Gut bacteria alleviate smoking-related NASH by degrading gut nicotine.

Tobacco smoking is positively correlated with non-alcoholic fatty liver disease (NAFLD)1-5, but the underlying mechanism for this association is unclear. Here we report that nicotine accumulates in the intestine during tobacco smoking and activates intestinal AMPKα. We identify the gut bacterium Bacteroides xylanisolvens as an effective nicotine degrader. Colonization of B. xylanisolvens reduces intestinal nicotine concentrations in nicotine-exposed mice, and it improves nicotine-exacerbated NAFLD progression. Mechanistically, AMPKα promotes the phosphorylation of sphingomyelin phosphodiesterase 3 (SMPD3), stabilizing the latter and therefore increasing intestinal ceramide formation, which contributes to NAFLD progression to non-alcoholic steatohepatitis (NASH). Our results establish a role for intestinal nicotine accumulation in NAFLD progression and reveal an endogenous bacterium in the human intestine with the ability to metabolize nicotine. These findings suggest a possible route to reduce tobacco smoking-exacerbated NAFLD progression.

Ultrafast universal fabrication of configurable porous silicone-based elastomers by Joule heating chemistry.

Silicone-based elastomers (SEs) have been extensively applied in numerous cutting-edge areas, including flexible electronics, biomedicine, 5G smart devices, mechanics, optics, soft robotics, etc. However, traditional strategies for the synthesis of polymer elastomers, such as bulk polymerization, suspension polymerization, solution polymerization, and emulsion polymerization, are inevitably restricted by long-time usage, organic solvent additives, high energy consumption, and environmental pollution. Here, we propose a Joule heating chemistry method for ultrafast universal fabrication of SEs with configurable porous structures and tunable components (e.g., graphene, Ag, graphene oxide, TiO2, ZnO, Fe3O4, V2O5, MoS2, BN, g-C3N4, BaCO3, CuI, BaTiO3, polyvinylidene fluoride, cellulose, styrene-butadiene rubber, montmorillonite, and EuDySrAlSiOx) within seconds by only employing H2O as the solvent. The intrinsic dynamics of the in situ polymerization and porosity creation of these SEs have been widely investigated. Notably, a flexible capacitive sensor made from as-fabricated silicone-based elastomers exhibits a wide pressure range, fast responses, long-term durability, extreme operating temperatures, and outstanding applicability in various media, and a wireless human-machine interaction system used for rescue activities in extreme conditions is established, which paves the way for more polymer-based material synthesis and wider applications.

Monocytes Reprogrammed by 4-PBA Potently Contribute to the Resolution of Inflammation and Atherosclerosis.

BACKGROUND: Chronic inflammation initiated by inflammatory monocytes underlies the pathogenesis of atherosclerosis. However, approaches that can effectively resolve chronic low-grade inflammation targeting monocytes are not readily available. The small chemical compound 4-phenylbutyric acid (4-PBA) exhibits broad anti-inflammatory effects in reducing atherosclerosis. Selective delivery of 4-PBA reprogrammed monocytes may hold novel potential in providing targeted and precision therapeutics for the treatment of atherosclerosis. METHODS: Systems analyses integrating single-cell RNA sequencing and complementary immunologic approaches characterized key resolving characteristics as well as defining markers of reprogrammed monocytes trained by 4-PBA. Molecular mechanisms responsible for monocyte reprogramming were assessed by integrated biochemical and genetic approaches. The intercellular propagation of homeostasis resolution was evaluated by coculture assays with donor monocytes trained by 4-PBA and recipient naive monocytes. The in vivo effects of monocyte resolution and atherosclerosis prevention by 4-PBA were assessed with the high-fat diet-fed ApoE-/- mouse model with IP 4-PBA administration. Furthermore, the selective efficacy of 4-PBA-trained monocytes was examined by IV transfusion of ex vivo trained monocytes by 4-PBA into recipient high-fat diet-fed ApoE-/- mice. RESULTS: In this study, we found that monocytes can be potently reprogrammed by 4-PBA into an immune-resolving state characterized by reduced adhesion and enhanced expression of anti-inflammatory mediator CD24. Mechanistically, 4-PBA reduced the expression of ICAM-1 (intercellular adhesion molecule 1) via reducing peroxisome stress and attenuating SYK (spleen tyrosine kinase)-mTOR (mammalian target of rapamycin) signaling. Concurrently, 4-PBA enhanced the expression of resolving mediator CD24 through promoting PPARγ (peroxisome proliferator-activated receptor γ) neddylation mediated by TOLLIP (toll-interacting protein). 4-PBA-trained monocytes can effectively propagate anti-inflammation activity to neighboring monocytes through CD24. Our data further demonstrated that 4-PBA-trained monocytes effectively reduce atherosclerosis pathogenesis when administered in vivo. CONCLUSIONS: Our study describes a robust and effective approach to generate resolving monocytes, characterizes novel mechanisms for targeted monocyte reprogramming, and offers a precision therapeutics for atherosclerosis based on delivering reprogrammed resolving monocytes.

An endoscopically compatible fast-gelation powder forms Janus-adhesive hydrogel barrier to prevent postoperative adhesions.

Postoperative adhesions occur widely in various tissues, bringing the risk of secondary surgery and increased medical burden. Hydrogel barriers with Janus-adhesive ability can achieve physical isolation of adjacent tissues and are therefore considered an ideal solution. However, integrating endoscopic delivery convenience and viscoelastic Janus hydrogel formation remains a great challenge. Here, we present a report of the in situ formation of Janus-adhesive hydrogel barrier using a sprayable fast-Janus-gelation (FJG) powder. We first methacrylate the polysaccharide macromolecules to break the intermolecular hydrogen bonds and impart the ability of rapid hydration. FJG powder can rapidly absorb interfacial water and crosslink through borate ester bonds, forming a toughly adhesive viscoelastic hydrogel. The Janus barrier can be simply formed by further hydrating the upper powder with cationic solution. We construct rat models to demonstrate the antiadhesions efficiency of viscoelastic FJG hydrogels in organs with different motion modalities (e.g., intestine, heart, liver). We also developed a low-cost delivery device with a standardized surgical procedure and further validated the feasibility and effectiveness of FJG powder in minimally invasive surgery using a preclinical translational porcine model. Considering the advantages in terms of therapeutic efficacy, clinical convenience, and commercialization, our results reveal the great potential of Janus-gelation powder materials as a next-generation antiadhesions barrier.

Extracellular matrix physical properties govern the diffusion of nanoparticles in tumor microenvironment.

Nanoparticles (NPs) are confronted with limited and disappointing delivery efficiency in tumors clinically. The tumor extracellular matrix (ECM), whose physical traits have recently been recognized as new hallmarks of cancer, forms a main steric obstacle for NP diffusion, yet the role of tumor ECM physical traits in NP diffusion remains largely unexplored. Here, we characterized the physical properties of clinical gastric tumor samples and observed limited distribution of NPs in decellularized tumor tissues. We also performed molecular dynamics simulations and in vitro hydrogel experiments through single-particle tracking to investigate the diffusion mechanism of NPs and understand the influence of tumor ECM physical properties on NP diffusion both individually and collectively. Furthermore, we developed an estimation matrix model with evaluation scores of NP diffusion efficiency through comprehensive analyses of the data. Thus, beyond finding that loose and soft ECM with aligned structure contribute to efficient diffusion, we now have a systemic model to predict NP diffusion efficiency based on ECM physical traits and provide critical guidance for personalized tumor diagnosis and treatment.

Role of TSP-1 and its receptor ITGB3 in the renal tubulointerstitial injury of focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS), a common cause of primary glomerulonephritis, has a poor prognosis and is pathologically featured by tubulointerstitial injury. Thrombospondin-1 (TSP-1) is an extracellular matrix protein that acts in combination with different receptors in the kidney. Here, we analyzed the tubular expression of TSP-1 and its receptor integrin ß3 (ITGB3) in FSGS. Previously the renal interstitial chip analysis of FSGS patients with tubular interstitial injury showed that the expression of TSP-1 and ITGB3 were upregulated. We found that the expression of TSP-1 and ITGB3 increased in the tubular cells of FSGS patients. The plasma level of TSP-1 increased and was correlated to the degree of tubulointerstitial lesions in FSGS patients. TSP-1/ITGB3 signaling induced renal tubular injury in HK-2 cells exposure to bovine serum albumin and the adriamycin (ADR)-induced nephropathy model. THBS1 KO ameliorated tubular injury and renal fibrosis in ADR-treated mice. THBS1 knockdown decreased the expression of KIM-1 and caspase 3 in the HK-2 cells treated with bovine serum albumin, while THBS1 overexpression could induce tubular injury. In vivo, we identified cyclo-RGDfK as an agent to block the binding of TSP-1 to ITGB3. Cyclo-RGDfK treatment could alleviate ADR-induced renal tubular injury and interstitial fibrosis in mice. Moreover, TSP-1 and ITGB3 were colocalized in tubular cells of FSGS patients and ADR-treated mice. Taken together, our data showed that TSP-1/ITGB3 signaling contributed to the development of renal tubulointerstitial injury in FSGS, potentially identifying a new therapeutic target for FSGS.

Carbonylation of Runx2 at K176 by 4-Hydroxynonenal Accelerates Vascular Calcification.

BACKGROUND: Vascular calcification, which is characterized by calcium deposition in arterial walls and the osteochondrogenic differentiation of vascular smooth muscle cells, is an actively regulated process that involves complex mechanisms. Vascular calcification is associated with increased cardiovascular adverse events. The role of 4-hydroxynonenal (4-HNE), which is the most abundant stable product of lipid peroxidation, in vascular calcification has been poorly investigated. METHODS: Serum was collected from patients with chronic kidney disease and controls, and the levels of 4-HNE and 8-iso-prostaglandin F2α were measured. Sections of coronary atherosclerotic plaques from donors were immunostained to analyze calcium deposition and 4-HNE. A total of 658 patients with coronary artery disease who received coronary computed tomography angiography were recruited to analyze the relationship between coronary calcification and the rs671 mutation in aldehyde dehydrogenase 2 (ALDH2). ALDH2 knockout (ALDH2-/-) mice, smooth muscle cell-specific ALDH2 knockout mice, ALDH2 transgenic mice, and their controls were used to establish vascular calcification models. Primary mouse aortic smooth muscle cells and human aortic smooth muscle cells were exposed to medium containing ß-glycerophosphate and CaCl2 to investigate cell calcification and the underlying molecular mechanisms. RESULTS: Elevated 4-HNE levels were observed in the serum of patients with chronic kidney disease and model mice and were detected in calcified artery sections by immunostaining. ALDH2 knockout or smooth muscle cell-specific ALDH2 knockout accelerated the development of vascular calcification in model mice, whereas overexpression or activation prevented mouse vascular calcification and the osteochondrogenic differentiation of vascular smooth muscle cells. In patients with coronary artery disease, patients with ALDH2 rs671 gene mutation developed more severe coronary calcification. 4-HNE promoted calcification of both mouse aortic smooth muscle cells and human aortic smooth muscle cells and their osteochondrogenic differentiation in vitro. 4-HNE increased the level of Runx2 (runt-related transcription factor-2), and the effect of 4-HNE on promoting vascular smooth muscle cell calcification was ablated when Runx2 was knocked down. Mutation of Runx2 at lysine 176 reduced its carbonylation and eliminated the 4-HNE-induced upregulation of Runx2. CONCLUSIONS: Our results suggest that 4-HNE increases Runx2 stabilization by directly carbonylating its K176 site and promotes vascular calcification. ALDH2 might be a potential target for the treatment of vascular calcification.

The Ginkgo biloba microRNA160-ERF4 module participates in terpene trilactone biosynthesis.

Terpene trilactones (TTLs) are important secondary metabolites in ginkgo (Ginkgo biloba); however, their biosynthesis gene regulatory network remains unclear. Here, we isolated a G. biloba ethylene response factor 4 (GbERF4) involved in TTL synthesis. Overexpression of GbERF4 in tobacco (Nicotiana tabacum) significantly increased terpenoid content and upregulated the expression of key enzyme genes (3-hydroxy-3-methylglutaryl-CoA reductase [HMGR], 3-hydroxy-3-methylglutaryl-CoA synthase [HMGS], 1-deoxy-D-xylulose-5-phosphate reductoisomerase [DXR], 1-deoxy-D-xylulose-5-phosphate synthase [DXS], acetyl-CoA C-acetyltransferase [AACT], and geranylgeranyl diphosphate synthase [GGPPS]) in the terpenoid pathway in tobacco, suggesting that GbERF4 functions in regulating the synthesis of terpenoids. The expression pattern analysis and previous microRNA (miRNA) sequencing showed that gb-miR160 negatively regulates the biosynthesis of TTLs. Transgenic experiments showed that overexpression of gb-miR160 could significantly inhibit the accumulation of terpenoids in tobacco. Targeted inhibition and dual-luciferase reporter assays confirmed that gb-miR160 targets and negatively regulates GbERF4. Transient overexpression of GbERF4 increased TTL content in G. biloba, and further transcriptome analysis revealed that DXS, HMGS, CYPs, and transcription factor genes were upregulated. In addition, yeast 1-hybrid and dual-luciferase reporter assays showed that GbERF4 could bind to the promoters of the HMGS1, AACT1, DXS1, levopimaradiene synthase (LPS2), and GGPPS2 genes in the TTL biosynthesis pathway and activate their expression. In summary, this study investigated the molecular mechanism of the gb-miR160-GbERF4 regulatory module in regulating the biosynthesis of TTLs. It provides information for enriching the understanding of the regulatory network of TTL biosynthesis and offers important gene resources for the genetic improvement of G. biloba with high contents of TTLs.

Alternative splicing of its 5'-UTR limits CD20 mRNA translation and enables resistance to CD20-directed immunotherapies.

Aberrant skipping of coding exons in CD19 and CD22 compromises the response to immunotherapy in B-cell malignancies. Here, we showed that the MS4A1 gene encoding human CD20 also produces several messenger RNA (mRNA) isoforms with distinct 5' untranslated regions. Four variants (V1-4) were detected using RNA sequencing (RNA-seq) at distinct stages of normal B-cell differentiation and B-lymphoid malignancies, with V1 and V3 being the most abundant. During B-cell activation and Epstein-Barr virus infection, redirection of splicing from V1 to V3 coincided with increased CD20 positivity. Similarly, in diffuse large B-cell lymphoma, only V3, but not V1, correlated with CD20 protein levels, suggesting that V1 might be translation-deficient. Indeed, the longer V1 isoform contained upstream open reading frames and a stem-loop structure, which cooperatively inhibited polysome recruitment. By modulating CD20 isoforms with splice-switching morpholino oligomers, we enhanced CD20 expression and anti-CD20 antibody rituximab-mediated cytotoxicity in a panel of B-cell lines. Furthermore, reconstitution of CD20-knockout cells with V3 mRNA led to the recovery of CD20 positivity, whereas V1-reconstituted cells had undetectable levels of CD20 protein. Surprisingly, in vitro CD20-directed chimeric antigen receptor T cells were able to kill both V3- and V1-expressing cells, but the bispecific T-cell engager mosunetuzumab was only effective against V3-expressing cells. To determine whether CD20 splicing is involved in immunotherapy resistance, we performed RNA-seq on 4 postmosunetuzumab follicular lymphoma relapses and discovered that in 2 of them, the downregulation of CD20 was accompanied by a V3-to-V1 shift. Thus, splicing-mediated mechanisms of epitope loss extend to CD20-directed immunotherapies.

Clinical outcomes of patients with mut-type methylmalonic acidemia identified through expanded newborn screening in China.

BACKGROUND: Isolated methylmalonic acidemia, an autosomal recessive disorder of propionate metabolism, is usually caused by mutations in the methylmalonyl-CoA mutase gene (mut-type). Because no universal consensus was made on whether mut-type methylmalonic acidemia should be included in newborn screening (NBS), we aimed to compare the outcome of this disorder detected by NBS with that detected clinically and investigate the influence of NBS on the disease course. DESIGN & METHODS: In this study, 168 patients with mut-type methylmalonic acidemia diagnosed by NBS were compared to 210 patients diagnosed after disease onset while NBS was not performed. Clinical data of these patients from 7 metabolic centers in China were analyzed retrospectively, including initial manifestations, biochemical metabolites, the responsiveness of vitamin B12 therapy, and gene variation, to explore different factors on the long-term outcome. RESULTS: By comparison of the clinically-diagnosed patients, NBS-detected patients showed younger age at diagnosis, less incidence of disease onset, better responsiveness of vitamin B12, younger age at start of treatment, lower levels of biochemical features before and after treatment, and better long-term prognosis (P < 0.01). Onset of disease, blood C3/C2 ratio and unresponsiveness of vitamin B12 were more positively associated with poor outcomes of patients whether identified by NBS. Moreover, the factors above as well as older age at start of treatment were positively associated with mortality. CONCLUSIONS: This research highly demonstrated NBS could prevent major disease-related events and allow an earlier treatment initiation. As a key prognostic factor, NBS is beneficial for improving the overall survival of infants with mut-type methylmalonic acidemia.

Author Correction: HER kinase inhibition in patients with HER2- and HER3-mutant cancers.

The 'Competing interests' statement of this Article has been updated; please see the accompanying Amendment. The original Article has not been corrected online.

MuSCs and IPCs: roles in skeletal muscle homeostasis, aging and injury.

Skeletal muscle is a highly specialized tissue composed of myofibres that performs crucial functions in movement and metabolism. In response to external stimuli and injuries, a range of stem/progenitor cells, with muscle stem cells or satellite cells (MuSCs) being the predominant cell type, are rapidly activated to repair and regenerate skeletal muscle within weeks. Under normal conditions, MuSCs remain in a quiescent state, but become proliferative and differentiate into new myofibres in response to injury. In addition to MuSCs, some interstitial progenitor cells (IPCs) such as fibro-adipogenic progenitors (FAPs), pericytes, interstitial stem cells expressing PW1 and negative for Pax7 (PICs), muscle side population cells (SPCs), CD133-positive cells and Twist2-positive cells have been identified as playing direct or indirect roles in regenerating muscle tissue. Here, we highlight the heterogeneity, molecular markers, and functional properties of these interstitial progenitor cells, and explore the role of muscle stem/progenitor cells in skeletal muscle homeostasis, aging, and muscle-related diseases. This review provides critical insights for future stem cell therapies aimed at treating muscle-related diseases.

Identification of STAT3 as a biomarker for cellular senescence in liver fibrosis: A bioinformatics and experimental validation study.

BACKGROUND: Cellular senescence is associated with a dysregulated inflammatory response, which is an important driver of the development of liver fibrosis (LF). This study aimed to investigate the effect of cellular senescence on LF and identify potential key biomarkers through bioinformatics analysis combined with validation experiments in vivo and in vitro. METHODS: The Gene Expression Omnibus (GEO) database and GeneCards database were used to download the LF dataset and the aging-related gene set, respectively. Functional enrichment analysis of differential genes was then performed using GO and KEGG. Hub genes were further screened using Cytoscape's cytoHubba. Diagnostic values for hub genes were evaluated with a receiver operating characteristic (ROC) curve. Next, CIBERSORTx was used to estimate immune cell types and ratios. Finally, in vivo and in vitro experiments validated the results of the bioinformatics analysis. Moreover, molecular docking was used to simulate drug-gene interactions. RESULTS: A total of 44 aging-related differentially expressed genes (AgDEGs) were identified, and enrichment analysis showed that these genes were mainly enriched in inflammatory and immune responses. PPI network analysis identified 6 hub AgDEGs (STAT3, TNF, MMP9, CD44, TGFB1, and TIMP1), and ROC analysis showed that they all have good diagnostic value. Immune infiltration suggested that hub AgDEGs were significantly associated with M1 macrophages or other immune cells. Notably, STAT3 was positively correlated with α-SMA, COL1A1, IL-6 and IL-1ß, and was mainly expressed in hepatocytes (HCs). Validation experiments showed that STAT3 expression was upregulated and cellular senescence was increased in LF mice. A co-culture system of HCs and hepatic stellate cells (HSCs) further revealed that inhibiting STAT3 reduced HCs senescence and suppressed HSCs activation. In addition, molecular docking revealed that STAT3 was a potential drug therapy target. CONCLUSIONS: STAT3 may be involved in HCs senescence and promote HSCs activation, which in turn leads to the development of LF. Our findings suggest that STAT3 could be a potential biomarker for LF.

Unlocking 4.9 V Quasi-Solid-State Lithium Metal Battery via Solvent Screening and Interfacial Manipulation.

Parlous structure integrity of the cathode and erratic interfacial microdynamics under high potential take responsibility for the degradation of solid-state lithium metal batteries (LMBs). Here, high-voltage LMBs have been operated by modulating the polymer electrolyte intrinsic structure through an intermediate dielectric constant solvent and further inducing the gradient solid-state electrolyte interphase. Benefiting from the chemical adsorption between trimethyl phosphate (TMP) and the cathode, the gradient interphase rich in LiPFxOy and LiF is induced, thereby ensuring the structural integrity and interface compatibility of the commercial LiNi0.8Co0.1Mn0.1O2 (NCM811) cathode even at the 4.9 V cutoff voltage. Eventually, the specific capacity of NCM811|Li full cell based on TMP-modulated polymer electrolyte increased by 27.7% from 4.5 to 4.9 V. Such a universal screening method of electrolyte solvents and its derived electrode interfacial manipulation strategy opens fresh avenues for quasi-solid-state LMBs with high specific energy.

Robust Ionics Reinforced Fiber As Implantable Sensor for Early Operando Monitoring Cell Thermal Safety of Commercial Lithium-Ion Batteries.

Commercial batteries have been largely applied in mobile electronics, electric vehicles, and scalable energy storage systems. However, thermal runaway of batteries still obstructs the reliability of electric equipment. Considering this, building upon recent investigations of energy thermal safety, commercially available organogel fiber-based implantable sensors have been developed through 3D printing technology for first operando implantable monitoring of cell temperature. The printed fibers present excellent reliability and superelasticity because of internal supramolecular cross-linking. High temperature sensitivity (-39.84% °C-1/-1.557% °C-1) within a wide range (-15 to 80 °C) is achieved, and the corresponding mechanism is clarified based on in situ temperature-dependent Raman technology. Furthermore, taking the pouch cell as an example, combined with finite element analysis, the real-time observation system of cell temperature is successfully demonstrated through an implanted sensor with wireless Bluetooth transmission. This enlightening approach paves the way for achieving safety monitoring and smart warnings for various electric equipment.

Role of oxidative stress in the concurrent development of osteoporosis and tendinopathy: Emerging challenges and prospects for treatment modalities.

Both osteoporosis and tendinopathy are widely prevalent disorders, encountered in diverse medical contexts. Whilst each condition has distinct pathophysiological characteristics, they share several risk factors and underlying causes. Notably, oxidative stress emerges as a crucial intersecting factor, playing a pivotal role in the onset and progression of both diseases. This imbalance arises from a dysregulation in generating and neutralising reactive oxygen species (ROS), leading to an abnormal oxidative environment. Elevated levels of ROS can induce multiple cellular disruptions, such as cytotoxicity, apoptosis activation and reduced cell function, contributing to tissue deterioration and weakening the structural integrity of bones and tendons. Antioxidants are substances that can prevent or slow down the oxidation process, including Vitamin C, melatonin, resveratrol, anthocyanins and so on, demonstrating potential in treating these overlapping disorders. This comprehensive review aims to elucidate the complex role of oxidative stress within the interlinked pathways of these comorbid conditions. By integrating contemporary research and empirical findings, our objective is to outline new conceptual models and innovative treatment strategies for effectively managing these prevalent diseases. This review underscores the importance of further in-depth research to validate the efficacy of antioxidants and traditional Chinese medicine in treatment plans, as well as to explore targeted interventions focused on oxidative stress as promising areas for future medical advancements.

Enhanced Superconductivity and Critical Current Density Due to the Interaction of InSe2 Bonded Layer in (InSe2)0.12NbSe2.

Superconductivity was discovered in (InSe2)xNbSe2. The materials are crystallized in a unique layered structure where bonded InSe2 layers are intercalated into the van der Waals gaps of 2H-phase NbSe2. The (InSe2)0.12NbSe2 superconductor exhibits a superconducting transition at 11.6 K and critical current density of 8.2 × 105 A/cm2. Both values are the highest among all transition metal dichalcogenide superconductors at ambient pressure. The present finding provides an ideal material platform for further investigation of superconducting-related phenomena in transition metal dichalcogenides.

Cellular senescence and SASP in tumor progression and therapeutic opportunities.

Cellular senescence (CS), a permanent and irreversible arrest of the cell cycle and proliferation leading to the degeneration of cellular structure and function, has been implicated in various key physiological and pathological processes, particularly in cancer. Initially, CS was recognized as a barrier to tumorigenesis, serving as an intrinsic defense mechanism to protect cells from malignant transformation. However, increasing evidence suggests that senescent cells can promote tumor progression to overt malignancy, primarily through a set of factors known as senescence-associated secretory phenotypes (SASPs), including chemokines, growth factors, cytokines, and stromal metalloproteinases. These factors significantly reshape the tumor microenvironment (TME), enabling tumors to evade immune destruction. Interestingly, some studies have also suggested that SASPs may impede tumor development by enhancing immunosurveillance. These opposing roles highlight the complexity and heterogeneity of CS and SASPs in diverse cancers. Consequently, there has been growing interest in pharmacological interventions targeting CS or SASPs in cancer therapy, such as senolytics and senomorphics, to either promote the clearance of senescent cells or mitigate the harmful effects of SASPs. In this review, we will interpret the concept of CS, delve into the role of SASPs in reshaping the TME, and summarize recent advances in anti-tumor strategies targeting CS or SASPs.

Paraspeckle protein NONO attenuates vascular calcification by inhibiting bone morphogenetic protein 2 transcription.

Vascular calcification is a pathological process commonly associated with atherosclerosis, chronic kidney disease, and diabetes. Paraspeckle protein NONO is a multifunctional RNA/DNA binding protein involved in many nuclear biological processes but its role in vascular calcification remains unclear. Here, we observed that NONO expression was decreased in calcified arteries of mice and patients with CKD. We generated smooth muscle-specific NONO-knockout mice and established three different mouse models of vascular calcification by means of 5/6 nephrectomy, adenine diet to induce chronic kidney failure, or vitamin D injection. The knockout mice were more susceptible to the development of vascular calcification relative to control mice, as verified by an increased calcification severity and calcium deposition. Likewise, aortic rings from knockout mice showed more significant vascular calcification than those from control mice ex vivo. In vitro, NONO deficiency aggravated high phosphate-induced vascular smooth muscle cell osteogenic differentiation and apoptosis, whereas NONO overexpression had a protective effect. Mechanistically, we demonstrated that the regulation of vascular calcification by NONO was mediated by bone morphogenetic protein 2 (BMP2). NONO directly bound to the BMP2 promoter using its C-terminal region, exerting an inhibitory effect on the transcription of BMP2. Thus, our study reveals that NONO is a novel negative regulator of vascular calcification, which inhibits osteogenic differentiation of vascular smooth muscle cell and vascular calcification via negatively regulating BMP2 transcription. Hence, NONO may provide a promising target for the prevention and treatment of vascular calcification.

Sex-determining region Y gene promotes liver fibrosis and accounts for sexual dimorphism in its pathophysiology.

BACKGROUND & AIMS: Men are more prone to develop and die from liver fibrosis than women. In this study, we aim to investigate how sex-determining region Y gene (SRY) in hepatocytes promotes liver fibrosis. METHODS: Hepatocyte-specific Sry knock-in (KI), Sry knockout (KO), and Sry KI with platelet-derived growth factor receptor α (Pdgfrα) KO mice were generated. Liver fibrosis was induced in mice by bile duct ligation for 2 weeks or carbon tetrachloride treatment for 6 weeks. In addition, primary hepatocytes, hepatic stellate cells (HSCs), and immortalized cell lines were used for in vitro studies and mechanistic investigation. RESULTS: Compared to females, the severity of toxin- or cholestasis-induced liver fibrosis is similarly increased in castrated and uncastrated male mice. Among all Y chromosome-encoded genes, SRY was the most significantly upregulated and consistently increased gene in fibrotic/cirrhotic livers in male patients and in mouse models. Sry KI mice developed exacerbated liver fibrosis, whereas Sry KO mice had alleviated liver fibrosis, compared to age- and sex-matched control mice after bile duct ligation or administration of carbon tetrachloride. Mechanistically, both our in vivo and in vitro studies illustrated that SRY in hepatocytes can transcriptionally regulate Pdgfrα expression, and promote HMGB1 (high mobility group box 1) release and subsequent HSC activation. Pdgfrα KO or treatment with the SRY inhibitor DAX1 in Sry KI mice abolished SRY-induced HMGB1 secretion and liver fibrosis. CONCLUSIONS: SRY is a strong pro-fibrotic factor and accounts for the sex disparity observed in liver fibrosis, suggesting its critical role as a potentially sex-specific therapeutic target for prevention and treatment of the disease. IMPACT AND IMPLICATION: We identified that a male-specific gene, sex-determining region Y gene (SRY), is a strong pro-fibrotic gene that accounts for the sex disparity observed in liver fibrosis. As such, SRY might be an appropriate target for surveillance and treatment of liver fibrosis in a sex-specific manner. Additionally, SRY might be a key player in the sexual dimorphism observed in hepatic pathophysiology more generally.