Life sciences最新文献_第2页

Testes-specific protease 50 heightens stem-like properties and improves mitochondrial function in colorectal cancer

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-03-12 DOI: 10.1016/j.lfs.2025.123560

Feng Gao , Sichen Liu , Yue Sun , Chunlei Yu , Lihua Zheng , Luguo Sun , Guannan Wang , Ying Sun , Yongli Bao , Zhenbo Song , Xiaoguang Yang , Chao Ke

Aims

The progression of colorectal cancer (CRC) is driven by a small subset of cancer stem-like cells (CSCs), and mitochondrial function is essential for maintaining their stemness. TSP50, a novel identified oncogene, has been found to promote cell proliferation in multiple cancer types. In this study, we detected the regulatory role of TSP50 in regulating CSC-like properties and mitochondrial mass in CRC.

Materials and methods

First, TSP50 expression and clinical relevance were analyzed via clinical databases and immunohistochemical (IHC). Subsequently, bioinformatic analyses, CRC cell lines, tumorsphere cultures, and mouse xenograft models were utilized to evaluate the relationship between TSP50 and CSC-like properties as well as mitochondrial mass. Finally, immunofluorescence, immunoprecipitation, and Western blotting were performed to dissect the regulatory mechanisms of TSP50, followed by rescue experiments conducted both in vitro and in vivo.

Key findings

TSP50 was overexpressed in CRC tissues, correlating with poor drug response and shorter overall survival (OS). Meanwhile, TSP50 was shown to enhance CSC-like properties in both CRC cells and mouse xenograft models, while concurrently increasing mitochondrial mass and reducing ROS levels, these effects were partially reversed by inhibition of the PI3K/AKT pathway. Mechanistic investigations revealed that TSP50-induced activation of PI3K/AKT signaling is primarily mediated by the enhanced catalytic activity of PI3K p110α subunit.

Significance

Collectively, TSP50 drives CRC malignancy by promoting CSC-like properties and enhancing mitochondrial function through PI3K/AKT signaling. These findings identify TSP50 as a potential therapeutic target for eliminating CSC-like cells and improving clinical outcomes in CRC treatment.

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引用次数: 0

Bifidobacterium bifidum 1007478 derived indole-3-lactic acid alleviates NASH via an aromatic hydrocarbon receptor-dependent pathway in zebrafish

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-03-10 DOI: 10.1016/j.lfs.2025.123557

Chao Tian , Shizhou Deng , Zhao Zhang , Kangdi Zheng , Lai Wei

Aims

This study investigates the potential of Bifidobacterium bifidum 1007478 (BB478) and its metabolite indole-3-lactic acid (ILA) in alleviating non-alcoholic steatohepatitis (NASH) induced by a high-fat diet (HFD) and fructose exposure.

Materials and methods

A zebrafish model of NASH was established by exposure to HFD and fructose. BB478 was administered, and the effects on liver lipid accumulation, oxidative stress, and inflammation were assessed. ILA production by BB478 was confirmed, and its impact on hepatic lipogenesis and inflammatory pathways was evaluated. The involvement of the aromatic hydrocarbon receptor (AhR) was also examined using an AhR inhibitor.

Key findings

BB478 supplementation inhibited lipid accumulation in the liver, reduced triglycerides (TG) and total cholesterol (TC), and mitigated oxidative stress, as evidenced by lower levels of reactive oxygen species (ROS) and malondialdehyde (MDA). ILA, produced by BB478, could alleviate the hepatic damage and fat deposition in liver. Mechanistically, it suppressed hepatic lipogenesis by downregulating lipogenesis-related genes, including sterol response element binding protein 1 (SREBP1) and fatty acid synthase (FASN). ILA also inhibited the expression of pro-inflammatory cytokines to suppress inflammation. The therapeutic effects of ILA were reversed by the AhR inhibitor, indicating that ILA's actions are AhR-dependent.

Significance

These findings reveal the potential of ILA, produced by Bifidobacterium bifidum, as a therapeutic agent for NASH. The mechanistic insights into AhR-mediated effects provide a foundation for further exploration of ILA as a novel approach for managing liver diseases.

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引用次数: 0

Corrigendum to "Aging-related hyperphosphatemia triggers the release of TNF-α from macrophages, promoting indicators of sarcopenia through the reduction of IL-15 expression in skeletal muscle" [Life Sci. 368 (2025) 123507].

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-03-10 DOI: 10.1016/j.lfs.2025.123550

Elena Alcalde-Estévez, Ariadna Moreno-Piedra, Ana Asenjo-Bueno, María Martos-Elvira, Mariano de la Serna-Soto, Marta Ruiz-Ortega, Gemma Olmos, Susana López-Ongil, María P Ruiz-Torres

引用次数: 0

Trimethylamine N-oxide induces cardiac diastolic dysfunction by down-regulating Piezo1 in mice with heart failure with preserved ejection fraction

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-03-10 DOI: 10.1016/j.lfs.2025.123554

Qian Chen , Huaxing Zhang , Yuhong Chen , Yangxuan Peng , Yuhan Yao , Hongmei Xue , Qi Guo , Danyang Tian , Lin Xiao , Xu Teng , Mingqi Zheng , Bing Xiao , Yuming Wu , Sheng Jin

Aims

The present study aimed to investigate the direct link between trimethylamine N-oxide (TMAO) and diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF).

Materials and methods

Diastolic dysfunction is the main manifestation of HFpEF, so the “two-hit” mouse HFpEF model are used. After treated with high-fat diet (HFD) and N^[w]-nitro-l-arginine methyl ester (L-NAME) for 8 weeks, the cardiac function, myocardial fibrosis, oxidative stress levels, and molecular alterations were assessed.

Key findings

The HFpEF mice displayed a declined diastolic function, characterized by an increase in the E/E' ratio, accompanied by a significant increase in plasma brain natriuretic peptide levels and cardiac fibrosis and down-regulation of SERCA2 expression, while, DMB treatment improved diastolic function. Subsequently, TMAO was injected intraperitoneally into the mice for 1 month and found that TMAO induced diastolic dysfunction. In addition, we found that either the HFD and L-NAME or TMAO treatment down-regulated Piezo1 expression, and the cardiomyocyte-specific Piezo1 knockout mice (Piezo1^ΔCM) also had diastolic dysfunction. Moreover, the NOX4 expression was up-regulated and the reactive oxygen species levels were increased in the heart tissues of Piezo1^ΔCM or TMAO-treated mice, which was reversed by a Piezo1 activator (Yoda1) in the TMAO-treated mice. Yoda1 also reversed diastolic dysfunction in the HFpEF mice.

Significance

In conclusion, our data revealed that TMAO-induced oxidative stress injury by down-regulating Piezo1 to be involve in cardiac diastolic dysfunction of HFpEF. It should be noted that this preclinical study did not evaluate HFpEF-related symptoms such as exercise intolerance or pulmonary congestion, which warrant further validation.

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引用次数: 0

Polymyxin B induces pigmentation by upregulating ATG2A-ERK/CREB-MITF-PMEL17 signaling axis

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-03-10 DOI: 10.1016/j.lfs.2025.123553

Miao-qing Zhang, Zheng-hao Wang, Dan-qing Song, Jing-pu Zhang

Polymyxin B serves as the last line of defense in treating multidrug-resistant Gram-negative bacterial infections. However, its distinctive side effect of hyperpigmentation significantly impacts patients' psychological well-being and treatment adherence. Currently, the underlying mechanism of polymyxin B-induced pigmentation remains to be incompletely investigated. This study aims to explore the correlation between polymyxin B-induced pigmentation and autophagy in zebrafish and melanoma cells. Comparative analysis between polymyxin B and its analog polymyxin E reveals opposite effects of the two polymyxins on PMEL17 expression and autophagic flux. Polymyxin B increases PMEL17 expression, correlating with elevated LC3B-II/I level and inhibition of autolysosomal degradation activity, while polymyxin E exerts the contrary effects. RNA-seq analysis of autophagy genes identifies a significant upregulation of ATG2A expression induced by polymyxin B. Moreover, polymyxin B, dependent on ATG2A, promotes MITF overexpression through the LC3B-II/pERK/pCREB pathway, subsequently enhancing PMEL17 expression. This study elucidates the mechanism linking polymyxin B-induced pigmentation and autophagy, demonstrating that polymyxin B causes the accumulation of PMEL17 within autophagosomes and inhibits its autophagic degradation, suggesting that autophagosomes may transform into melanosomes. These findings further contribute to the theoretical basis for autophagy regulating melanin synthesis, highlighting the multifaceted functions of autophagic proteins beyond degradation within autolysosomes.

{"title":"Polymyxin B induces pigmentation by upregulating ATG2A-ERK/CREB-MITF-PMEL17 signaling axis","authors":"Miao-qing Zhang, Zheng-hao Wang, Dan-qing Song, Jing-pu Zhang","doi":"10.1016/j.lfs.2025.123553","DOIUrl":"10.1016/j.lfs.2025.123553","url":null,"abstract":"<div><div>Polymyxin B serves as the last line of defense in treating multidrug-resistant Gram-negative bacterial infections. However, its distinctive side effect of hyperpigmentation significantly impacts patients' psychological well-being and treatment adherence. Currently, the underlying mechanism of polymyxin B-induced pigmentation remains to be incompletely investigated. This study aims to explore the correlation between polymyxin B-induced pigmentation and autophagy in zebrafish and melanoma cells. Comparative analysis between polymyxin B and its analog polymyxin E reveals opposite effects of the two polymyxins on PMEL17 expression and autophagic flux. Polymyxin B increases PMEL17 expression, correlating with elevated LC3B-II/I level and inhibition of autolysosomal degradation activity, while polymyxin E exerts the contrary effects. RNA-seq analysis of autophagy genes identifies a significant upregulation of ATG2A expression induced by polymyxin B. Moreover, polymyxin B, dependent on ATG2A, promotes MITF overexpression through the LC3B-II/pERK/pCREB pathway, subsequently enhancing PMEL17 expression. This study elucidates the mechanism linking polymyxin B-induced pigmentation and autophagy, demonstrating that polymyxin B causes the accumulation of PMEL17 within autophagosomes and inhibits its autophagic degradation, suggesting that autophagosomes may transform into melanosomes. These findings further contribute to the theoretical basis for autophagy regulating melanin synthesis, highlighting the multifaceted functions of autophagic proteins beyond degradation within autolysosomes.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"369 ","pages":"Article 123553"},"PeriodicalIF":5.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143609891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The role of the TREM receptor family in cardiovascular diseases: Functions, mechanisms, and therapeutic target

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-03-09 DOI: 10.1016/j.lfs.2025.123555

Jin-Yi Xue , Ming-Tai Chen , Yu-Hong Jian , Ling-Ling Liang , Xin-Rui Yang , Shi-Han Sun , Ping Liu , Qiu-Yu Liu , Yan Jiang , Meng-Nan Liu

The Triggering Receptor Expressed in the Myeloid Cells (TREM) family represents an emerging subgroup within the immunoglobulin superfamily, which includes key members such as TREM-1, TREM-2, TREM-3, TREM-like transcript-1 (TLT-1), TLT-2, and TLT-4. TREM-1 serves as a potent amplifier of immune responses, exacerbating atherosclerosis and myocardial injury by enhancing inflammatory reactions. In contrast, TREM-2 exerts protective effects by regulating lipid metabolism, mitigating inflammation, and promoting phagocytic activity, thereby attenuating cardiovascular damage. Both soluble TLT-1 and TLT-4 have been identified as potential biomarkers for cardiovascular risk. In recent years, the roles of the TREM family in the pathogenesis of cardiovascular diseases (CVD) have garnered growing interest within the scientific community. This review aims to illuminate the functional roles, underlying mechanisms, and clinical relevance of TREM family members in the regulation of CVD, while exploring their potential applications in early diagnosis, disease monitoring, and the development of novel therapeutic targets for CVD, ultimately laying a foundation for their clinical translation and advancement in precision medicine.

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引用次数: 0

To explore the influencing factors of clinical failure of anti-tumor necrosis factor-α (TNF-α) therapy in sepsis

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-03-09 DOI: 10.1016/j.lfs.2025.123556

Yonghong Zhou , Zhaoran Yu , Yiming Lu

Sepsis, a condition of significant clinical concern, is characterized by life-threatening organ dysfunction that arises from an infection and is exacerbated by a dysregulated host response. Targeting immune modulation, particularly against tumor necrosis factor-alpha (TNF-α), has emerged as a promising anti-inflammatory therapeutic strategy. However, approaches such as blood purification to eliminate inflammatory mediators or the use of anti-TNF-α therapies have shown limited efficacy in clinical practice. This literature review aims to elucidate the pathogenesis of sepsis and dissect the factors contributing to unfavorable outcomes in TNF-α-targeted treatments. Our analysis highlights several potential reasons for therapeutic failure. Complete blockade of TNF-α may adversely affect both TNFR1 and TNFR2 signaling, thereby reducing the efficacy of TNF-α inhibitors. Additionally, the complex heterogeneity of sepsis, including the etiology of infection, patient-specific factors (e.g., immune responsiveness, body mass index, and obesity), the development of anti-drug antibodies, and treatment duration, significantly influences therapeutic outcomes. Based on these insights, we emphasize the need for precision medicine in sepsis management. This includes stratifying patients into subgroups, using TNFR2 agonists or TNFR1-specific antagonists, refining drug design, implementing multi-target combination therapies, and considering the patient's physiological state at the time of treatment. Collectively, these strategies could enhance the efficacy of sepsis management. This review underscores the multifaceted nature of sepsis treatment and highlights the imperative for personalized, multimodal therapeutic approaches to improve clinical outcomes.

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引用次数: 0

Artery tertiary lymphoid organs in atherosclerosis: A review

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-03-08 DOI: 10.1016/j.lfs.2025.123549

Yanni Li , Sihe Gong , Kaijie Yan , Zhonghong Shi , Yimin Bao , Ke Ning

Atherosclerosis (AS) is the common pathological basis for many cardiovascular diseases. Initial investigations into AS predominantly centered on endothelial immune responses associated with plaque formation. However, recent studies increasingly underscore the salutary immune modulation occurring on the aorta adventitia as the atheromatous plaque progresses. The immune responses extend from the intima of the vessel to the adventitia, and the artery tertiary lymphoid organ (ATLO) assumes a major immune role in advanced stages of AS, according to available studies conducted on ApoE^−/− mice. In this review, we collate the history of studies on the participation of ATLOs in immunity to AS, detailing its structure, classification, cellular composition, and formation mechanisms. We elucidate the distinct roles of ATLO components in immune regulation, emphasizing unique features such as territorial organization, T cell-driven autoimmunity, and the T follicular helper-germinal center B cell axis, which distinguish ATLOs from conventional lymphoid responses. Furthermore, based on the latest research, we propose that ATLOs cooperate with the nervous system to regulate the progression of AS. Moreover, we highlight that aging has a great impact on the deterioration of AS and this impact is related to ATLOs. We conclude by suggesting that a focus on ATLOs is important for the clinical management of AS, and we offer a perspective for further research on ATLO and suggest whether it will be beneficial or detrimental to ATLOs.

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引用次数: 0

Olmesartan attenuates doxorubicin-elicited testicular toxicity: The interaction between sirtuin-1, HMGB1/NLRP3 inflammasome/gasdermin D signaling, and AMPK/mTOR-driven autophagy

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-03-07 DOI: 10.1016/j.lfs.2025.123545

Hemat A. Elariny , Hanan Abdelmawgoud Atia , Marwa H. Abdallah , Amany M. Khalifa , Maaly A. Abd Elmaaboud , Mennatallah A. Elkady , Ahmed M. Kabel

Abstract

Background

In the recent years, there has been an increased incidence of testicular toxicity associated with doxorubicin (DOX) use in cancer therapy. The mechanisms of this adverse effect may include induction of oxidative stress with augmentation of the inflammatory and the apoptotic signals in the testicular tissues. The ongoing research is directed towards the exploration of new agents that are capable of overcoming this health problem. This study was a trial to evaluate the efficacy of Olmesartan as a protective agent against DOX-induced testicular dysfunction in male rats.

Materials and methods

Forty adult male Sprague-Dawley rats were divided into control group, DOX-injected group, and three DOX-injected groups treated with olmesartan at 3 dose levels (1, 5, and 10 mg/kg/day). The effect of the different treatments was assessed at the biochemical and the morphological levels.

Key findings

Olmesartan administered to DOX-treated rats induced dose-dependent restoration of the testicular weight and functions, normalization of the hormonal profile, augmentation of the antioxidant defenses, and potentiation of AMPK/mTOR-driven autophagy in comparison to rats treated with DOX alone. These effects were accompanied with a dose-dependent significant mitigation of the cellular events related to pyroptosis and inflammation and a significant amelioration of the testicular morphological changes induced by DOX.

Significance

Olmesartan may represent a promising therapy for DOX-elicited testicular dysfunction, possibly via dose-dependent antioxidant, anti-pyroptotic, anti-inflammatory, and autophagy enhancing effects.

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引用次数: 0

Unveiling the potential of tankyrase I inhibitors for the treatment of type 2 diabetes mellitus: A hybrid approach using network pharmacology, 2D structural similarity, molecular docking, MD simulation and in-vitro studies

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-03-07 DOI: 10.1016/j.lfs.2025.123548

Ruchi Yadav , Krishnaprasad Baby , Yogendra Nayak , Dhaval Patel , Kasinath Viswanathan , Krishnarup Ghoshdastidar , Ankit Patel , Bhumika Patel

Aims

This study explores the association between the Wnt signaling pathway and T2DM, emphasizing the role of Tankyrase1 (TNKS1) in metabolic regulation. Using network pharmacology and computational approaches, it aims to identify potential FDA-approved drugs for repurposing as Wnt inhibitors to improve insulin sensitivity and reduce fat accumulation.

Materials and methods

Network pharmacology analysis was performed to explore the association between the Wnt pathway and T2DM, identifying Catenin Beta 1 (CTNBB1) as a key hub gene involved in disease progression. A 2D structural similarity search was conducted using reference tankyrase inhibitors (E7449 and XAV939). Potential drug candidates were subjected to molecular docking and 100 ns molecular dynamics (MD) simulations with the Tankyrase I (PDB ID: 4W6E) protein. The shortlisted compounds were further evaluated for Wnt inhibitory activity using the TCF/LEF reporter assay, while their anti-diabetic potential was assessed through a glucose uptake assay in L6 myoblast cells.

Key findings

Niclosamide, Capmatinib, Esomeprazole, and Fenofibrate were identified as promising candidates with strong binding affinities and stable interactions with key amino acids (Gly1185, Ser1221, Tyr1224, Asp1198, Tyr1213, and His1201). Experimental validation through in-vitro Wnt inhibition and glucose uptake assays confirmed that drugs Fenofibrate and Conivaptan exhibited significant Wnt inhibitory activity, suggesting their potential role in modulating T2DM-related pathways.

Significance

This study highlights the role of the Wnt signaling pathway in T2DM pathogenesis and identifies potential drug candidates for repurposing as Tankyrase1/Wnt inhibitors. The findings provide a foundation for further in-vivo investigations into the anti-diabetic potential of the identified drugs, paving the way for novel therapeutic strategies in T2DM management.

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引用次数: 0