Life Sciences[JOURNAL]
Sun
200 papers
Inhibiting SIRT2 attenuates sepsis-associated acute kidney injury via NEU1 acetylation-mediated CD44/PI3K/AKT pathway activation.
Jiang Y, Li D, Chen L … +3 more , Zhan Z, Huang Z, Yi B
Life Sci · 2026 Sep · PMID 42361896 · Publisher ↗
AIMS: Sepsis-associated acute kidney injury (S-AKI) is a severe complication of sepsis, characterized by high morbidity and mortality, yet lacks effective treatment options in clinical practice. This study aims to invest...
AIMS: Sepsis-associated acute kidney injury (S-AKI) is a severe complication of sepsis, characterized by high morbidity and mortality, yet lacks effective treatment options in clinical practice. This study aims to investigate the role of SIRT2 in mediating renal injury and inflammation in S-AKI. MATERIALS AND METHODS: LPS-induced S-AKI models were established in wild-type and SIRT2 whole-body knockout mice, as well as in HK-2 cells with SIRT2 knockdown or overexpression. Renal injury, inflammatory cytokines, macrophage infiltration, and cell death were evaluated by histological, biochemical, and molecular analyses. NEU1 acetylation, sialidase activity, CD44 sialylation, and downstream PI3K/AKT signaling were further examined. Pharmacological inhibition studies in mice were performed using SIRT2 selective inhibitor AGK2 and a nano-formulation of AGK2 (Nano-AGK2). KEY FINDINGS: We found that SIRT2 whole-body knockout significantly alleviated renal damage and reduced pro-inflammatory cytokines in S-AKI. Knockdown of SIRT2 attenuated LPS-induced inflammation and cell death in HK-2 cells, whereas its overexpression exacerbated the inflammatory response and cell death. Mechanistically, SIRT2 was shown to deacetylate NEU1 at lysine 395. Inhibiting SIRT2 caused hyperacetylated NEU1, which reduced NEU1 sialidase activity and enhanced CD44 sialylation and CD44/HA binding, promoting PI3K/AKT signaling and renal protection. Furthermore, pharmacological inhibition using AGK2 mitigated LPS-induced renal injury and inflammation, while Nano-AGK2 exhibited enhanced renal accumulation and therapeutic efficacy compared to free AGK2. SIGNIFICANCE: These findings identify SIRT2 as a novel post-translational regulator in S-AKI, suggesting that SIRT2 inhibition may serve as a potential therapeutic target for S-AKI, which deserves further preclinical investigation.
SLCs in diabetic kidney disease: From pathogenic roles to therapeutic promises.
Zhang Y, Zheng D, Han R … +3 more , Liu J, Wang X, Fu S
Life Sci · 2026 Jun · PMID 42349830 · Publisher ↗
Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, with its burden rising alongside diabetes prevalence. Current treatments only slow disease progression, highlighting an urgent need for new the...
Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, with its burden rising alongside diabetes prevalence. Current treatments only slow disease progression, highlighting an urgent need for new therapeutic targets. Solute carrier (SLC) transporters, critical for nutrient transport and metabolic homeostasis, are emerging as key regulators in DKD pathogenesis. The efficacy of SGLT2 inhibitors further supports a significant role for SLCs in DKD. Through a comprehensive literature search (PubMed, Web of Science; September 2020-2025), this review synthesizes evidence on the regulatory roles and mechanisms of SLC family members in DKD progression. We summarize kidney-enriched SLC members and their distribution, focusing on SGLTs (SLC5), GLUTs (SLC2), SLC12A3, and SLC7A11 in DKD progression. These transporters mediate glucose, amino acids, and electrolyte flux, and are extensively involved in oxidative stress, ferroptosis, inflammation, and fibrosis. Finally, we discuss current status and future directions of SLC-based DKD therapies, aiming to overcome therapeutic bottlenecks and identify novel targets.
Inflammation-mediated diabetes-liver disease cross-organ crosstalk: From molecular mechanisms to precision therapeutic strategies.
Guo Y, Ma Q, Guo Z … +3 more , Chu J, Wu N, Qi Y
Life Sci · 2026 Jun · PMID 42342070 · Publisher ↗
The rising global prevalence of diabetes mellitus and its liver complications presents a significant public health challenge. Inflammation-driven cross-organ communication plays a central role in linking these conditions...
The rising global prevalence of diabetes mellitus and its liver complications presents a significant public health challenge. Inflammation-driven cross-organ communication plays a central role in linking these conditions. This review explores current insights into the molecular interactions between diabetes and liver disease, focusing on the role of inflammatory mediators in disease progression and therapeutic resistance. Chronic low-grade inflammation connects insulin resistance, hepatic steatosis, and fibrosis through a network of cytokines and other signaling molecules. Key processes include oxidative stress, activation of inflammatory pathways, and extracellular vesicle-mediated signaling, which together contribute to a cycle of metabolic dysfunction and tissue damage. Emerging precision therapies targeting these inflammatory pathways offer potential for disrupting the diabetes-liver axis. These include traditional anti-inflammatory drugs, cytokine inhibitors, gene therapies, and innovative delivery systems that improve treatment specificity. The integration of artificial intelligence and systems biology helps identify patient-specific inflammatory profiles, supporting personalized treatment approaches. This review discusses the challenges and potential of these therapies, emphasizing strategies that balance inflammation modulation with metabolic stability, and outlines future directions for individualized management of diabetes-related liver disease.
Identification of JEV capsid interacting domain(s) with host protein(s): Novel target for developing anti-JEV therapeutics.
Archana K, Agrahari A, Mishra S … +6 more , Mishra P, Sarbariya Y, Bohra B, Haldar S, Siddiqi MI, Tripathi RK
Life Sci · 2026 Sep · PMID 42342069 · Publisher ↗
UNLABELLED: The Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus. There are no approved drugs for the treatment of JEV infection. AIM: The virus-host protein interactions are essential for viral replicati...
UNLABELLED: The Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus. There are no approved drugs for the treatment of JEV infection. AIM: The virus-host protein interactions are essential for viral replication and could be novel drug targets. The JEV capsid protein does not have enzymatic functions; therefore, all functions are mediated by protein-protein interactions. We wanted to develop inhibitors to prevent such interactions. MATERIALS AND METHODS: Our study has identified two functional domains of the capsid protein by competitive peptide binding (P2 and P7) that is crucial for JEV replication. Using pull-down and MALDI-TOF-TOF techniques, we showed that the JEV capsid protein interacts with the ANXA2 host protein via these peptide domains. KEY FINDINGS: In the presence of P2 and P7, ANXA-2-capsid interaction in infected cells was inhibited, and concomitantly, JEV growth was reduced in the presence of both P2 and P7. Further, we docked ~55,000 molecules from the Maybridge library and identified 10 compounds that showed favourable binding to the P7 domain. From the pool of 10 compounds, we identified SPB07257, which inhibited Capsid-ANXA2 interaction, prevented JEV infection with an IC50 of 10 μM and CC50 of ⟩50 μM. SIGNIFICANCE: Our study demonstrates a novel antiviral strategy.
Prenatal glucocorticoids and long-term brain vulnerability: GR signaling, epigenetic programming, and crosstalk with peripheral tissues.
Gaggi G, Di Credico A, Marchisio M … +2 more , Di Baldassarre A, Ghinassi B
Life Sci · 2026 Sep · PMID 42342068 · Publisher ↗
Glucocorticoids (GCs) are key regulators of stress responses and fetal maturation, and their physiological rise during pregnancy supports coordinated organ development. Clinically relevant GC exposure during sensitive wi...
Glucocorticoids (GCs) are key regulators of stress responses and fetal maturation, and their physiological rise during pregnancy supports coordinated organ development. Clinically relevant GC exposure during sensitive windows of brain development occurs in several contexts, including antenatal treatment for risk of preterm birth to promote lung maturation, prolonged maternal therapy for chronic inflammatory or autoimmune conditions, and postnatal GC treatment in preterm infants, including regimens used to prevent or treat bronchopulmonary dysplasia. Although these contexts differ in timing, dose, and duration, they share the capacity to engage a glucocorticoid receptor (GR) signaling during critical windows of neurodevelopment, with possible long-term consequences for brain development and stress responsiveness. This review synthesizes clinical, experimental, and stem cell-based evidence to examine how GC signaling can shape brain structure and function across the lifespan. We discuss GR signaling in the central nervous system (CNS) and summarize evidence that sustained activation can be associated with paradoxical pro-inflammatory and neurotoxic phenotypes. We highlight epigenetic mechanisms through which GC signals may produce persistent changes in gene regulation, and we integrate data from prenatal exposure together with evidence on maternal metabolic and inflammatory context as modifiers of developmental risk. Finally, we propose an integrated view in which CNS outcomes attributed to GCs reflect a composite of direct neural actions and indirect effects shaped by peripheral tissues. We discuss adipose- and muscle-linked pathways as candidate mediators of systemic-to-central communication. This perspective links stress endocrinology, metabolism, and brain vulnerability, and highlights key mechanistic gaps and translational priorities for future research.
The generation of brown and white adipose organoids from induced pluripotent stem cells through differentiation into a neuromesodermal stage.
Bulut-Okumuş E, Böke ÖB, Şenkal-Turhan S … +4 more , Soydan HE, Sümer E, Beydilli Ö, Doğan A
Life Sci · 2026 Sep · PMID 42342067 · Publisher ↗
Adipose tissue is a highly heterogeneous endocrine organ with essential roles in energy storage, metabolic regulation, and thermogenesis. Here, brown adipose (BA) and white adipose (WA) organoids were generated from indu...
Adipose tissue is a highly heterogeneous endocrine organ with essential roles in energy storage, metabolic regulation, and thermogenesis. Here, brown adipose (BA) and white adipose (WA) organoids were generated from induced pluripotent stem cells (iPSCs) via differentiation into a neuromesodermal progenitor (NMP) state for the first time, and brown and white differentiation was confirmed by uncoupling protein 1 (UCP1) and fatty acid binding protein 4 (FABP4) expression. Morphological, histological, and ultrastructural analyses revealed depot-specific lipid droplet morphologies. Fatty-acid profiling revealed depot-like lipid signatures, and elevated triglycerides across lipid classes confirmed robust lipid accumulation in the organoids. Notably, small-molecule treatment used for obesity screening induced tissue-relevant responses in adipose organoids, highlighting their potential for drug testing. Moreover, liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomics analysis revealed distinct programs associated with brown and white adipose-like states, including mitochondrial/thermogenic signatures in BA organoids and enrichment of endomembrane-trafficking pathways in WA organoids. Furthermore, transplantation into CD1 nude mice demonstrates tissue integration with enhanced vascularization of the graft. iPSC-derived adipose organoids reproduce key depot-like phenotypes, lipid composition, proteomic programs, and treatment responsiveness, providing a scalable human platform for metabolic research and future patient-oriented screening.
Chronic stress impairs multi-scale visual processing in V1.
Yang X, Yang Z, Wang Z … +4 more , Xie Y, Yao D, Xia Y, Chen K
Life Sci · 2026 Sep · PMID 42342066 · Publisher ↗
Visual perceptual deficits are increasingly acknowledged as a core yet underexplored feature of Major Depressive Disorder (MDD), involving impairments in contrast sensitivity, contextual modulation, and social-emotional...
Visual perceptual deficits are increasingly acknowledged as a core yet underexplored feature of Major Depressive Disorder (MDD), involving impairments in contrast sensitivity, contextual modulation, and social-emotional perception. However, the underlying circuit-, neuron-, and network-level mechanisms through which depressive states influence early visual processing remain poorly understood. In this study, mice subjected to chronic restraint stress (CRS) underwent single-unit recordings in layer 2/3 (L2/3) of the primary visual cortex (V1) under light anesthesia to examine the effects of chronic stress on visually evoked neuronal responses and local network dynamics. V1 neurons in CRS-exposed mice exhibited broadened orientation tuning bandwidths, diminished surround suppression, and impaired center-surround discontinuity discrimination. At the network level, visually evoked oscillatory power in the θ, low γand high γ frequency bands was significantly attenuated in CRS mice, accompanied by a marked reduction in visual evoked potential (VEP) amplitude. These findings show that chronic stress impairs both the tuning of V1 neurons to visual stimuli and the local neural rhythms underlying early visual processing. The results uncover a multi-level physiological basis for depression-related visual deficits and provide a preclinical framework that could help develop objective sensory biomarkers for MDD.
SETD2 governs the regenerative threshold in the liver by gating STAT5-dependent Cox2 signaling.
Luo L, Chen T, Long Y … +14 more , Wang C, Li P, Zhou X, Du Z, Tang T, Wang J, Zou Q, Xu L, Liu B, Li L, Lai M, Li Y, Wang L, Dai X
Sci China Life Sci · 2026 Jun · PMID 42337187 · Publisher ↗
Abstract loading — click title to view on PubMed.
Nesfatin-1 mitigates calcium oxalate nephropathy in mice through GPR12 receptor modulation and PKCα/NADPH oxidase pathway inhibition.
Lahane GP, Bhat A, Kulkarni O … +1 more , Dhar A
Life Sci · 2026 Jun · PMID 42335987 · Publisher ↗
AIMS: Nephrolithiasis, a prevalent and recurring kidney disease is associated with oxidative stress, inflammation, apoptosis, necroptosis, and fibrosis. Nesfatin-1, a bioactive peptide, is known to have antioxidant, anti...
AIMS: Nephrolithiasis, a prevalent and recurring kidney disease is associated with oxidative stress, inflammation, apoptosis, necroptosis, and fibrosis. Nesfatin-1, a bioactive peptide, is known to have antioxidant, anti-inflammatory, and antifibrotic properties, however, its role in nephrolithiasis associated pathological changes remains unexplored. Moreover, the receptor by which nesfatin-1 exerts its protective effects is unknown. Thus, the present study aimed to elucidate the role and underlying molecular mechanisms of nesfatin-1 in a mouse model of glyoxylate-induced nephrolithiasis/nephrocalcinosis. MATERIALS AND METHODS: Mouse model of nephrolithiasis was created via administration of glyoxylate, and cell injury models of tubular epithelial cells were done using calcium oxalate monohydrate (COM). Kidney function, histopathology, oxidative stress, inflammation, apoptosis, and renal interstitial fibrosis were measured using assay kits, confocal microscopy and protein/mRNA expression analysis. Moreover, co-immunoprecipitation was performed to investigate the receptors involved and underlying molecular mechanism. KEY FINDINGS: Nephrolithiasis mice showed reduced nesfatin-1 expression and elevated markers of kidney damage, including, histological abnormalities, inflammation, necroptosis, and fibrosis. Mechanistically, nesfatin-1 modulated the GPR 12 oligomerization and inhibited the COM-induced PKCα/NADPH oxidase pathway via modulation of GPR 12 receptor signaling. SIGNIFICANCE: This study is the first to report that nesfatin-1 may be a potential therapeutic agent for nephrocalcinosis/nephrolithiasis via modulation of GPR12 receptor signaling pathway. This study also highlights nesfatin-1's protective role against kidney stone formation and related tubular injury by suppressing the oxidative PKCα/NADPH oxidase pathway.
CIRBP exerts neuroprotective effects in ischemic injury by inhibiting IFN-I signaling.
Tang D, Long J, Gao B … +1 more , Ren Z
Life Sci · 2026 Sep · PMID 42335986 · Publisher ↗
BACKGROUND: Ischemic brain injury (IBI) is a severe neurological disorder with poorly defined pathogenesis and limited treatments. Cold-inducible RNA-binding protein (CIRBP) mediates stress responses, yet its post-transc...
BACKGROUND: Ischemic brain injury (IBI) is a severe neurological disorder with poorly defined pathogenesis and limited treatments. Cold-inducible RNA-binding protein (CIRBP) mediates stress responses, yet its post-transcriptional regulatory role in IBI remains unclear. This study investigated CIRBP's function and mechanisms to provide IBI therapeutic insights. METHODS: An oxygen-glucose deprivation/reoxygenation (OGD/R) model was established in differentiated PC12 cells to mimic IBI in vitro. CIRBP-overexpressing PC12 cells were constructed, and cell viability, apoptosis and oxidative stress were detected. RNA-seq identified CIRBP-regulated differentially expressed genes (DEGs) and alternative splicing (AS) events; PPI networks screened hub genes, and RIP-seq characterized CIRBP's RNA-binding profile. RESULTS: CIRBP overexpression significantly attenuated OGD/R-induced neuronal damage by improving cell morphology, enhancing viability, reducing apoptosis and suppressing oxidative stress. RNA-seq revealed 114 CIRBP-regulated DEGs, with downregulated genes enriched in type I interferon (IFN-I) signaling and neuroinflammation; Oas2 was the core hub gene, with multiple IFN-I-related hub genes identified. CIRBP regulated 506 AS events (mainly IntronR, A5SS, A3SS) linked to axon extension and NF-κB regulation. RIP-seq showed CIRBP preferentially bound to CDS, Nc-exon and antisense regions, recognized miRNA-targeted motifs, and Prrc2b was a potential regulator of CIRBP-binding mRNAs. CONCLUSIONS: CIRBP exerts neuroprotection in OGD/R models by inhibiting oxidative stress and IFN-I-related neuroinflammation, and regulating AS of IBI-associated genes. It has a distinct RNA-binding pattern and may crosstalk with miRNAs in post-transcriptional regulation, highlighting CIRBP as a potential therapeutic target and its regulated genes/AS events as promising IBI biomarkers.
The role of T helper 9 cells and interleukin-9 in allergic diseases.
Yu C, Xue Z, He R … +2 more , Wu H, Tu J
Life Sci · 2026 Jun · PMID 42335985 · Publisher ↗
Allergic diseases, including asthma and food allergies, pose a global public health challenge. However, the complex immunopathological mechanisms have not been fully elucidated yet. Although T helper 2 (Th2) cells are re...
Allergic diseases, including asthma and food allergies, pose a global public health challenge. However, the complex immunopathological mechanisms have not been fully elucidated yet. Although T helper 2 (Th2) cells are regarded as central drivers, they cannot fully explain the clinical heterogeneity and therapeutic resistance of these diseases. This review aimed to systematically illustrate the key roles and regulatory mechanisms of T helper 9 (Th9) cells and their effector cytokine interleukin-9 (IL-9) in various allergic diseases. Th9 cells differentiate under the synergistic induction of transforming growth factor-β (TGF-β) and interleukin-4 (IL-4), and their specific transcription factors (such as Spi-1 proto-oncogene (PU.1), Interferon Regulatory Factor 4 (IRF4)) and epigenetic modifications jointly regulate IL-9 expression. IL-9 acts on mast cells, B cells, eosinophils, and epithelial cells, forming a positive-feedback inflammatory amplification loop that connects adaptive immunity to structural tissue cells. Although drug development targeting IL-9 (such as enokizumab) has faced challenges, intervention strategies targeting key nodes of this axis remain a highly promising research direction. The Th9/IL-9 axis, as a critical hub linking immune activation and pathological tissue changes, provides a new theoretical framework for understanding the heterogeneity of allergic diseases and represents a potential therapeutic target.
Strength training induces ABHD5-ATGL axis to counteract mesenteric fat accumulation in obese Swiss mice.
de Melo DG, Ramos CO, da Cruz Rodrigues VC … +4 more , de Sá Pereira GJ, Dos Santos Brícola R, Cintra DEC, de Moura LP
Life Sci · 2026 Sep · PMID 42335984 · Publisher ↗
Adipose tissue plays a central role in systemic metabolic regulation, and impairments in lipid turnover are a hallmark of obesity associated adipose dysfunction. Lipolytic activation depends on perilipin-1 (PLIN1) phosph...
Adipose tissue plays a central role in systemic metabolic regulation, and impairments in lipid turnover are a hallmark of obesity associated adipose dysfunction. Lipolytic activation depends on perilipin-1 (PLIN1) phosphorylation, which enables the release of α/β-hydrolase domain-containing-5 (ABHD5), a key co-activator of adipose triglyceride lipase (ATGL). Obesity disrupts this regulatory axis, reducing ABHD5 expression and favoring a lipogenic and monounsaturated fatty acid (MUFA) enriched environment driven in part by increased stearoyl-CoA desaturase-1 (SCD1). These contribute to adipocyte hypertrophy, impaired lipid mobilization, and dysfunctional extracellular matrix. This study investigated whether a brief strength training protocol following fourteen weeks of induction on a high-fat diet containing 35% fat could restore the lipolytic machinery and rebalance lipid metabolism in the mesenteric adipose tissue of obese Swiss mice. Seven days of strength training at 70% of loading capacity increased ABHD5 gene expression (p = 0,0012) and protein content (p = 0,0003), accompanied by elevations in pHSL and pPLIN1 (p = 0,0062 and p = 0,0002), indicating lipolytic activation. Exercise reduced mass and adipocyte size, and demonstrated that obesity increased MUFA abundance (p = 0,0039). Correlation revealed that SCD1 showed a positive association with sedentarism, these gene as central determinant of lipid composition in mesenteric adipose tissue. Additionally, strength training decreases MMP2 and increases MMP9 activity (p = 0,002 and p = 0,0001), a pattern consistent with adaptive structural reorganization rather than fibrotic progression. Collectively, these findings indicate that short-term strength training is a non-pharmacological strategy to counteract mesenteric adipose dysfunction by restoring lipolytic balance and improving lipid metabolic profiles before mass loss and changes in eating behavior occur.
A clinically practical aging clock (physical clock) for healthy aging: development, validation, and application for health assessment and intervention.
Wang XM, Pang J, Yu X … +27 more , Zhang X, Wang SB, Pan Q, Chen A, Xu L, Li N, Li X, Wang Y, Gu Y, Chen S, Ma W, Zhang LQ, Zhang C, Liu W, Li CB, Shen T, Dai DP, Wang F, Li Y, Li Y, Dong J, Chen W, Yao Y, Liu B, Cai JP, Zhang T, Cui J
Sci China Life Sci · 2026 Jun · PMID 42329515 · Publisher ↗
Aging is the primary risk factor for most chronic diseases, yet substantial heterogeneity highlights a fundamental gap between chronological age and biological aging processes. Despite the high predictive accuracy of mul...
Aging is the primary risk factor for most chronic diseases, yet substantial heterogeneity highlights a fundamental gap between chronological age and biological aging processes. Despite the high predictive accuracy of multi-omics clocks, their clinical implementation remains limited by cost and complexity, underscoring the need for scalable and clinically actionable alternatives. Here, we developed a physical clock that integrates routine clinical biomarkers with multidimensional physical performance using ElasticNet regression in the large-scale PENG ZU cohort. This model was further reduced to a simplified 11-marker model, primarily capturing key domains of kidney function, glucose metabolism, and physical performance. Accelerated aging, as measured by physical clock-derived ΔPhysicalAge, was strongly associated with chronic disease incidence, functional decline, reduced intrinsic capacity, and mortality. Across independent validation in UKB Biobank and NHANES, it robustly predicted disease onset, disease-specific, and all-cause mortality. Notably, ΔPhysicalAge outperformed ΔPhenoAge in predicting major age-related diseases and enabled effective risk stratification even among individuals conventionally classified as low risk. We observed an association between postmenopausal HRT use and lower ΔPhysicalAge, providing preliminary evidence supporting the validity and responsiveness of the physical clock. To facilitate clinical translation, we established age- and sex-specific healthy reference intervals (HRI) derived from individuals with normal or decelerated aging, demonstrating that maintenance within these ranges is associated with substantially reduced mortality risk. Furthermore, modifiable lifestyle and psychosocial factors, including healthy diet, physical activity, health consciousness, and social engagement, were associated with slower aging, highlighting actionable intervention pathways. Together, the physical clock bridges the gap between biological aging assessment and real-world clinical practice, offering a clinically accessible tool for risk stratification and personalized intervention to promote healthy aging.
Corrigendum to "Decoding the mitochondrial metabolic engine for tumor metastasis and clinical therapeutic opportunities" [Life Sci. 393 (2026) 124326].
Ye Z, Zeng P, Kang Y … +3 more , Liu W, Li H, Luo X
Life Sci · 2026 Sep · PMID 42321137 · Publisher ↗
Abstract loading — click title to view on PubMed.
BARD1 phase separation orchestrates a repair hub by enriching XRCC5 to drive chemoresistance in glioma.
Wang C, Cheng X, Liu Z … +3 more , Wang Y, Gao Y, Liu Y
Life Sci · 2026 Sep · PMID 42309254 · Publisher ↗
Temozolomide (TMZ) resistance is a major challenge in glioblastoma (GBM). The role of BRCA1-associated RING domain protein 1 (BARD1), a DNA damage response protein, in GBM and its potential link to liquid-liquid phase se...
Temozolomide (TMZ) resistance is a major challenge in glioblastoma (GBM). The role of BRCA1-associated RING domain protein 1 (BARD1), a DNA damage response protein, in GBM and its potential link to liquid-liquid phase separation (LLPS) remain unclear. Bioinformatics analysis of TCGA, CGGA, and GEO datasets revealed that high BARD1 expression correlates with poor prognosis in GBM. Functional studies demonstrated that BARD1 knockdown inhibited glioma cell proliferation, migration, and invasion. We discovered that BARD1 undergoes LLPS via its intrinsically disordered region (IDR, aa 113-425). Upon TMZ-induced DNA damage, BARD1 forms nuclear condensates that recruit X-ray repair cross-complementing protein 5 (XRCC5) to damage sites, promoting repair and driving TMZ resistance. Disrupting this phase separation capability impaired DNA repair. Through structure-based virtual screening, our results suggest that Ziprasidone and Apomorphine may disrupt the BARD1-XRCC5 interaction. Combining either compound with TMZ enhanced cytotoxicity in vitro and suppressed tumor growth in vivo. Our findings unveil a novel LLPS-mediated mechanism by which BARD1 confers TMZ resistance in GBM, positioning it as a prognostic marker and a therapeutic target. Targeting the BARD1-XRCC5 axis presents a promising strategy to overcome chemoresistance.
EIF3B promotes oral squamous cell carcinoma progression via the PI3K/AKT pathway and is negatively regulated by miR-124-3p.
Zheng X, Gao B, Li J … +4 more , Ji Y, Lin Y, Lin L, Qiu Y
Life Sci · 2026 Sep · PMID 42302928 · Publisher ↗
Oral squamous cell carcinoma (OSCC) has a poor prognosis and lacks effective therapeutic targets. Eukaryotic initiation factor 3B (EIF3B) is aberrantly overexpressed in multiple cancers, yet its role in OSCC remains uncl...
Oral squamous cell carcinoma (OSCC) has a poor prognosis and lacks effective therapeutic targets. Eukaryotic initiation factor 3B (EIF3B) is aberrantly overexpressed in multiple cancers, yet its role in OSCC remains unclear. Bioinformatic analyses identified EIF3B as a potential target of the tumor-suppressive microRNA miR-124-3p. In this study, the expression of miR-124-3p and EIF3B was examined in OSCC tissues and cell lines by qRT-PCR and western blotting, and their direct interaction was verified using a dual-luciferase assay. Functional effects on proliferation, migration, apoptosis, and tumorigenicity were evaluated through in vitro and xenograft assays. The underlying mechanisms were explored via analysis of PI3K/AKT signaling and epithelial-mesenchymal transition (EMT) markers, with LY294002 used to confirm pathway dependency. EIF3B was significantly upregulated, while miR-124-3p was downregulated, in OSCC tissues (n = 49). EIF3B expression correlated with advanced TNM stage and poor prognosis. EIF3B promoted proliferation, migration, and invasion, and inhibited apoptosis, whereas miR-124-3p exerted the opposite effects. miR-124-3p directly targeted the 3'UTR of EIF3B, and EIF3B overexpression reversed its suppressive effects. EIF3B activated PI3K/AKT signaling and EMT, both of which were abolished by miR-124-3p or LY294002. These findings define the miR-124-3p/EIF3B/PI3K-AKT axis as a key regulator of OSCC progression and suggest EIF3B as a potential prognostic biomarker and therapeutic target.
Development of a short-term mouse model of early MASLD for non-invasive pathophysiological tracking via urinary metabolomics and micro-CT.
Yu L, Wang L, Hu F … +2 more , Liu L, Wu Z
Life Sci · 2026 Jun · PMID 42302927 · Publisher ↗
INTRODUCTION: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are common chronic liver disorders linked to hepatocellula...
INTRODUCTION: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are common chronic liver disorders linked to hepatocellular carcinoma. However, the lack of time-efficient preclinical models, coupled with the shortage of integrated and longitudinal non-invasive monitoring strategies, has restricted mechanistic investigations and therapeutic development. AIM: This study aimed to establish a short-term modified Western diet (mWD)-induced MASLD model in middle-aged mice and to evaluate the feasibility of integrating urinary metabolomics and micro-computed tomography (Micro-CT) for non-invasive tracking of metabolic and imaging changes associated with early-stage MASLD. MATERIALS AND METHODS: Ten-month-old mice were fed a high-fat, high-fructose mWD for 90 days, with systematic assessments of food and water intake, body weight, body composition, and urinary metabolite profiles conducted throughout the intervention. At the endpoint, oral glucose tolerance tests (OGTT) and micro-CT scans were performed to characterize key metabolic and imaging phenotypes in this dietary model. KEY FINDINGS: mWD feeding was associated with significant adiposity gain, glucose metabolism impairment, and systemic metabolic reprogramming in mice. Untargeted urinary metabolomics further revealed progressive perturbations in lipid and amino acid metabolic pathways, as well as candidate biomarkers associated with diet-induced metabolic alterations. SIGNIFICANCE: Collectively, this work provides initial proof-of-concept for the feasibility of integrating urinary metabolomics with micro-CT for non-invasive monitoring of an early MASLD-like phenotype, and a basis for future studies incorporating histopathological and cardiometabolic confirmation.
Plasma proteomics reveal key proteins mediating vascular aging.
Chen S, Gao J, Li Z
Life Sci · 2026 Sep · PMID 42302926 · Publisher ↗
AIMS: To identify plasma proteins with causal roles in vascular aging and to quantify the mediating effects of blood pressure, lipids, and glucose. MATERIALS AND METHODS: We performed a systematic proteome-wide Mendelian...
AIMS: To identify plasma proteins with causal roles in vascular aging and to quantify the mediating effects of blood pressure, lipids, and glucose. MATERIALS AND METHODS: We performed a systematic proteome-wide Mendelian randomization (MR) study using genetic instruments from the UK Biobank Pharma Proteomics Project and the Decode cohort. Genetic colocalization (posterior probability ≥70%) was applied to identify shared causal variants between protein levels and multiple vascular aging-related phenotypes. Mediation MR analyses were conducted to quantify the contributions of blood pressure, lipids, and glucose. Phenome-wide association studies (PheWAS) validated the broader phenotypic impact of the identified proteins. KEY FINDINGS: Four plasma proteins (PCSK9, FES, TMEM106B and FURIN) were identified as potential mediators of vascular aging, supported by strong MR causal effects and genetic colocalization evidence. Mediation MR analyses indicated that a substantial proportion (26.7%-75.3%) of their effects on vascular aging was mediated through low-density lipoprotein cholesterol and systolic blood pressure regulation. PheWAS further supported these findings. SIGNIFICANCE: This study identifies four key plasma proteins with potential causal roles in vascular aging, highlighting blood pressure and lipids as major mediators of their effects on vascular aging. These findings provide new insights into the molecular basis of vascular aging and prioritize promising targets for future mechanistic and therapeutic investigation.
Beyond lipid-lowering effects: Challenges and insights in fenofibrate repurposing for oncology.
Peng L, Zhu N, Zhang CJ … +5 more , Long JP, Shi YN, Yang Q, Gong YZ, Qin L
Life Sci · 2026 Sep · PMID 42302925 · Publisher ↗
Fenofibrate, a well-established peroxisome proliferator-activated receptor alpha (PPARα) agonist, is widely used clinically for managing hypercholesterolemia and hyperlipidemia. In recent years, its potential anti-tumor...
Fenofibrate, a well-established peroxisome proliferator-activated receptor alpha (PPARα) agonist, is widely used clinically for managing hypercholesterolemia and hyperlipidemia. In recent years, its potential anti-tumor properties have garnered considerable attention. Accumulating evidence demonstrates that fenofibrate inhibits the growth of various malignancies, including breast, liver, prostate, and lung cancers, by modulating lipid metabolism, suppressing cancer cell proliferation, and inducing apoptosis. The anti-tumor mechanisms of fenofibrate involve both PPARα-dependent pathways through direct regulation of PPARα and associated lipid metabolic enzymes, and PPARα-independent pathways, such as inhibition of the Akt/mTOR, TNF-α/NF-κB, and Cx43/EGF/ERK1/2 signaling axes. Furthermore, fenofibrate exhibits synergistic effects with conventional chemotherapeutic agents (e.g., paclitaxel and docetaxel) by enhancing T-cell viability, activating immune responses, and thereby improving chemotherapy sensitivity. This review comprehensively summarizes the efficacy and underlying mechanisms of fenofibrate against diverse cancer types and discusses the potential applications and challenges associated with its repurposing for cancer therapy. A deeper understanding of fenofibrate's anti-cancer capabilities and molecular targets may provide novel insights for the development of innovative therapeutic strategies.
Endothelial-to-mesenchymal transition in ischemic diseases: Molecular mechanisms, pathophysiological roles, and emerging therapeutic strategies.
He Z, Yang Q, Ji X … +2 more , Li J, Xu M
Life Sci · 2026 Sep · PMID 42302924 · Publisher ↗
Ischemic diseases, characterized by insufficient blood perfusion and vascular dysfunction, are a major cause of morbidity and mortality worldwide, including myocardial infarction (MI), ischemic stroke (IS), peripheral ar...
Ischemic diseases, characterized by insufficient blood perfusion and vascular dysfunction, are a major cause of morbidity and mortality worldwide, including myocardial infarction (MI), ischemic stroke (IS), peripheral artery disease (PAD), and ischemic retinopathy. Endothelial-to-mesenchymal transition (EndMT) plays important roles in both physiological and pathophysiological processes. Under physiological conditions, EndMT is a tightly regulated developmental process required for embryonic cardiovascular formation. However, under pathological conditions such as ischemia, EndMT can be aberrantly activated by hypoxia, inflammatory signaling, and oxidative stress. Accumulating evidence indicates that EndMT plays dual roles in ischemic diseases. Partial EndMT may contribute to adaptive vascular remodeling and angiogenesis during the early phase of tissue injury, whereas persistent activation promotes endothelial dysfunction, extracellular matrix deposition, fibrosis, and chronic inflammation, thereby exacerbating disease progression. In this review, we summarize the current understanding of EndMT in ischemic diseases, focusing on the major regulatory signaling pathways, including TGF-β/Smad, Wnt/β-catenin, and Notch signaling, as well as epigenetic mechanisms such as histone modifications, DNA methylation, and non-coding RNAs. We further discuss emerging therapeutic strategies targeting EndMT, encompassing endogenous hormones, traditional Chinese medicine formulations, natural compounds, small molecule compounds, and RNA-based therapeutics. The clinical translation of EndMT is hindered by the lack of standardized diagnostic criteria and the limitations of existing experimental models. A deeper understanding of the EndMT regulatory network may provide new insights into vascular remodeling and facilitate the development of novel therapeutic strategies.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe