ACW, Paudel KR, Singh G … +8 more , Gupta G, Singh SK, Chellappan DK, De Rubis G, Pathak S, Gregory George Oliver B, Dua K, Dhanasekaran M
Mol Cell Biochem · 2026 Feb · PMID 41252097 · Full text
The widespread presence of microplastics (MPs) in the environment has raised significant concerns about their potential impact on human health. As of 2023, the Ocean Conservancy estimates that adults may ingest up to 121...
The widespread presence of microplastics (MPs) in the environment has raised significant concerns about their potential impact on human health. As of 2023, the Ocean Conservancy estimates that adults may ingest up to 121,000 MPs annually. While the majority of these particles are cleared from the body, a small fraction can persist, as MPs are non-biodegradable and resist breakdown, posing long-term health risks that remain poorly understood. This review explores the emerging link between MP exposure and the development of neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease [1]. MPs appear capable of triggering neurotoxic pathways, including activation of resident immune cells in the brain, oxidative stress, blood-brain barrier (BBB) disruption, mitochondrial dysfunction, and neuronal damage, which may contribute to neuroinflammation and disease progression. Specifically, six MP-related mechanistic pathways associated with AD were identified: BBB disruption, chronic inflammation, oxidative stress and ROS generation, mitochondrial dysfunction, impaired autophagy and proteostasis, and epigenetic alterations. Similarly, six pathways were implicated in PD: BBB disruption, oxidative stress in dopaminergic neurons, mitochondrial dysfunction, microglial-driven neuroinflammation, α-synuclein aggregation, and gut-brain axis [2] disruption. Ultimately, our findings underscore the urgent need for further research into the neurological consequences of chronic MP exposure in humans and highlight the importance of strengthening global policies to curb plastic pollution and mitigate its long-term health risks.
How cells die determines the consequences of tissue repair: roles of programmed cell death in lung injury on the progression of pulmonary fibrosis.
Zhou L, Zhu X, Hua E … +2 more , Xu L, Feng J
Mol Cell Biochem · 2026 Feb · PMID 41252096 · Publisher ↗
Pulmonary fibrosis (PF) is a pathological change in the development of end-stage lung disease, referring to an irreversible lesion in which lung tissue undergoes an abnormal repair response during injury repair, resultin...
Pulmonary fibrosis (PF) is a pathological change in the development of end-stage lung disease, referring to an irreversible lesion in which lung tissue undergoes an abnormal repair response during injury repair, resulting in the replacement of normal alveolar structure by fibrous scarring. The main mechanisms of pulmonary fibrosis progression are activation of epithelial cell and macrophage repair after oxidative stress, fibroblast proliferation leading to extracellular matrix deposition in the lung, and a repair process involving multiple modes of death and molecular mechanisms that cross-talk in macrophages and alveolar epithelial cells, accelerating extracellular matrix deposition. Cell death is controlled by programmed cell death (PCD), which mainly includes apoptosis, necrotic apoptosis, pyroptosis, ferroptosis and autophagy. There is increasing evidence that PCD plays an important role in the pathogenesis of pulmonary fibrosis progression. In this review, we discuss recent advances in the role of PCD in lung injury-accelerated fibrosis, show how the mode of death of alveolar epithelial cells, macrophages, and fibroblasts promotes or inhibits the progression of lung injury, and explore associations between different types of PCD, with the aim of exploring the molecular mechanisms underlying the progression of recurrent lung injury and searching for new therapeutic targets.
Mechanostimulation of neuroendocrine cells and their clinical relevance.
Brayer M, Zderic V, Jeremic A
Mol Cell Biochem · 2026 Feb · PMID 41252095 · Publisher ↗
Mechanosensitive channels uniquely convert mechanical stimuli like pressure or stretch into electrochemical signals. They largely function as ion channels that create changes in electrochemical gradients across membranes...
Mechanosensitive channels uniquely convert mechanical stimuli like pressure or stretch into electrochemical signals. They largely function as ion channels that create changes in electrochemical gradients across membranes. Mammals express a variety of mechanosensitive channels including piezo and transient receptor potential family members that have demonstrated essential functions in excitable tissues. Although the role of mechanosensitive channels has become well established in nervous tissues, the role of these channels in other excitable tissues is only now becoming apparent. Neuroendocrine cells are similarly excitable tissue but also have the endocrine-specific ability to produce and secrete hormones. Here, we summarize the typical function of various neuroendocrine cells while highlighting the roles of mechanosensitive channels in each with further elaboration of their clinical and functional uses.
Cell death forms in myocardial ischemia-reperfusion injury and their potential clinical applications.
Xu Y, Wu S, Zhang L … +2 more , Zhang M, Jiang Y
Mol Cell Biochem · 2026 Feb · PMID 41252094 · Publisher ↗
Timely and effective reperfusion therapy is an effective means of relieving ischemic damage to cardiomyocytes and is also the most commonly used treatment for clinical ischemic heart disease. However, while reperfusion s...
Timely and effective reperfusion therapy is an effective means of relieving ischemic damage to cardiomyocytes and is also the most commonly used treatment for clinical ischemic heart disease. However, while reperfusion saves the ischemic myocardium, the explosive production of reactive oxygen species (ROS) and calcium overload can cause additional damage to cardiac tissue cells. This review describes the pathophysiological mechanisms of myocardial ischemia-reperfusion injury and the forms of myocardial tissue cell death mediated by the reperfusion process, including ferroptosis, pyroptosis, and necroptosis. We also report the latest research progress in treating myocardial reperfusion injury by targeting ferroptosis, pyroptosis, and necroptosis. The aim is to understand the mechanism of myocardial reperfusion injury better and provide new treatment ideas to reduce myocardial ischemia-reperfusion injury.
GNB2 promotes breast cancer progression by up-regulating HSPA5/GPX4 and inhibiting ferroptosis.
Wang Y, Liu R, Tian C … +5 more , Kang Z, Xu Z, Wang Z, Xu S, Zhong J
Mol Cell Biochem · 2026 Feb · PMID 41240217 · Publisher ↗
G protein subunit beta 2 (GNB2) is a potential biomarker identified recently in human cancers. However, the specific role and its underlying mechanism in breast cancer (BRCA) remain unclear. Expression levels of GNB2 wer...
G protein subunit beta 2 (GNB2) is a potential biomarker identified recently in human cancers. However, the specific role and its underlying mechanism in breast cancer (BRCA) remain unclear. Expression levels of GNB2 were examined in human BRCA tissues and cells by real-time quantitative PCR (qPCR), immunohistochemistry (IHC) and Western blot. Biological functions of GNB2 were determined by a series of in vitro experiments (CCK-8, colony formation assay, Transwell and wound healing) and in vivo ones (subcutaneous transplantation tumor and pulmonary metastasis model). Mechanism of GNB2 in BRCA was explored by co-immunoprecipitation (Co-IP), qPCR, Western blot, flow cytometry and some rescue experiments. Increased expression of GNB2 was found in BRCA, which indicated poorer clinical prognosis of the patients. The over-expression of GNB2 increased proliferation, migration of BRCA cells, while it decreased the intracellular contents of reactive oxygen species (ROS), Fe and malondialdehyde (MDA). In addition, GNB2 over-expression increased the expression of heat-shock-protein family A(HSP70) member 5 (HSPA5) and the expression of glutathione peroxidase 4 (GPX4), which inhibited the cell death induced from Erastin. After knockdown of GNB2, all the above indicators were significantly reversed. Restored expression of HSPA5 in BRCA cells with GNB2 knockdown rescued the effects. Therefore, the current study verifies GNB2 as an important driver in BRCA progression by up-regulating HSPA5/GPX4 and inhibiting ferroptosis, which highlights its potential role in the clinical diagnosis and treatment of BRCA.
IGF-1 protects against acute pancreatitis by suppressing NF-κB activation through the β-arrestin1/STAT3 pathway.
Huang X, Tao L, Liu H … +2 more , Luo H, Guo Y
Mol Cell Biochem · 2026 Feb · PMID 41217674 · Full text
Acute pancreatitis (AP) is a prevalent inflammatory condition with an upward trend in incidence in recent years. Recent studies have demonstrated the important role of IGF-1 and β-arrestin-1 in inflammation, but their ro...
Acute pancreatitis (AP) is a prevalent inflammatory condition with an upward trend in incidence in recent years. Recent studies have demonstrated the important role of IGF-1 and β-arrestin-1 in inflammation, but their role in AP remains unexplored. Our study explored the role of IGF-1 in acute pancreatitis (AP) using caerulein-induced AP models in wild-type (WT) and β-arrestin1-knockout (KO) mice treated with IGF-1, picropodophyllotoxin (PPP, an IGF-1R inhibitor), Bay11708 (an NF-κB inhibitor), and the STAT3 inhibitor VI. Caerulein injection induced AP, characterized by elevated serum amylase levels, increased MPO activity, and pancreatic pathology. IGF-1 treatment reduced the severity of AP, whereas PPP worsened it. β-arrestin1 deficiency exacerbated pancreatitis and abolished the protective effect of IGF-1. NF-κB and STAT3 were involved in the protective mechanism of IGF-1 through β-arrestin1 regulation. Inhibiting NF-κB or STAT3 altered the protective effect of IGF-1 in AP. In vitro, the protective effect of IGF-1 against caerulein-induced injury was demonstrated in AR42J cells. This study revealed that IGF-1 protected against AP by suppressing NF-κB activation through the β-arrestin1/STAT3 pathway, providing new insights into the role of IGF-1 in AP and potential therapeutic targets.
Camphor alleviates renal fibrosis by suppressing oxidative stress and inflammation, up-regulating SIRT1 and down-regulating NF-κB and TGF-β.
Abdollahi M, Asle-Rousta M
Mol Cell Biochem · 2026 Feb · PMID 41217673 · Publisher ↗
Renal fibrosis is the main pathological change observed in the progression of chronic kidney disease. This study aimed to investigate the effects of camphor (a type of monoterpene) on the biochemical, molecular, histopat...
Renal fibrosis is the main pathological change observed in the progression of chronic kidney disease. This study aimed to investigate the effects of camphor (a type of monoterpene) on the biochemical, molecular, histopathological, and functional alterations associated with thioacetamide (TA)-induced kidney fibrosis in adult male Wistar rats. Animals were divided into four groups: Control, Camphor, TA, and TA + Camphor. Intraperitoneal administration of camphor (10 mg/kg, daily) and TA (200 mg/kg, twice a week) was conducted for a duration of 4 weeks. Camphor reduced malondialdehyde and nitric oxide levels in the kidneys of rats treated with TA and increased glutathione content and superoxide dismutase activity. It decreased the expression of proinflammatory cytokines, nuclear factor kappa-B (NF-κB), and transforming growth factor-beta (TGF-β). Camphor also stimulated sirtuin 1 (SIRT1) expression. This monoterpene inhibited collagen expression and deposition in the kidneys and reduced histopathological damage. It also lowered the levels of creatinine and serum blood urea nitrogen and decreased the expression of kidney injury molecule-1. We concluded that camphor alleviates TA-induced renal fibrosis by reducing oxidative stress and inflammation. Its renoprotective effects are achieved through the upregulation of SIRT1 and the downregulation of NF-κB and TGF-β.
AURKA modulates tight junction functionality to influence the proliferation and metastasis of lung adenocarcinoma.
Mi Y, Mao J, Li X … +6 more , Wang Z, Zuo X, Chang Z, Wang R, Wang L, Wang L
Mol Cell Biochem · 2026 Feb · PMID 41201786 · Publisher ↗
Aberrant overexpression of AURKA (aurora kinase A) is strongly associated with various malignancies. However, limited research exists regarding its clinical significance and pathogenic mechanisms in lung adenocarcinoma....
Aberrant overexpression of AURKA (aurora kinase A) is strongly associated with various malignancies. However, limited research exists regarding its clinical significance and pathogenic mechanisms in lung adenocarcinoma. This study elucidates clinical correlations and provides experimental evidence supporting AURKA's potential as a therapeutic target for lung adenocarcinoma (LUAD). We analyzed AURKA expression levels and prognostic value using data from TCGA and GEO databases. qRT-PCR compared AURKA expression in LUAD tissues and adjacent normal specimens. siRNA-mediated knockdown efficiency was verified through western blotting and qRT-PCR. Cellular proliferation was assessed via CCK-8 assays and tumor ball assay, while migration capacity was evaluated using transwell chambers. Flow cytometry analyzed cell cycle progression and apoptosis. Phosphoproteomic sequencing identified downstream pathways, with western blot validation of key targets. The changes of tight junctions were observed by transmission electron microscopy, fluorescein isothiocyanate dextran 4 kDa (FD4) permeation experiment and immunofluorescence. A subcutaneous xenograft model in nude mice evaluated AURKA's in vivo tumorigenic effects. Our work illustrated that Elevated AURKA expression correlated significantly with poor LUAD prognosis. AURKA silencing markedly suppressed A549 cell proliferation and migration capacity while inducing G2/M phase arrest and apoptosis. Phosphorylated protein sequencing shows that AURKA knockdown is closely related to Cortactin (CTTN) mediated tight junction. Meanwhile, Xenograft models demonstrated that AURKA knockdown substantially inhibited tumor growth and metastatic progression. It was concluded that AURKA serves as a prognostic biomarker in LUAD. Mechanistically, AURKA promotes tumor progression through Cortactin phosphorylation-mediated tight junction disruption. Our findings establish AURKA inhibition as a promising therapeutic strategy for LUAD management.
Advancements in single-cell sequencing for cervical cancer research.
Pu C, Xing B, Wang S … +2 more , Liu Z, Zhao Y
Mol Cell Biochem · 2026 Feb · PMID 41199110 · Full text
Single-cell sequencing has revolutionized our understanding of cervical cancer (CC), revealing unprecedented cellular heterogeneity, tumor microenvironment (TME) dynamics, and molecular mechanisms underlying progression...
Single-cell sequencing has revolutionized our understanding of cervical cancer (CC), revealing unprecedented cellular heterogeneity, tumor microenvironment (TME) dynamics, and molecular mechanisms underlying progression and therapy resistance. These technologies have identified distinct molecular subtypes (hypoxic, proliferative, and immunoreactive) and epithelial states (cytokeratin⁺, immune-interacting, and senescent), while uncovering HPV-driven oncogenic mechanisms, including viral integration hotspots (e.g., 8q24.21) and immune evasion strategies (e.g., SPP1⁺ TAMs and GALNT3-mediated immunosuppression). Metabolic reprogramming further stratifies tumors into spatially organized Warburg effect and OXPHOS-dominant niches, each associated with unique immune infiltration patterns. The TME exhibits a complex interplay between exhausted PD-1⁺LAG3⁺TIM3⁺ T cells, immunosuppressive stromal cells (MYH9⁺ CAFs, PODXL⁺ ECs), and rare but potent effector populations (FGFBP2⁺ NK cells, CXCL13⁺ TRMs). Despite these advances, clinical translation faces challenges, including resistance mechanisms (NFKB1 mutations, BCL10⁺ Treg suppression) and a lack of inhibitors for key targets (PCLAF⁺ TAEpis, MYH9⁺ CAFs). Promising therapeutic strategies include epigenetic modulation (SALL4), sialylation inhibition (GALNT3/12), and immune-stromal co-targeting (PD-1 + LAG3/TIM3, NRG1-ERBB3 blockade). Future efforts must prioritize functional validation of novel targets (DKK2, ELF3), spatial multi-omics to resolve CAF-immune-metabolic crosstalk, and biomarker-driven clinical trials integrating single-cell classifiers. By bridging single-cell insights with mechanistic and translational studies, the field can overcome stromal-mediated resistance and usher in an era of precision immunotherapy for CC.
Retraction Note: Exploring the potential function of trace elements in human health: a therapeutic perspective.
Islam MR, Akash S, Jony MH … +5 more , Alam MN, Nowrin FT, Rahman MM, Rauf A, Thiruvengadam M
Mol Cell Biochem · 2026 Feb · PMID 41186858 · Publisher ↗
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The lysosomal cysteine protease cathepsin L promotes stemness and multidrug resistance of non-small cell lung cancer by targeting HGF activator.
Shi H, Xu J, Wu J … +7 more , Hu S, Chen X, Hu Q, Liu Q, Yu Y, Ding X, Wang W
Mol Cell Biochem · 2026 Feb · PMID 41182650 · Full text
Multidrug resistance (MDR) in non-small cell lung cancer (NSCLC) causes chemotherapy failure, with lung cancer stem cells (LCSCs) playing a central role in the development of MDR. Although cathepsin L (CTSL) is known to...
Multidrug resistance (MDR) in non-small cell lung cancer (NSCLC) causes chemotherapy failure, with lung cancer stem cells (LCSCs) playing a central role in the development of MDR. Although cathepsin L (CTSL) is known to be associated with tumor progression, its function in LCSCs and MDR remains unclear. The chemotherapeutic sensitivities of spheroid from NSCLC cell lines were evaluated using the CCK-8 assay. Western blot and qPCR analyses were performed to assess the expression levels of CTSL, stem cell markers (CD133 and CD44), stemness-maintaining molecules (OCT4 and SOX2), drug resistance proteins (MDR1 and ABCG2). In vivo experiments were conducted to validate the chemosensitizing effects of CTSL inhibitor, while the relationship between CTSL and the secretion levels of hepatocyte growth factor activator (HGFAC) and HGF was analyzed by RNA-seq, ELISA, qPCR and ChIP-qPCR methods. Our results demonstrated that spheroid cells exhibited pronounced MDR. High expression of CTSL correlated with poor prognosis in patients with NSCLC and enhanced MDR in NSCLC spheroids. Interfering with CTSL increased the sensitivity of NSCLC spheroids to multiple chemotherapy drugs while reducing cell stemness and survival. Moreover, the combination of CTSL inhibitor and docetaxel effectively suppressed tumor growth in vivo. Additionally, there is a positive correlation between CTSL and HGFAC at the mRNA level, and CTSL has a direct transcriptional regulatory effect on HGFAC. Finally, CTSL mediates chemotherapy resistance by regulating the expression of HGFAC/HGF/Met signaling pathway. Taken together, our findings establish CTSL as a pivotal driver of MDR in NSCLC, highlighting its promise as a therapeutic target to overcome this challenge.
Investigating the role of the kynurenine pathway in traumatic brain injury: a systematic review.
de Barros JLVM, de Freitas Cardoso MG, da Silva TM … +3 more , Costa VV, Teixeira AL, de Miranda AS
Mol Cell Biochem · 2026 Feb · PMID 41182649 · Publisher ↗
Traumatic brain injury (TBI) disrupts normal brain function through inflammatory cascades that may persist for months or years. This review aimed to gather the evidence regarding kynurenine pathway (KP) dysregulation fol...
Traumatic brain injury (TBI) disrupts normal brain function through inflammatory cascades that may persist for months or years. This review aimed to gather the evidence regarding kynurenine pathway (KP) dysregulation following TBI and to examine how altered KP metabolites correlate with clinical outcomes. We systematically identified relevant human studies in PubMed and Lilacs databases using descriptors linked to TBI and KP metabolites. We included original research in English, Portuguese, or Spanish with no publication date restriction. We extracted data on participant characteristics, TBI severity, metabolite levels, and clinical endpoints. We appraised risk of bias using standardized checklists for cohort and cross‑sectional designs. Twelve studies met inclusion criteria. TBI increases circulating levels of quinolinic acid (QUIN), with higher QUIN linked to mortality in severe TBI and worse mood or cognitive sequelae in mild TBI. Kynurenine and kynurenic acid changes varied across cohorts, reflecting the complexity of post-injury inflammatory processes. TBI can disrupt KP metabolism and increased levels of QUIN are associated with poor neurological outcomes. Future research should define the dynamics of KP metabolite production over time and assess whether targeted interventions can lessen neurotoxic load. Post‑injury neuroinflammation remains a critical focus for potential therapeutic intervention strategies.
Intricate interplay between ORMDL3, ER stress, and autophagy in the diabetic intestine.
Malicevic U, Rai V, Skrbic R … +1 more , Agrawal DK
Mol Cell Biochem · 2026 Feb · PMID 41182648 · Full text
Diabetes mellitus (DM) and inflammatory bowel disease (IBD) are prevalent chronic conditions characterized by immune dysregulation and metabolic disturbances. The global incidence of both diseases is increasing, with mou...
Diabetes mellitus (DM) and inflammatory bowel disease (IBD) are prevalent chronic conditions characterized by immune dysregulation and metabolic disturbances. The global incidence of both diseases is increasing, with mounting evidence highlighting the critical role of intestinal barrier dysfunction and inflammation in their pathogenesis. Although genome-wide association studies (GWAS) have implicated the orosomucoid-like protein 3 (ORMDL3), also known as ORMDL sphingolipid biosynthesis regulator 3, in susceptibility to both IBD and DM, its precise role in diabetes-associated intestinal alterations remains poorly defined. In this study, we examined intestinal changes in a Sprague Dawley rat model of experimentally induced diabetes, focusing on ORMDL3 expression and its relationship with endoplasmic reticulum (ER) stress and autophagy. Diabetic rats exhibited pronounced histopathological alterations, including villous atrophy, goblet cell depletion, inflammatory cell infiltration, and lipofuscin accumulation, indicative of compromised intestinal barrier integrity and chronic low-grade inflammation. ORMDL3 expression was significantly elevated at both the transcript and protein levels. A strong positive correlation between ORMDL3 and ATF6 suggests the activation of ER stress pathways within the diabetic intestine. Additionally, increased expression of autophagy-related genes, including NOD2, ULK1, and ATG4, was particularly evident in female diabetic rats, indicating a sex-specific modulation of autophagic responses to hyperglycemic stress. The observed molecular and histological changes reflect key mechanisms implicated in IBD, potentially indicating shared pathways driving both diabetic and inflammatory intestinal disorders. Collectively, our findings underscore a complex interplay between hyperglycemia-induced ER stress and autophagy in the diabetic intestine, positioning ORMDL3 as an orchestrator in the underlying pathogenesis and a potential therapeutic target for IBDs.
Parthenolide promotes glucagon-like peptide-1 secreting in human Caco-2 cells via regulation of bitter taste receptor-induced of calcium signaling.
Li S, Chen Y, Song Z … +4 more , Ou P, Duan Y, Liu Q, Wang W
Mol Cell Biochem · 2026 Feb · PMID 41182647 · Publisher ↗
Bitter taste receptors (TAS2Rs), in addition to being expressed in oral tissues, are also present in the gastrointestinal tract and are promising targets for inducing glucagon-like peptide-1 (GLP-1) secretion and treatin...
Bitter taste receptors (TAS2Rs), in addition to being expressed in oral tissues, are also present in the gastrointestinal tract and are promising targets for inducing glucagon-like peptide-1 (GLP-1) secretion and treating type 2 diabetes mellitus (T2DM). However, natural bitter agonists capable of enhancing endogenous GLP-1 secretion remain scarce. In this study, we aimed to identify natural bitter agonists with GLP-1-inducing potential through comprehensive screening of the BitterDB and BitterX databases, and to evaluate their effects and underlying mechanisms in human enteroendocrine Caco-2 cells. Parthenolide (PTL) was identified as a high-affinity TAS2R4 agonist candidate. Cellular thermal shift assays (CETSA) confirmed its direct binding to TAS2R4, enhancing its thermal stability. Molecular docking revealed strong interactions, including hydrogen bonding with ASN-65 and hydrophobic contacts with PHE-62 and PHE-88. Functionally, PTL promotes GLP-1 secretion in a dose-dependent manner. Mechanistically, PTL treatment enhances TAS2R4 expression and upregulates its key downstream signaling molecule, phospholipase C β2 (PLCβ2), which catalyzes the production of inositol trisphosphate (IP3). This indicates that PTL promotes secretion by activating the TAS2R4 signaling pathway. PTL treatment leads to increase in intracellular calcium ion (Ca) levels, and the induced GLP-1 secretion is a calcium-dependent vesicle fusion process. Moreover, calcium further activates the transient receptor potential channel melastatin 5 (TRPM5), amplifying calcium signaling. These findings suggest that PTL is a novel natural agonist of TAS2R4 that promotes GLP-1 secretion via TAS2R4 signaling, supporting its potential as a lead compound for the development of TAS2R4-targeted functional foods or nutraceuticals for T2DM.
Differential effects of vesicular urokinase receptor uPAR on vascular cell migration and proliferation.
Klimovich P, Maier A, Dzreyan V … +12 more , Ivleva M, Gurielidze L, Voloshin N, Romashin D, Plekhanova O, Shilova A, Popov V, Karagyaur M, Sysoeva V, Semina E, Rubina K, Tkachuk V
Mol Cell Biochem · 2026 Jan · PMID 41152550 · Publisher ↗
Angiogenesis is essential for organ and tissue regeneration, as blood vessels provide necessary nutrients and oxygen for cellular restoration and growth. The present study explores a novel mechanism of uPAR involvement i...
Angiogenesis is essential for organ and tissue regeneration, as blood vessels provide necessary nutrients and oxygen for cellular restoration and growth. The present study explores a novel mechanism of uPAR involvement in angiogenesis through its incorporation into extracellular vesicles derived from mesenchymal stem/stromal cells (MSCs). MSC-derived vesicles were isolated using ultrafiltration and characterized by flow cytometry, western blotting (WB) and nanoparticle tracking analysis. Model of aortic ring in Matrigel was used to assess capillary-like structure formation and vascular cells migration. To analyze cell migration from explants immunofluorescent staining, phase-contrast and confocal microscopy were used. Endothelial cells (ECs) and smooth muscle cells (SMCs) images of growing cell populations were captured with microscope and then counted with deep learning object detection model. The activation of Akt signaling in these cells was evaluated by WB. uPA and uPAR content in MSCs and vesicles samples was analyzed using WB and ELISA. uPA and uPAR are incorporated into vesicles secreted by MSCs and regulate the proliferation and migration of ECs and SMCs. Vesicles from MSCs isolated from adipose tissue of mice lacking uPAR stimulate SMCs migration but lose their ability to promote ECs migration and capillary-like structure formation. Moreover, in MSCs lacking uPAR, uPA expression is dysregulated, leading to its increased presence in vesicles. These data suggest that ECs are more sensitive to the absence of uPAR, while uPA preferentially stimulates SMCs. These findings offer new insights into the regulatory roles of extracellular vesicles in angiogenesis, while broadening our understanding of the urokinase system's functional diversity.
FOXP1-transcriptionally regulated AEG-1 enhances tumor cell stemness to promote hepatocellular carcinoma radioresistance.
Li W, Xue H, Li P … +1 more , Zhang X
Mol Cell Biochem · 2026 Jan · PMID 41152549 · Publisher ↗
Radiotherapy is the standard adjuvant treatment for hepatocellular carcinoma (HCC). Cancer stem cells (CSCs) have been identified as the primary factor contributing to radiation resistance. Astrocyte elevated gene-1 (AEG...
Radiotherapy is the standard adjuvant treatment for hepatocellular carcinoma (HCC). Cancer stem cells (CSCs) have been identified as the primary factor contributing to radiation resistance. Astrocyte elevated gene-1 (AEG-1) could regulate β-catenin signaling to maintain tumor stem-like stemness and self-renewal. This study aims to explore the role and mechanism of AEG-1 in the radioresistance of HCC. The mRNA levels of AEG-1 and FOXP1 were determined using RT-qPCR. AEG-1, FOXP1, Oct4, CD133, Nanog, β-catenin, and c-Myc protein levels were detected using western blot. The radiosensitivity of HCC cells was assessed using cell colony formation assay, γ-H2AX immunofluorescence, and flow cytometry. The CSC characteristics of cells were examined using sphere formation assay. The biological role of AEG-1 on HCC tumor growth and radiation resistance was examined by the mouse xenograft tumor model. Correlation between AEG-1 and FOXP1 in HCC patients was analyzed using Pearson correlation analysis. Binding between FOXP1 and AEG-1 promoter was predicted by JASPAR and verified by ChIP, the electrophoretic mobility shift assays (EMSA), and dual-luciferase reporter assays. AEG-1 was highly expressed in HCC patients, and positively associated with FOXP1 expression. Moreover, AEG-1 knockdown could enhance the radiosensitivity of HCC cells by promoting ionizing radiation (IR)-DNA damage and apoptosis in vitro. AEG-1 mediated radiation resistance by maintaining HCC tumor stem cell properties. In vivo investigation revealed that AEG-1 silencing repressed HCC tumor growth and increased radiosensitivity. Mechanistically, FOXP1 was a transcription factor of AEG-1 that promoted AEG-1 transcription by binding to its promoter region. FOXP1 promoted the Wnt/β-catenin pathway by regulating AEG-1. Overall, overexpressing FOXP1 drives stem cell properties and radioresistance of HCC cells by promoting AEG-1-mediated Wnt/β-catenin pathway, providing a promising therapeutic target for enhancing radiotherapy efficacy.
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