Life Sciences[JOURNAL]
Sun
200 papers
The key regulator of ferroptosis: HIF-1α and its complex roles and treatment strategies in related diseases.
Zhao X, Wang Q, Jin JY … +1 more , Xiang R
Life Sci · 2026 Jul · PMID 42103071 · Publisher ↗
Ferroptosis is a form of regulated cell death characterized by dysregulated iron metabolism and accumulation of lipid peroxides, which is closely associated with various pathological conditions. Hypoxia-inducible factor...
Ferroptosis is a form of regulated cell death characterized by dysregulated iron metabolism and accumulation of lipid peroxides, which is closely associated with various pathological conditions. Hypoxia-inducible factor 1α (HIF-1α), as the principal subunit of the hypoxia-inducible transcription factor complex, controls the balance between iron homeostasis and antioxidant defense system within the hypoxic microenvironment. In oncology, PI3K/AKT signaling pathway of some tumor cells is amplified to activate HIF-1α. Then HIF-1α upregulate the SLC7A11/GPX4 axis to evade cell death. Restoration of ferroptosis signaling through pharmacological or genetic approaches, triggers iron accumulation and the production of lipid reactive oxygen species (ROS). However, this will lead to immunogenic cell death and subsequent tumor regression. In neurodegenerative disorders, excessive iron deposition in neurons occurs and coupled with compromised antioxidant defenses. As a result, ferroptosis becomes a key pathogenic mechanism in neurodegenerative disorders. In renal pathology: activation of HIF-1α suppresses GPX4 activity to mitigate lipid ROS during acute kidney injury, thereby exerting protective effects. Under conditions of chronic diabetic hypoxia, upregulation of heme oxygenase-1 (HO-1) promotes iron release, exacerbating tubular ferroptosis and accelerating fibrotic progression. Context-specific manifestations of ferroptosis are found in various systemic diseases, where its biological outcomes are determined by the dynamic equilibrium between iron homeostasis and antioxidant mechanisms. Despite compounds targeting HIF-1α have demonstrated therapeutic potential in ferroptosis-related diseases, specialized treatment strategies still depend on the underlying pathological context. Therefore, a systematic summary of the existing molecular mechanisms and discovering new mechanisms of HIF-1α regulates ferroptosis will greatly enhance our understanding of ferroptosis-related diseases, providing novel insights for precise therapeutic approaches.
Advances in neuropharmacology: Innovative drug strategies targeting synaptic plasticity, neuroinflammation, and ion channel regulation for future CNS treatments.
Shrivastava A, Kirushnakumar SS, Gupta P … +5 more , Dwivedi S, Chaturvedi P, Chhabra GS, Kumar A, Dey DK
Life Sci · 2026 Jul · PMID 42103070 · Publisher ↗
As our understanding of the molecular and cellular mechanisms underlying central nervous system (CNS) disorders expands, neuropharmacology is undergoing a paradigm shift. Despite the increasing burden of neurodegenerativ...
As our understanding of the molecular and cellular mechanisms underlying central nervous system (CNS) disorders expands, neuropharmacology is undergoing a paradigm shift. Despite the increasing burden of neurodegenerative and neuropsychiatric diseases, challenges such as blood-brain barrier (BBB) impermeability, drug resistance, and complex pathophysiology continue to limit effective therapeutic development. This review highlights key emerging targets, including ion channel regulation, neuroinflammation, and synaptic plasticity, as important entry points for next-generation neurotherapeutics. Advances in nanotechnology and non-invasive delivery strategies are discussed for their potential to enhance brain-targeted drug delivery and address pharmacokinetic limitations. In addition, modulation of glial networks, neurotransmitter systems, and epigenetic regulators is explored as a promising therapeutic approach. Computational tools, including artificial intelligence (AI), machine learning, and in silico modelling, are increasingly used to improve target identification and support personalised treatment strategies. Furthermore, pharmacogenomics and biomarker-based approaches enable more precise and effective treatments across diverse patient populations. Emerging interventions, such as gene-modifying therapies and nanoformulated drugs, show promise for clinical application; however, challenges related to safety, scalability, and validation remain. Overall, the integration of advanced delivery systems, computational approaches, and precision medicine is driving a shift towards mechanism-based and individualised therapies, with the potential to improve outcomes in complex CNS disorders. These challenges underscore the need for advanced drug delivery strategies capable of improving brain targeting and therapeutic efficacy in CNS disorders.
Next-generation gene editing strategies in cancer: Integrating CRISPR, PROTACs, and advanced molecular technologies.
Vikal A, Maurya R, Kumar P … +2 more , Verma N, Mishra AK
Life Sci · 2026 Jul · PMID 42103069 · Publisher ↗
Cancer is a significant therapeutic problem as tumors are heterogeneous, multidrug-resistant, and oncogenic drivers are undruggable. Genome editing and targeted protein degradation are emerging approaches that are transf...
Cancer is a significant therapeutic problem as tumors are heterogeneous, multidrug-resistant, and oncogenic drivers are undruggable. Genome editing and targeted protein degradation are emerging approaches that are transforming precision oncology by allowing genetic and proteomic interventions. Such technologies as CRISPR-based systems and proteolysis-targeting chimeras (PROTACs) are alternative methods of correcting genes and the selective removal of a protein. Their combination provides them with new possibilities regarding long-lasting and specific cancer treatment and discovery of new therapeutic targets. Although this has good news, there are delivery, off-target effects and safety challenges. The continued advancements in nanotechnology, artificial intelligence (AI), and personalized medicine will be likely to improve clinical translation. Generally, the integration of these technologies is an inducing trend in the treatment of cancer in the next generation.
Decoding immunotherapy resistance in multiple myeloma: genetic insights and approaches to counter resistance.
Li H, Xia Q, Yu M … +15 more , Lv Y, Xiao J, Guo X, Dong K, Zhou Y, Zhong L, Wang T, Wu W, Gan C, Li M, Xiao N, Wang Q, Chang H, He Y, Gong B
Sci China Life Sci · 2026 Apr · PMID 42101566 · Publisher ↗
Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells and presents major therapeutic challenges due to its intrinsic heterogeneity and frequent development of resistance...
Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells and presents major therapeutic challenges due to its intrinsic heterogeneity and frequent development of resistance to immunotherapy. Although recent advances in immunotherapeutic strategies, including immunomodulatory drugs (IMiDs), chimeric antigen receptor T-cell (CAR-T) therapies, monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and bispecific antibodies (BsAbs), have significantly improved patient outcomes, disease relapse remains nearly inevitable. This review systematically categorizes resistance mechanisms to immunotherapy in MM by examining intrinsic tumor cell factors, including genetic and epigenetic alterations, modulation or loss of target antigens, immune effector cell dysfunction such as T-cell exhaustion, and the complex suppressive features of the bone marrow microenvironment. In addition, we discuss the application of emerging technologies such as single-cell sequencing and CRISPR/Cas9-based functional screening to uncover resistance pathways and guide target discovery. Finally, we highlight rational strategies to overcome resistance, including synergistic combination regimens, development of next-generation therapeutics, and approaches to reprogram the tumor microenvironment. These insights provide a conceptual framework for the design of more effective and durable immunotherapeutic interventions in MM.
TcrDesign: de novo design of epitope-specific full-length T cell receptors.
Diao K, Chen J, Zhao X … +5 more , Wu T, Qiu D, Wang W, Wang H, Liu XS
Sci China Life Sci · 2026 Apr · PMID 42101565 · Publisher ↗
T cell receptors (TCRs) are essential for adaptive immune recognition. Recently, computational tools have been developed to predict the interactions between TCR and epitope, and artificial intelligence models have been p...
T cell receptors (TCRs) are essential for adaptive immune recognition. Recently, computational tools have been developed to predict the interactions between TCR and epitope, and artificial intelligence models have been proposed to generate the complementarity determining region 3 (CDR3) region of β chain TCR. However, de novo design of experimentally validated, functional, full-length epitope-specific TCRs remains a significant challenge. Here, we developed TcrDesign, a deep learning framework based on large-scale, unlabeled TCR and epitope datasets to generate epitope-specific, full-length TCRs. TcrDesign comprises two modules: TcrDesign-B for TCR-pMHC binding prediction with state-of-the-art accuracy, and TcrDesign-G for functional full-length TCR sequence generation. Pre-trained on large-scale unlabeled datasets using transformer-based architectures, TcrDesign achieves state-of-the-art performance in both TCR-epitope binding prediction and de novo TCR sequence generation. Furthermore, epitope-major histocompatibility complex (MHC) binding and functional activation of TcrDesign-generated TCRs were experimentally validated. TcrDesign provides an efficient and modular approach for designing epitopespecific full-length TCRs, with experimental validation confirming its utility.
Alnustone ameliorates obesity and polycystic ovary syndrome by remodeling adipose metabolism via AMPK signaling.
Qin Y, Hu S, Xu Y … +10 more , Lin Z, Liang X, Liu Y, Li Y, Geng C, Chen X, Feng X, Chen ZJ, Zhao H, Zhang Y
Sci China Life Sci · 2026 Apr · PMID 42101564 · Publisher ↗
Polycystic ovary syndrome (PCOS) is a prevalent reproductive and metabolic disorder frequently accompanied by obesity, creating a dual burden of infertility and metabolic disease for women, yet therapeutic options addres...
Polycystic ovary syndrome (PCOS) is a prevalent reproductive and metabolic disorder frequently accompanied by obesity, creating a dual burden of infertility and metabolic disease for women, yet therapeutic options addressing both pathologies remain limited. Here, using high-fat diet-induced obese and dehydroepiandrosterone-induced PCOS mouse models, we demonstrate that alnustone, a naturally derived compound, exerts coordinated benefits on both metabolic and reproductive dysfunctions in females. Long-term alnustone administration effectively attenuated body weight gain, adipocyte hypertrophy, and insulin resistance. Critically, hyperandrogenism, estrous cycle irregularity, and polycystic ovarian morphology were concurrently reversed. Mechanistically, alnustone enhanced energy expenditure by activating brown adipose tissue (BAT) and promoting white adipose tissue browning through induction of thermogenic programs. Transcriptomic profiling further revealed that alnustone corrected lipid metabolic dysregulation in obese and PCOS mice via activating adipose tissue AMPK signaling. These findings establish alnustone as a dual-action therapeutic agent that restores both metabolic homeostasis and reproductive function through adipose tissue remodeling, highlighting its potential as a natural intervention for integrated management of obesity and PCOS.
Deoxyinosine enhances GnRH biosynthesis by promoting estradiol production in the hypothalamus and ovaries.
Li S, Wang Y, Meng Y … +9 more , Fan Y, Tu J, Zeng X, Cai S, Tan C, Zhang S, Chen F, Cai C, Zeng X
Sci China Life Sci · 2026 Apr · PMID 42101563 · Publisher ↗
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Drinking water temperatures modulate gut microbiota-L-cysteine axis to enhance adipose thermogenesis and alleviate obesity-related metabolic disorders in mice.
Wang H, Li T, Yang J … +5 more , Zhang W, Chen S, Song M, Wang S, Liu C
Life Sci · 2026 Jul · PMID 42097400 · Publisher ↗
AIMS: Although people living in different countries prefer to drink water at various temperatures, the influence of drinking water temperature on metabolic homeostasis remains largely unexplored. This study investigated...
AIMS: Although people living in different countries prefer to drink water at various temperatures, the influence of drinking water temperature on metabolic homeostasis remains largely unexplored. This study investigated how different drinking-water temperatures affect metabolic regulation and the underlying gut microbiota-metabolite interactions. MATERIALS AND METHODS: High-fat diet (HFD)-fed mice were given water at 0 °C, 25 °C, or 40 °C. Metabolic alterations were assessed by histopathology, serum biochemistry, and body-composition analysis, with food intake and core temperature monitored. Gut microbiota causality was examined using antibiotic depletion and reciprocal fecal microbiota transplantation (FMT). 16S rRNA gene sequencing and metabolomics were performed to characterize fecal microbial and metabolite profiles. Adipose stromal vascular fraction (SVF) cells were used in vitro to examine the effects of L-cysteine on lipid metabolism. KEY FINDINGS: Both 0 °C and 40 °C water ameliorated HFD-induced metabolic dysfunction through increased energy expenditure, reduced liver steatosis, and enhanced adipose-tissue thermogenesis, independent of differences in intake. Cold water selectively enriched Bifidobacterium pseudolongum and Adlercreutzia equolifaciens, whereas warm water increased Bacteroides acidifaciens, Alistipes inops and Alistipes obesi, indicating distinct microbiota configurations. Antibiotic ablation blunted these benefits, while cross-group FMT reproduced the metabolic and thermogenic phenotypes, confirming a microbiota-dependent mechanism. Despite divergent microbiota structures, both temperature regimens consistently elevated L-cysteine, which reduced lipid accumulation and enhanced thermogenic gene expression in SVF cells. SIGNIFICANCE: These findings highlight drinking-water temperature as a simple, safe, and sustainable lifestyle factor with translational potential to mitigate obesity-related metabolic dysfunction, potentially via a gut microbiota-L-cysteine axis that enhances adipose thermogenesis and systemic metabolic homeostasis.
Targeting the AMPK/ACC pathway with luteolin suppresses de novo lipogenesis and limits tumor burden in a MASH-HCC mouse model.
Shao G, Sun C, Ye C … +9 more , Liu Y, Pan J, Liu Y, Lu L, Wang L, Lin Z, Yang F, Ji G, Xu H
Life Sci · 2026 Jul · PMID 42097399 · Publisher ↗
AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is a primary driver of hepatocellular carcinoma (HCC), yet effective therapeutic interventions remain limited. While luteolin is known for its anti-inflammato...
AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is a primary driver of hepatocellular carcinoma (HCC), yet effective therapeutic interventions remain limited. While luteolin is known for its anti-inflammatory properties, its efficacy and underlying mechanism in the MASH-HCC transition are not fully understood. This study investigated the protective effects of luteolin against MASH-HCC and the role of the AMPK/ACC signaling pathway in this process. MATERIALS AND METHODS: In vivo, a MASH-HCC mouse model was established using diethylnitrosamine (DEN) combined with a high-fat, high-cholesterol (HFHC) diet. Mice were treated with vehicle or luteolin (50 or 100 mg/kg) for 26 weeks. Progression was monitored via serum alpha-fetoprotein (AFP), histological analysis, and Western blotting. In vitro, HepG2 and Huh-7 cells were challenged with cholesterol and treated with luteolin. The AMPK inhibitor BAY-3827 was employed to verify whether the metabolic benefits of luteolin were pathway-dependent. KEY FINDINGS: Luteolin treatment significantly reduced tumor burden, lowered serum AFP levels, and attenuated hepatic lipid accumulation and fibrosis in MASH-HCC mice. In vitro results mirrored these findings, showing that luteolin reduced cholesterol-induced lipid loading. Mechanistically, luteolin increased the phosphorylation of AMPK and its downstream target, ACC. Furthermore, pharmacological inhibition of AMPK with BAY-3827 abolished the lipid-lowering effects of luteolin in hepatic cells, confirming that its therapeutic benefits are mediated through AMPK activation. SIGNIFICANCE: Luteolin suppresses the progression of MASH to HCC by activating the AMPK/ACC signaling pathway and subsequently inhibiting de novo lipogenesis. These findings highlight luteolin as a promising potential therapeutic candidate for the prevention and treatment of MASH-related liver cancer.
Nattokinase: A multifunctional food-derived enzyme for thrombophilia management.
Ma Y, Jia H, Fan J … +4 more , Kang X, Huang W, Li Y, Li J
Life Sci · 2026 Jul · PMID 42097398 · Publisher ↗
A thrombophilic tendency (thrombophilia) is a hypercoagulable state that significantly increases the risk of thromboembolic events. Although conventional anticoagulant therapy is effective, the inherent risk of bleeding...
A thrombophilic tendency (thrombophilia) is a hypercoagulable state that significantly increases the risk of thromboembolic events. Although conventional anticoagulant therapy is effective, the inherent risk of bleeding limits its long-term use, creating an urgent need for safer and more effective alternatives. Nattokinase (NK)- a serine protease derived from the fermentation of natto by Bacillus subtilis- exerts its antithrombotic effects through multiple mechanisms and targets, including direct degradation of fibrin, inhibition of platelet aggregation, and antioxidant/anti-inflammatory actions, while offering oral bioavailability and potential for long-term prevention. However, bottlenecks such as insufficient pH and thermal stability, limited clinical evidence, and a lack of standardization hinder its translation into clinical practice. This review systematically integrates the multifunctional mechanisms and pharmacokinetic characteristics of NK, proposing a 'dynamic equilibrium model of thrombolysis and haemostasis' as a theoretical framework to guide end-to-end optimization from molecular modification to personalized therapy. We first compare and evaluate the therapeutic advantages of NK against traditional and novel antithrombotic drugs. And then we critically analyze the technical maturity and clinical feasibility of engineering modifications (surface charge regulation, regional stiffening, AI-assisted design) and delivery systems (polysaccharide encapsulation, liposomes, nanocarriers). Finally, we identify priority research areas such as standardized production, genotype-guided dosing and trials in high-risk populations, thereby providing a roadmap for the translation of NK from functional foods to clinical drugs.
Primary cilia disruption reprograms extracellular vesicle signaling in endothelial dysfunction and cardiovascular disease.
Piquet M, Recoquillon S, Esnaud R … +3 more , Andriantsitohaina R, Gagnadoux F, Martinez MC
Life Sci · 2026 Jul · PMID 42097397 · Publisher ↗
AIMS: Primary cilia disruption profoundly alters vascular integrity. Extracellular vesicles (EVs) released during ciliary decapitation have emerged as potential mediators of these effects, yet their functional contributi...
AIMS: Primary cilia disruption profoundly alters vascular integrity. Extracellular vesicles (EVs) released during ciliary decapitation have emerged as potential mediators of these effects, yet their functional contribution remains unclear. Here, we investigated the effects of extracellular vesicles (EVs) released by deciliated endothelial cells on endothelial responses and evaluated their clinical relevance. MATERIALS AND METHODS: EVs released by HUVECs and circulating EVs isolated from patients with obstructive sleep apnea syndrome (OSAS) were collected by differential centrifugation. The presence of ciliary markers was then assessed by Western blot analysis. KEY FINDINGS: Pharmacological ablation of primary cilia in HUVECs induced the release of EVs enriched in ciliary markers. EVs from deciliated cells did not alter nitric oxide bioavailability but triggered a significant and sustained increase in cytosolic reactive oxygen species, independent of xanthine oxidase and NADPH oxidase activity. By contrast, EVs from intact cilia exerted protective effects, enhancing endothelial migration and preserving barrier integrity during TNF-α-induced hyperpermeability. Loss of cilia abolished these protective actions, revealing a functional dichotomy determined by EV origin. Circulating EVs from OSAS patients with endothelial dysfunction showed a trend toward increased acetylated α-tubulin expression, suggesting that cilia EV signatures may represent emerging biomarkers of vascular impairment in OSAS. SIGNIFICANCE: These findings reveal EVs from deciliated endothelial cells as previously unrecognized modulators of endothelial behavior, capable of directing vascular responses toward protection or oxidative damage according to ciliary status. Our study uncovers a mechanistic connection between cilia dynamics, EV signaling, and endothelial dysfunction.
Targeting P2X purinergic receptors with suramin alleviates rotenone-induced Parkinson's-like pathology via modulation of mitophagy and NLRP3-pyroptosis: Comparison with metformin.
Attia MS, Shahin NN, Kamel AS … +4 more , Khattab MA, Shabayek MI, Darwish HA, El-Sawalhi MM
Life Sci · 2026 Jul · PMID 42070766 · Publisher ↗
Purinergic P2X receptor overactivation, impaired mitophagy, and NLRP3 inflammasome-driven neuroinflammation have been increasingly implicated in Parkinson's disease (PD) pathogenesis. Suramin, a purinergic receptor antag...
Purinergic P2X receptor overactivation, impaired mitophagy, and NLRP3 inflammasome-driven neuroinflammation have been increasingly implicated in Parkinson's disease (PD) pathogenesis. Suramin, a purinergic receptor antagonist, has recently attracted attention for its neuroprotective effects in several neurological disorders. However, its potential to modulate the P2X/mitophagy/NLRP3 axis in PD remains unexplored. This study evaluated the neuroprotective effects of suramin in comparison with metformin, a reported mitophagy and inflammasome modulator, in a rotenone-induced PD rat model. Rotenone (1.5 mg/kg, s.c.) was administered on alternate days for three weeks. Suramin (100 mg/kg, I.V.) was administered on days 11 and 18, while metformin (200 mg/kg, p.o.) was given from days 11 to 21. Behavioral outcomes were evaluated using the open-field, footprint, grip strength, and rotarod tests. Expression levels of selected target signals were quantified using qPCR, ELISA, Western blot, and immunohistochemistry. Suramin and metformin significantly improved motor and behavioral performance, preserved dopaminergic integrity, improved tyrosine hydroxylase expression, and diminished α-synuclein accumulation, with suramin demonstrating greater efficacy. At the molecular level, suramin more effectively downregulated striatal P2X7R, P2X4R, and ROS levels and increased p-AMPK/t-AMPK ratio. Both treatments promoted mitophagy, as evidenced by increased PINK1, Parkin, and BNIP3 levels along with reduced LC3-II/I ratio. They also suppressed NLRP3 inflammasome activation and pyroptosis, with suramin showing more potent anti-inflammatory effects. Altogether, suramin's neuroprotective effects could be mediated via suppressing P2X7/P2X4 receptors, enhancing mitophagy and counteracting NLRP3-driven pyroptosis in the striatum, with its relatively stronger profile attributable to more robust P2X7/P2X4 signaling inhibition, underscoring its potential as a therapeutic candidate for PD.
Calycosin attenuates renal fibrosis by modulating lipid metabolism via the PCK1/TWIST1/CPT1α axis.
Qu Z, Li Z, Wang Y … +4 more , Jiang B, Liu J, He R, Yang S
Life Sci · 2026 Aug · PMID 42069300 · Publisher ↗
AIMS: Renal lipid metabolic dysregulation drives tubular injury and fibrosis in chronic kidney disease (CKD), yet endogenous targets governing tubular lipid homeostasis remain incompletely understood. This study aimed to...
AIMS: Renal lipid metabolic dysregulation drives tubular injury and fibrosis in chronic kidney disease (CKD), yet endogenous targets governing tubular lipid homeostasis remain incompletely understood. This study aimed to elucidate how calycosin (CAL), an O-methylated isoflavone from Astragali Radix, corrects renal lipid metabolic dysregulation and attenuates fibrosis in CKD. MATERIALS AND METHODS: An adenine-induced CKD mouse model and TGF-β1-stimulated HK-2 cells were treated with CAL. Lipidomics and network pharmacology screened candidate targets. Surface plasmon resonance (SPR) and molecular dynamics simulations validated target binding. Adeno-associated virus (AAV)-mediated renal phosphoenolpyruvate carboxykinase 1 (PCK1) overexpression in vivo and lentiviral overexpression in vitro established the regulatory relationship. The PCK1 inhibitor 3-mercaptopicolinic acid served as reverse validation. KEY FINDINGS: CAL improved renal function, alleviated fibrosis, and reduced lipid deposition both in vivo and in vitro. Lipidomics revealed that CAL bidirectionally modulated renal lipid metabolism by suppressing glycerophospholipid, sphingolipid, and glycerolipid accumulation while restoring omega-3 PUFA-enriched lipids and decreasing lipid saturation. SPR confirmed direct binding of CAL to PCK1. Gain-of-function experiments demonstrated that PCK1 negatively regulates Twist family BHLH transcription factor 1 (TWIST1) in the kidney. Accordingly, CAL activated the PCK1/TWIST1/carnitine palmitoyltransferase 1 A (CPT1α) axis, restoring fatty acid oxidation and suppressing lipid uptake, thereby attenuating lipotoxicity-driven oxidative stress and tubular apoptosis. SIGNIFICANCE: This study identifies PCK1 as an endogenous binding target of CAL in the kidney and delineates the PCK1/TWIST1/CPT1α axis as the downstream signaling circuitry through which CAL corrects tubular lipid metabolic disorders and attenuates renal fibrosis, providing mechanistic rationale for targeted CKD therapy.
Consumption of hydrogen-rich water ameliorates atherosclerosis by modulating gut microbiota and enhancing short-chain fatty acid levels.
Meng F, Xue M, Li H … +9 more , Tao G, Chen W, Li Y, Pei H, Liu Z, Yin D, Qin S, Xue J, Liu B
Life Sci · 2026 Jul · PMID 42069299 · Publisher ↗
AIMS: Molecular hydrogen (H) is a safe gaseous signaling molecule with anti-inflammatory properties. This study aimed to explore the anti-atherosclerotic effects of hydrogen-rich water (HW) and clarify the underlying mec...
AIMS: Molecular hydrogen (H) is a safe gaseous signaling molecule with anti-inflammatory properties. This study aimed to explore the anti-atherosclerotic effects of hydrogen-rich water (HW) and clarify the underlying mechanism involving the gut microbiota and its metabolites. MATERIALS AND METHODS: ApoE mice were administered HW to evaluate atherosclerotic plaque development and stability. Gut microbiota composition and short-chain fatty acid levels were analyzed. Antibiotic-induced microbiota depletion and fecal microbiota transplantation (FMT) were used to verify the mediating role of the gut microbiota. In vitro assays were performed to examine the effects of propionate on macrophage inflammation and polarization. KEY FINDINGS: HW consumption significantly attenuated plaque formation and enhanced plaque stability in ApoE mice, accompanied by altered gut microbiota structure and short-chain fatty acid profiles. Antibiotic treatment abolished the protective effects of HW, while FMT from HW-treated mice transferred the anti-atherosclerotic phenotype. HW notably increased propionate levels in cecal contents and serum. Propionate directly suppressed inflammatory responses and M1 macrophage polarization in vitro. SIGNIFICANCE: This study demonstrates that HW alleviates atherosclerosis by modulating the gut microbiota-propionate-macrophage axis. Our findings highlight HW as a promising and safe intervention for atherosclerosis and provide new mechanistic insights into the crosstalk between gut microbial metabolites and vascular inflammation.
Piezo1: A potential therapeutic target for endothelial dysfunction-related diseases.
Qiu X, Liu H, Yao S … +3 more , Zheng F, Yao P, Zhao H
Life Sci · 2026 Jul · PMID 42069298 · Publisher ↗
Mechanotransduction is a process converting mechanical cues into electrochemical signals. Piezo1, a mechanically sensitive cation channel protein, is widely distributed in non-sensory cells of mammals, particularly highl...
Mechanotransduction is a process converting mechanical cues into electrochemical signals. Piezo1, a mechanically sensitive cation channel protein, is widely distributed in non-sensory cells of mammals, particularly highly expressed in the endothelial cells (ECs). Piezo1 is implicated in various physiological activities, including the regulation of vascular tone, angiogenesis, and maintenance of the endothelial barrier. Under pathological mechanical forces, Piezo1 is involved in the development of endothelial dysfunction-related diseases, including atherosclerosis (AS), hypertension, heart failure (HF), myocardial infarction (MI), pulmonary arterial hypertension (PAH), acute respiratory distress syndrome (ARDS), and diabetes mellitus (DM). In this review, we focus on the underlying mechanisms of Piezo1 in different endothelial dysfunction-related diseases, highlighting its roles in regulating endothelial function. Moreover, we present some activators and inhibitors targeting Piezo1, and discuss their different effects in distinct contexts. Overall, targeting Piezo1 may open a novel avenue of therapeutic tactic for endothelial dysfunction-related diseases.
Thioredoxin-1 attenuates atrial remodeling in pressure-overload heart failure by inhibiting SP1/TGF-beta/Smad signal.
Huang Y, Chen Z, Dong Y … +7 more , Chen Q, Chen Y, Fan X, Hua Y, Zhao W, Xu R, Zhang F
Life Sci · 2026 Apr · PMID 42069297 · Publisher ↗
AIMS: Oxidative stress is a core pathological hallmark of pressure-overload heart failure (HF), and thioredoxin-1 (Trx1) exerts critical cytoprotective effects against oxidative injury. Here, we hypothesized that Trx1 do...
AIMS: Oxidative stress is a core pathological hallmark of pressure-overload heart failure (HF), and thioredoxin-1 (Trx1) exerts critical cytoprotective effects against oxidative injury. Here, we hypothesized that Trx1 downregulation in atrial fibroblasts contributes to elevated atrial fibrillation (AF) susceptibility in the setting of pressure-overload HF. METHODS: To investigate Trx1's gain-of-function effects on atrial remodeling, we developed adeno-associated virus 9 (AAV9)-mediated atrial-specific Trx1-overexpressing mice. These mice underwent transverse aortic constriction (TAC) to induce pressure overload. Cardiac function and atrial fibroblasts were evaluated in both groups post-TAC. Conversely, Trx1 knockdown was performed to assess loss-of-function effects. Atrial tissue proteomic sequencing explored the underlying molecular mechanisms. RESULTS: Bioinformatic analysis revealed significant Trx1 downregulation in cardiac tissues from patients with pressure-overload HF. In TAC mice, atrial Trx1 expression was markedly reduced, predominantly in atrial fibroblasts. Atrial-specific Trx1 overexpression in TAC-induced mice ameliorated HF phenotypes, attenuated atrial dilation, reduced atrial fibrosis by 15%, decreased AF incidence by 15%, and shortened AF episode duration by 80% versus empty vector controls. Conversely, atrial-specific Trx1 knockdown in TAC mice exacerbated HF, atrial dilation, and fibrosis (90% increase), with 17% higher AF incidence and doubled AF duration. Mechanistically, proteomic and validation assays revealed that Trx1 deficiency relieved its inhibitory effect on specificity protein 1 (SP1); upregulated SP1 enhanced TGF-β1 transcription and Smad family protein binding, thereby activating atrial fibroblasts and driving pathological atrial fibrosis. CONCLUSIONS: Trx1 alleviates pressure-overload TAC-induced atrial structural remodeling and reduces AF susceptibility via suppressing SP1 expression and inhibiting the TGF-β/Smad signaling cascade.
GSTK1 alleviates ectopic fat deposition as a protective mechanism against diabetic renal tubulointerstitial lesions.
Chen H, Liu Y, Zhao MG … +11 more , Wu XQ, Dai AM, Wang Y, Yang YY, Li AM, Zhang W, Wang JP, Zhou ZJ, Ti-Chen, Zhang H, Yang S
Life Sci · 2026 Jul · PMID 42069296 · Publisher ↗
AIMS: The kappa class of glutathione S-transferases 1 (GSTK1) is a vital regulatory factor in metabolic diseases. This study was conducted to investigate the regulatory effects of GSTK1 on renal ectopic fat deposition (E...
AIMS: The kappa class of glutathione S-transferases 1 (GSTK1) is a vital regulatory factor in metabolic diseases. This study was conducted to investigate the regulatory effects of GSTK1 on renal ectopic fat deposition (EFD) and lipotoxic injury in diabetic nephropathy (DN) . RESULTS: HK-2 cells under high glucose(HG) / high fatty acid (HFA) stimulation, diabetic mice and human renal biopsy tissues were used. GSTK1 plasmid, GSTK1 siRNA and OSBPL8 siRNA were applied in vitro. Lipid accumulation was analyzed in the renal tissue of type 2 DN patients, diabetic mice and HK-2 cells under HG/HFA stimulation. The expression of GSTK1, DGAT1, ACAT1, CPT-1, BECLIN1, LC3II, ATG5 and RAB7 in renal tubular cells of diabetic mice and HK-2 cells under HG/HFA condition decreased significantly. Metformin treatment restored the expression of GSTK1 in diabetic mice. Additionally, the GSTK1 pharmacological modulator metformin relieved lipophagy dysfunction and promoted fatty acid (FA) β-oxidation enzyme CPT-1. In vitro, GSTK1 plasmid reduced lipid accumulation, fibrosis and inflammation and up-regulated the expression of CPT1 in HK-2 cells, but GSTK1 plasmid had no effect on lipid metabolizing enzymes (ACAT1, DGAT1) . In addition, GSTK1 plasmid could obviously restore lipophagy. However, pretreatment of HK-2 cells with the AMPK inhibitor Compound C, GSTK1 siRNA or OSBPL8 siRNA negated the activating effects of GSTK1 on lipophagy. CONCLUSION: This study indicated that GSTK1 could contribute to alleviate EFD in DN tubular cell through increasing the expression of FA β-oxidation enzyme CPT-1 and restoring lipophagy via AMPK-OSBPL8 pathway.
Aerobic exercise as a non-pharmacological approach to restless legs syndrome: Evidence from an ID-induced model.
Franco B, Rocha VD, Holanda ASS … +10 more , Dias LM, Gomes BB, Veras ACC, Torsoni MA, Manconi M, Clemens S, Oliveira MCG, Ignacio-Souza LM, Torsoni AS, Esteves AM
Life Sci · 2026 Jul · PMID 42069295 · Publisher ↗
INTRODUCTION: Restless Legs Syndrome (RLS) is a sleep disorder characterized by the urge to move, primarily affecting the legs, especially during rest and at night, leading to difficulty or inability to initiate and main...
INTRODUCTION: Restless Legs Syndrome (RLS) is a sleep disorder characterized by the urge to move, primarily affecting the legs, especially during rest and at night, leading to difficulty or inability to initiate and maintain sleep. Exercise is a strategy that can improve symptoms; however, it remains underexplored. AIM: In this context, the aim of this study was to evaluate the effects of chronic aerobic exercise on sleep and on dopamine, adenosine, and glutamate systems in an iron-deficient animal model of Restless Legs Syndrome (RLS). METHODS: Male Wistar rats were assigned to a control group (CTRL, standard diet), an iron-deficient group (ID, iron-restricted diet), an exercised control group (CTRLEX), and an exercised iron-deficient group (IDEX). After 9 weeks of diet, the exercise groups underwent treadmill running for four weeks, followed by sleep (electrocorticographic and electromyographic activity) and molecular (western blotting, PCR and ELISA) analyses. KEY FINDINGS: The ID group showed impairments in all expected sleep parameters associated with RLS, including reduced total sleep time and sleep efficiency, along with increased wakefulness, arousals, and limb movements compared with CTRL. In contrast, the IDEX group showed improvements in all these parameters compared with ID. Additionally, exercise increased dopamine transporter (DAT) and adenosine A1 receptor (A1R) levels, which may underlie the observed symptom improvements. SIGNIFICANCE: These findings highlight the potential of physical exercise as a non-pharmacological treatment for sleep problems associated with RLS and provide insights into possible molecular pathways underlying these improvements.
miR-302 protects the liver from glucolipotoxicity-induced lipid accumulation through activating AMPK and suppressing Elovl6 in HepG2 cells and also in mice.
Tsou SH, Chen WL, Liao CC … +6 more , Lin SC, Wang CC, Weng LH, Weng SH, Lin CL, Huang CN
Life Sci · 2026 Jul · PMID 42067127 · Publisher ↗
INTRODUCTION: Metabolic dysfunction-associated steatotic liver disease (MASLD) is driven by glucolipotoxicity, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and insulin resistance. Although microRNAs regu...
INTRODUCTION: Metabolic dysfunction-associated steatotic liver disease (MASLD) is driven by glucolipotoxicity, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and insulin resistance. Although microRNAs regulate metabolic homeostasis, the role of the miR-302 cluster in hepatic lipid dysregulation and MASLD pathogenesis remains unclear. METHODS: In HepG2 cells, glucolipotoxicity was induced using high glucose plus free fatty acids (HG + FFA). miR-302 cluster was overexpressed to assess protective effects. Lipid accumulation, triglycerides (TG), AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation, Elovl6 expression, long-chain fatty acids (LCFA) content, ER stress markers, stemness factors, mitochondrial function, and insulin signaling were evaluated using biochemical assays, qPCR, and Western blotting. In db/db mice fed a high-fat diet (HFD), AAV8-mediated hepatic miR-302 delivery was used to evaluate steatosis and AMPK/Akt signaling. RESULTS: HG + FFA induced lipid droplet accumulation, elevated neutral lipids and triglycerides, increased stearoyl-CoA desaturase 1 (SCD1) mRNA and LCFAs with Elovl6 upregulation, suppressed AMPK/ACC phosphorylation, activated ER stress, impaired mitochondrial function, elevated reactive oxygen species (ROS), and reduced insulin-stimulated Akt activation. miR-302 overexpression reversed these effects, restoring AMPK signaling, suppressing Elovl6 expression and SCD1 mRNA induction, reducing LCFAs, ROS, rescuing mitochondrial polarization, and normalizing insulin signaling. miR-302 also preserved stemness-related proteins, an effect abolished by AMPK inhibition. In db/db-HFD mice, miR-302 reduced hepatic steatosis, suppressed Elovl6, and restored hepatic AMPK and Akt phosphorylation. CONCLUSION: miR-302 protects hepatocytes from glucolipotoxic metabolic injury by activating AMPK and suppressing the Elovl6-LCFA axis, thereby improving mitochondrial, ER, and insulin-signaling homeostasis. These findings position miR-302 as an RNA therapeutic for MASLD.
Schwann cells as immunomodulators in the tumor immune microenvironment: Mechanisms and therapeutic implications.
Yang T, Zhao WW, Zhang X … +2 more , Zhang WJ, Zou R
Life Sci · 2026 Jul · PMID 42035986 · Publisher ↗
Schwann cells (SCs), the predominant glial cells in the peripheral nervous system (PNS), are increasingly recognized as crucial modulators of the tumor immune microenvironment (TIME). In response to tumor-derived signals...
Schwann cells (SCs), the predominant glial cells in the peripheral nervous system (PNS), are increasingly recognized as crucial modulators of the tumor immune microenvironment (TIME). In response to tumor-derived signals, SCs undergo repair-like phenotypic reprogramming and regulate TIME immune cells by secreting chemokines, cytokines, immunomodulatory lipids, and remodeling the tumor metabolic milieu. Their immunomodulatory activity exhibits context-dependent duality: SCs promote tumor progression in pancreatic cancer (via CCL2-mediated TAM polarization), melanoma (via COX-2/PGE2-induced T cell suppression), lung cancer (via M2 macrophage polarization), breast cancer (via CXCL2-mediated pain and immunosuppression), colorectal cancer (via COX-2/PGE2-driven immunosuppression), and cervical cancer (via PACAP-facilitated perineural invasion); while they suppress tumor growth in early pancreatic cancer (via sympathetic innervation-enhanced anti-tumor immunity) and specific stages of neuroblastoma (NB, via anti-angiogenic factors including SPARC and PEDF). Beyond immune modulation, SCs influence tumor neuroinvasion, pain, and angiogenesis, further shaping tumor progression. The intricate SC-TIME interplay presents novel therapeutic avenues: preclinical and clinical evidence supports strategies including modulating SC activation, selective SC depletion, interrupting SC-TIME interactions, and supplementing SC-derived factors. For instance, modulating SC activation shows promise in pancreatic ductal adenocarcinoma preclinical models, and SC-derived anti-angiogenic factors are a potential strategy for NB therapy-with several approaches advancing to clinical trials or securing approval. Critical challenges persist, including clarifying SC functions in distinct tumor microenvironments and developing selective interventions that target SCs' tumor immunoregulatory roles without impairing their normal PNS physiology. Nevertheless, targeted modulation of SC-mediated immunomodulation may pave the way for enhancing cancer immunotherapies and improving patient outcomes.
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