Life sciences最新文献_第8页

Identification of a novel fibroblast growth factor receptor-agonistic peptide and its effect on diabetic wound healing

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-28 DOI: 10.1016/j.lfs.2025.123432

Mariya Farooq , Moonjung Hwang , Abdul Waheed Khan , Maria Batool , Bilal Ahmad , Wook Kim , Moon Suk Kim , Sangdun Choi

Aims

Fibroblast growth factor (FGF) is a broad class of secretory chemicals that act via FGF receptors (FGFR). The study aims to explore the role of a novel peptide, FAP1 (FGFR-agonistic peptide 1), in tissue regeneration and repair. It investigates whether FAP1 mimics basic fibroblast growth factor (bFGF) and accelerates wound healing both in vitro and in vivo.

Main methods

In this study, a novel peptide was designed and its ability to mimic bFGF was assessed through different in vitro experiments including its effect on cell proliferation, wound healing, cell signaling including FGFR1 phosphorylation and activation of mitogen-activated protein kinases (MAPKs). Specificity was confirmed through surface plasmon resonance (SPR) analysis and co-treatment with FGFR inhibitor, erdafitinib. In vivo, the effect of FAP1 on diabetic wound healing was tested in a mouse model, examining collagen production and the migration and proliferation of keratinocytes and fibroblasts.

Key findings

FAP1 specifically phosphorylated FGFR and activated MAPKs similar to bFGF. In vitro, it induced cell proliferation and accelerated wound healing. In vivo, FAP1 improved diabetic wound healing by increasing collagen production and promoting keratinocyte and fibroblast migration and proliferation. The specificity of FAP1 was confirmed through SPR.

Significance

FAP1 shows potential as a novel pharmacological alternative to natural bFGF for skin tissue regeneration and repair. Its ability to accelerate wound healing and its specificity for FGFR suggest that FAP1 could serve as a cost-effective substitute for bFGF protein in therapeutic applications.

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引用次数: 0

Hyperoside mitigates PCOS-associated adipogenesis and insulin resistance by regulating NCOA2-mediated PPAR-γ ubiquitination and degradation

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-27 DOI: 10.1016/j.lfs.2025.123417

Qi Zhou , Hong Tang , Yongfeng Wang , Yu Hua , Xiaoling Ouyang , Linxia Li

Aims

Polycystic ovary syndrome (PCOS) is closely associated with metabolic disorders such as insulin resistance and obesity, but the role of adipogenesis in its pathophysiology remains unclear. This study investigates the role of adipogenesis in PCOS development and evaluates whether hyperoside (HPS), an anti-adipogenic herbal compound, can improve PCOS by inhibiting adipogenesis.

Main methods

A combination of in vivo and in vitro models was used to assess the impact of HPS on ovarian function, insulin resistance, and adipogenesis. PCOS mice were treated with HPS, and their ovarian function and insulin resistance were evaluated. In vitro adipocyte differentiation assays were conducted to examine the effects of HPS on adipogenesis. The target of HPS was analyzed by Surface plasmon resonance. The expression levels of NCOA2 and PPAR-γ ubiquitination and degradation were analyzed using quantitative real-time PCR and Western blotting. Additionally, NCOA2 knockdown experiments were performed to investigate its role in ovarian function, insulin resistance, and adipogenesis in PCOS mice.

Key findings

HPS treatment significantly improved ovarian function, reduced insulin resistance, and suppressed adipogenesis in PCOS mice. Mechanistically, HPS inhibited adipogenesis by reducing NCOA2 expression, thereby preventing PPAR-γ ubiquitination and degradation. Knockdown of NCOA2 further validated its role by improving ovarian function, insulin resistance, and adipogenesis in PCOS models.

Significance

These findings demonstrate that HPS alleviates PCOS by regulating NCOA2-mediated PPAR-γ ubiquitination and degradation, offering new insights into the role of adipogenesis in PCOS pathophysiology.

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引用次数: 0

Identification and regulation of a novel leptin receptor-linked enhancer during zebrafish ventricle regeneration

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-25 DOI: 10.1016/j.lfs.2025.123415

Qi Li , Yan Zhao , Fang Geng , Xiamisiya Tuniyazi , Chunxiao Yu , Hongbo Lv , Hongbo Yang , Ruilin Zhang

Aims

Vertebrates vary greatly in their abilities to regenerate injured hearts. Zebrafish possess a remarkable capacity for cardiac regeneration, making them an excellent model for regeneration research. Recent studies have reported the activation and underlying regulatory mechanisms of leptin b (lepb) and the leptin b-linked enhancer (LEN) in injured hearts. However, the regenerative response activity of the leptin receptor (lepr) and its regulatory mechanisms still warrant further exploration.

Materials and methods

We identified a novel lepr-linked enhancer (leprEnh) and generated a stable transgenic zebrafish line for validation. We also employed a genetic ventricle ablation system to elucidate the mechanisms governing its activation. Immunofluorescence, in situ hybridization and confocal imaging of larvae treated with various inhibitors during ventricle regeneration were performed.

Key findings

Our results revealed that both lepr expression and leprEnh-directed EGFP fluorescence were weakly expressed in the ventricle during early heart development but displayed a sharp increase after ventricle ablation. Strong injury response activity was also observed in the atrium. Furthermore, the regeneration-responsive activity was attenuated by hemodynamic force alteration and was modulated by Notch, ErbB2 and BMP signaling pathways.

Significance

Our study sheds light on the regulation of lepr and leprEnh during heart regeneration and provide a basis for screening for novel therapeutic targets for myocardial infarction.

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引用次数: 0

Reproductive outcomes in female mice offspring due to maternal metformin treatment

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-25 DOI: 10.1016/j.lfs.2025.123416

Candela Velazquez , Yamila Herrero , Katherine Prost , Mayra Bordaquievich , Melanie Neira , Fernanda Parborell , Dalhia Abramovich

Aims

Metformin has shown beneficial effects on reproduction in women. However, its use during pregnancy remains controversial, as metformin can cross the placenta. Most studies have focused on the metabolic impact on the offspring of treated mothers, with limited information regarding its reproductive effects. The aim of this study was to evaluate potential alterations in ovarian function and fertility in female offspring of mothers treated with metformin during pregnancy and lactation.

Materials and methods

C57BL/6 female mice were treated with metformin four weeks before mating, and the treatment was maintained during gestation and lactation. Seven weeks after weaning, metabolic parameters as well as ovarian and reproductive function of the offspring were analyzed.

Key findings

The offspring of treated mothers were lighter at birth and, in adulthood, they had more gonadal adipose tissue with no alterations in body weight. No changes in glucose metabolism were observed. Their follicular development was modified, with more early antral and atretic follicles and less primary and late antral follicles. Anti-Müllerian hormone expression and ovarian angiogenesis were increased. The estrous cycle, hormonal production and fertility were not affected by metformin exposure, however, the F2 generation showed higher body weight at birth.

Significance

Metformin can induce fetal programming in animals exposed to it during development, impacting metabolism and ovarian functionality in adulthood. Under physiological conditions, these alterations do not result in reduced fertility or endocrine disruptions. Our data warrant studies in women to make informed decisions regarding metformin administration during critical developmental periods in clinical settings.

{"title":"Reproductive outcomes in female mice offspring due to maternal metformin treatment","authors":"Candela Velazquez , Yamila Herrero , Katherine Prost , Mayra Bordaquievich , Melanie Neira , Fernanda Parborell , Dalhia Abramovich","doi":"10.1016/j.lfs.2025.123416","DOIUrl":"10.1016/j.lfs.2025.123416","url":null,"abstract":"<div><h3>Aims</h3><div>Metformin has shown beneficial effects on reproduction in women. However, its use during pregnancy remains controversial, as metformin can cross the placenta. Most studies have focused on the metabolic impact on the offspring of treated mothers, with limited information regarding its reproductive effects. The aim of this study was to evaluate potential alterations in ovarian function and fertility in female offspring of mothers treated with metformin during pregnancy and lactation.</div></div><div><h3>Materials and methods</h3><div>C57BL/6 female mice were treated with metformin four weeks before mating, and the treatment was maintained during gestation and lactation. Seven weeks after weaning, metabolic parameters as well as ovarian and reproductive function of the offspring were analyzed.</div></div><div><h3>Key findings</h3><div>The offspring of treated mothers were lighter at birth and, in adulthood, they had more gonadal adipose tissue with no alterations in body weight. No changes in glucose metabolism were observed. Their follicular development was modified, with more early antral and atretic follicles and less primary and late antral follicles. Anti-Müllerian hormone expression and ovarian angiogenesis were increased. The estrous cycle, hormonal production and fertility were not affected by metformin exposure, however, the F2 generation showed higher body weight at birth.</div></div><div><h3>Significance</h3><div>Metformin can induce fetal programming in animals exposed to it during development, impacting metabolism and ovarian functionality in adulthood. Under physiological conditions, these alterations do not result in reduced fertility or endocrine disruptions. Our data warrant studies in women to make informed decisions regarding metformin administration during critical developmental periods in clinical settings.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"363 ","pages":"Article 123416"},"PeriodicalIF":5.2,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046499","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

Cell–cell communications in the brain of hepatic encephalopathy: The neurovascular unit

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-23 DOI: 10.1016/j.lfs.2025.123413

Kyuwan Choi , Yena Cho , Yerin Chae , So Yeong Cheon

Many patients with liver diseases are exposed to the risk of hepatic encephalopathy (HE). The incidence of HE in liver patients is high, showing various symptoms ranging from mild symptoms to coma. Liver transplantation is one of the ways to overcome HE. However, not all patients can receive liver transplantation. Moreover, patients who have received liver transplantation have limitations in that they are vulnerable to hepatocellular carcinoma, allograft rejection, and infection. To find other therapeutic strategies, it is important to understand pathological factors and mechanisms that lead to HE after liver disease. Oxidative stress, inflammatory response, hyperammonaemia and metabolic disorders seen after liver diseases have been reported as risk factors of HE. These are known to affect the brain and cause HE. These peripheral pathological factors can impair the blood-brain barrier, cause it to collapse and damage the neurovascular unit component of multiple cells, including vascular endothelial cells, astrocytes, microglia, and neurons, leading to HE. Many previous studies on HE have suggested the impairment of neurovascular unit and cell–cell communication in the pathogenesis of HE. This review focuses on pathological factors that appear in HE, cell type-specific pathological mechanisms, miscommunication/incorrect relationships, and therapeutic candidates between brain cells in HE. This review suggests that regulating communications and interactions between cells may be important in overcoming HE.

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引用次数: 0

Understanding the physiological mechanisms and therapeutic targets of diseases: Lipidomics strategies

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-21 DOI: 10.1016/j.lfs.2025.123411

Qiang Yang , Ying Cai , Zhibo Wang , Sifan Guo , Shi Qiu , Aihua Zhang

As a pivotal branch of metabolomics, lipidomics studies global changes in lipid metabolism under different physiological and pathological conditions or drug interventions, discovers key lipid markers, and elaborates the associated lipid metabolism network. There are a considerable number of lipids in the host, which act on various functional networks such as metabolism and immune regulation. As an indispensable research method, lipidomics plays a key character in the analysis of lipid composition in organisms, the elaboration of the physiological mechanism of lipids, and the decoding of their character in the occurrence and development of diseases by exploring the character of lipids in the host environmental network. As an essential means of driving lipidomics research, High-throughput and High-resolution mass spectrometry is helpful in exploring disease phenotypic characteristics, diagnosing disease biomarkers, regulating related metabolic pathways, and discovering related active components. In this paper, we discuss the specific role of lipidomics in the analysis of disease diagnosis, prognosis and treatment, which is conducive to the realization of accurate and personalized medicine.

{"title":"Understanding the physiological mechanisms and therapeutic targets of diseases: Lipidomics strategies","authors":"Qiang Yang , Ying Cai , Zhibo Wang , Sifan Guo , Shi Qiu , Aihua Zhang","doi":"10.1016/j.lfs.2025.123411","DOIUrl":"10.1016/j.lfs.2025.123411","url":null,"abstract":"<div><div>As a pivotal branch of metabolomics, lipidomics studies global changes in lipid metabolism under different physiological and pathological conditions or drug interventions, discovers key lipid markers, and elaborates the associated lipid metabolism network. There are a considerable number of lipids in the host, which act on various functional networks such as metabolism and immune regulation. As an indispensable research method, lipidomics plays a key character in the analysis of lipid composition in organisms, the elaboration of the physiological mechanism of lipids, and the decoding of their character in the occurrence and development of diseases by exploring the character of lipids in the host environmental network. As an essential means of driving lipidomics research, High-throughput and High-resolution mass spectrometry is helpful in exploring disease phenotypic characteristics, diagnosing disease biomarkers, regulating related metabolic pathways, and discovering related active components. In this paper, we discuss the specific role of lipidomics in the analysis of disease diagnosis, prognosis and treatment, which is conducive to the realization of accurate and personalized medicine.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"363 ","pages":"Article 123411"},"PeriodicalIF":5.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029137","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

Mucin1 N-domain variant contributes to dry eye syndrome in diabetes by increasing immature mucus secretory granules

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-21 DOI: 10.1016/j.lfs.2025.123412

Wenbei Ma , Chunling Huang , Wanyi Fang , Shanshan Liu , Yingli Li , Yanyan Zhong , Daming Zuo , Xiaohe Lu

Background

Diabetes-associated dry eye syndrome (DMDES) affects 20–54 % of diabetes, leading to ocular irritation and blurry vision. Decreased conjunctival goblet cell mucus secretion is one of the major pathological processes of DMDES. This study aims to investigate the mechanism of mucus granule maturation and secretion disturbance in DMDES.

Methods

Tear samples from diabetic patients with and without dry eye syndrome were analyzed by mass spectrometry to identify proteins associated with ocular mucous layer reduction. The N-terminal domain fragment of Mucin1 (MUC1-ND) was transfected into the mouse conjunctiva to investigate alterations in goblet cell mucus secretion. Protein localization and granule morphology were explored through transmission electron microscopy with colloidal gold labeling and immunohistochemistry. Immunofluorescence, co-immunoprecipitation, and integrative computational modeling of protein interactions were employed to explore protein-protein interactions.

Results

Tear proteomic analysis revealed significantly elevated MUC1-ND levels in tears from DMDES patients, which correlated with reduced goblet cell mucus secretion and tear film instability. Upregulation of MUC1-ND in mice conjunctiva inhibited the maturation of secretory mucus granules, contributing to tear mucous layer reduction. Protein docking and co-immunoprecipitation analysis demonstrated that the binding of MUC1-ND and Syntaxin6 prevents granule fusion and maintains the immature state of secretory granules, which leads to reduced mucus secretion.

Conclusion

In DMDES, MUC1-ND binds with Syntaxin6 to disrupt the fusion and maturation of secretory mucus granules in conjunctival goblet cells, which provides a new insight into DMDES pathophysiology.

{"title":"Mucin1 N-domain variant contributes to dry eye syndrome in diabetes by increasing immature mucus secretory granules","authors":"Wenbei Ma , Chunling Huang , Wanyi Fang , Shanshan Liu , Yingli Li , Yanyan Zhong , Daming Zuo , Xiaohe Lu","doi":"10.1016/j.lfs.2025.123412","DOIUrl":"10.1016/j.lfs.2025.123412","url":null,"abstract":"<div><h3>Background</h3><div>Diabetes-associated dry eye syndrome (DMDES) affects 20–54 % of diabetes, leading to ocular irritation and blurry vision. Decreased conjunctival goblet cell mucus secretion is one of the major pathological processes of DMDES. This study aims to investigate the mechanism of mucus granule maturation and secretion disturbance in DMDES.</div></div><div><h3>Methods</h3><div>Tear samples from diabetic patients with and without dry eye syndrome were analyzed by mass spectrometry to identify proteins associated with ocular mucous layer reduction. The N-terminal domain fragment of Mucin1 (MUC1-ND) was transfected into the mouse conjunctiva to investigate alterations in goblet cell mucus secretion. Protein localization and granule morphology were explored through transmission electron microscopy with colloidal gold labeling and immunohistochemistry. Immunofluorescence, co-immunoprecipitation, and integrative computational modeling of protein interactions were employed to explore protein-protein interactions.</div></div><div><h3>Results</h3><div>Tear proteomic analysis revealed significantly elevated MUC1-ND levels in tears from DMDES patients, which correlated with reduced goblet cell mucus secretion and tear film instability. Upregulation of MUC1-ND in mice conjunctiva inhibited the maturation of secretory mucus granules, contributing to tear mucous layer reduction. Protein docking and co-immunoprecipitation analysis demonstrated that the binding of MUC1-ND and Syntaxin6 prevents granule fusion and maintains the immature state of secretory granules, which leads to reduced mucus secretion.</div></div><div><h3>Conclusion</h3><div>In DMDES, MUC1-ND binds with Syntaxin6 to disrupt the fusion and maturation of secretory mucus granules in conjunctival goblet cells, which provides a new insight into DMDES pathophysiology.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"363 ","pages":"Article 123412"},"PeriodicalIF":5.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029136","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

Afobazole alleviates streptozotocin-induced diabetic nephropathy in rats via hypoglycemic, antioxidant, anti-inflammatory, and anti-apoptotic properties: Role of the S1R/Nrf2 antioxidant axis

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-20 DOI: 10.1016/j.lfs.2025.123410

Alaa S. Wahba , Dalia M. Asal , Noha M. Mesbah , Dina M. Abo-Elmatty , Reem M. Hazem , Asmaa R. Abdel-Hamed

Aims

Sigma-1 receptor (S1R) activation was recently identified as a promising target for preventing diabetic nephropathy (DN) by mitigating hypoxia, oxidative stress, and inflammation. This study aimed to investigate the potential reno-protective effect of the S1R agonist afobazole against streptozotocin (STZ)-induced DN in rats compared to metformin.

Materials and methods

Rats were split into six groups: the normal control group; the diabetic control group received STZ (55 mg/kg i.p.); the other four groups received STZ and were treated with different doses of either afobazole (10, 15, and 20 mg/kg) or metformin (200 mg/kg). Metabolic parameters and renal function were assessed. Expression levels of oxidative stress markers and inflammatory cytokines were measured using ELISA, apoptosis-related proteins were evaluated using immunohistochemistry, and gene expression of S1R, Nrf2, NF-κB, and TLR-4 was determined. Histopathological analysis was performed on kidney tissues.

Key findings

Both afobazole and metformin exerted hypoglycemic effects, alleviating renal injury, reducing blood urea nitrogen (BUN) and serum creatinine, and restoring oxidant/antioxidant balance in diabetic rats. Both treatments boosted renal S1R and Nrf2 levels, suppressed inflammatory proteins and cytokines, and reduced apoptotic features.

Significance

The study revealed that afobazole provided nephroprotection in STZ-induced DN through a hypoglycemic, antioxidant, anti-inflammatory, and anti-apoptotic potential mediated by activating the S1R/Nrf2 antioxidant axis. The 15 mg/kg dose elicited the most pronounced nephroprotective effects, outperforming other treatment groups.

{"title":"Afobazole alleviates streptozotocin-induced diabetic nephropathy in rats via hypoglycemic, antioxidant, anti-inflammatory, and anti-apoptotic properties: Role of the S1R/Nrf2 antioxidant axis","authors":"Alaa S. Wahba , Dalia M. Asal , Noha M. Mesbah , Dina M. Abo-Elmatty , Reem M. Hazem , Asmaa R. Abdel-Hamed","doi":"10.1016/j.lfs.2025.123410","DOIUrl":"10.1016/j.lfs.2025.123410","url":null,"abstract":"<div><h3>Aims</h3><div>Sigma-1 receptor (S1R) activation was recently identified as a promising target for preventing diabetic nephropathy (DN) by mitigating hypoxia, oxidative stress, and inflammation. This study aimed to investigate the potential reno-protective effect of the S1R agonist afobazole against streptozotocin (STZ)-induced DN in rats compared to metformin.</div></div><div><h3>Materials and methods</h3><div>Rats were split into six groups: the normal control group; the diabetic control group received STZ (55 mg/kg i.p.); the other four groups received STZ and were treated with different doses of either afobazole (10, 15, and 20 mg/kg) or metformin (200 mg/kg). Metabolic parameters and renal function were assessed. Expression levels of oxidative stress markers and inflammatory cytokines were measured using ELISA, apoptosis-related proteins were evaluated using immunohistochemistry, and gene expression of S1R, Nrf2, NF-κB, and TLR-4 was determined. Histopathological analysis was performed on kidney tissues.</div></div><div><h3>Key findings</h3><div>Both afobazole and metformin exerted hypoglycemic effects, alleviating renal injury, reducing blood urea nitrogen (BUN) and serum creatinine, and restoring oxidant/antioxidant balance in diabetic rats. Both treatments boosted renal S1R and Nrf2 levels, suppressed inflammatory proteins and cytokines, and reduced apoptotic features.</div></div><div><h3>Significance</h3><div>The study revealed that afobazole provided nephroprotection in STZ-induced DN through a hypoglycemic, antioxidant, anti-inflammatory, and anti-apoptotic potential mediated by activating the S1R/Nrf2 antioxidant axis. The 15 mg/kg dose elicited the most pronounced nephroprotective effects, outperforming other treatment groups.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"363 ","pages":"Article 123410"},"PeriodicalIF":5.2,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024070","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 CC motif chemokine ligand 11 contributes to alcoholic liver disease

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-20 DOI: 10.1016/j.lfs.2025.123409

Jichen Li , Ben Wang , Shunjie Wang , Jieguo Wang , Anqi Zhou , Shanwen Gong , Yu Wang , Xiulian Miao , Yan Guo , Hao Wang , Hailong Ge

Aims

Alcoholic liver disease (ALD) is characterized by aberrant lipid metabolism and chronic inflammation that eventually give rise to cirrhosis and hepatocellular carcinoma. In the present study we investigated the contribution of CC motif chemokine ligand 11 (CCL11) to ALD pathogenesis.

Methods and materials

ALD was induced in mice by binge ethanol gavage or chronic ethanol feeding.

Key findings

Bioinformatic analysis of sequencing data indicated that CCL11 expression was up-regulated in hepatocytes from mice subjected to ethanol feeding compared to those from the control mice. Exposure to ethanol led to CCL11 up-regulation in primary murine hepatocytes in vitro. Consistently, Oil Red O (ORO) staining detected elevated lipid accumulation whereas quantitative PCR (qPCR) detected augmented expression of pro-inflammatory mediators in primary murine hepatocytes treated with recombinant CCL11. On the contrary, CCL11 knockout mice (KO) developed a less severe form of ALD compared to wild type littermates when subjected to either binge or chronic ethanol feeding. Finally, CCL11 antagonism by administration with an inhibitor to CCL11 receptor CCR3 (CCR3i) attenuated ALD in mice.

Significance

Our data support a role for CCL11 in ALD pathogenesis and provide proof-of-concept that targeting CCL11 can be considered as a therapeutic approach for ALD intervention.

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引用次数: 0

Characterizing the diabetes-induced pathological changes of the mouse lung by single-cell RNA sequencing 单细胞RNA测序表征糖尿病引起的小鼠肺病理变化。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-01-18 DOI: 10.1016/j.lfs.2025.123408

Ying-Ming Tsai , Yi Hsuan Lee , Chao-Yuan Chang , Hung-Pei Tsai , Yu-Yuan Wu , Hsiao-Chen Lee , Ling-Yu Wu , Chai-Tung Ong , Chien-Hui Sun , Ming-Ju Tsai , Ya-Ling Hsu

Pulmonary disorders are exacerbated by high blood sugar, leading to a disordered immune defense and increased susceptibility to infection. Type 2 diabetes mellitus (T2D) is characterized by insulin resistance and inadequate insulin production. Mechanisms leading to pulmonary alternation due to T2D are not clear. The advancements in single-cell RNA sequencing aid in characterizing the effects of T2D on lungs and its altered mechanisms. Our results first revealed that in late-stage diabetic mice, the number of immune cells in the lungs significantly increased, with these immune cells predominantly being immature polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). At the early stages of diabetes, alveolar cell type I and type II (AT I & II) exhibited a mesenchymal phenotype and showed reduced expression of several key cytokines essential for maintaining lung immunity, including Cxcl15, Cxcl14, and Il34. Additionally, the antigen-presenting cell function of AT II, resulting from the downregulation of several MHC type II proteins, was markedly diminished in diabetic mice. Moreover, decreased expressions of interferon-related genes Ifnar1 and Ifnar2, along with impaired Sftpd expression, compromised lung immunity impairment in diabetic mice. These pathogenic changes contributed to the increased susceptibility and severity of respiratory syncytial virus and tuberculosis in the lung of diabetes. In addition to alveolar cells, pulmonary capillary endothelial cells also exhibited an immature transition phenotype, with a significant increase in angiogenic capacity. Our findings provided a comprehensive exploration of lung pathology under the influence of diabetes and explained the multiple factors impacting lung immunity in diabetic conditions.

高血糖会加重肺部疾病，导致免疫防御紊乱和对感染的易感性增加。2型糖尿病（T2D）以胰岛素抵抗和胰岛素分泌不足为特征。T2D导致肺交替的机制尚不清楚。单细胞RNA测序的进步有助于表征T2D对肺部的影响及其改变的机制。我们的研究结果首先表明，在晚期糖尿病小鼠中，肺部免疫细胞的数量显著增加，这些免疫细胞主要是未成熟的多形核髓源性抑制细胞（PMN-MDSCs）。在糖尿病的早期阶段，I型和II型肺泡细胞（At I和II）表现出间充质表型，并表现出维持肺免疫所必需的几种关键细胞因子的表达减少，包括Cxcl15、Cxcl14和Il34。此外，由于几种MHC II型蛋白的下调，AT II的抗原呈递细胞功能在糖尿病小鼠中明显减弱。此外，干扰素相关基因Ifnar1和Ifnar2的表达降低，以及sfpd表达受损，会损害糖尿病小鼠的肺免疫功能。这些致病变化导致糖尿病患者肺部呼吸道合胞病毒和肺结核的易感性和严重程度增加。除了肺泡细胞外，肺毛细血管内皮细胞也表现出不成熟的过渡表型，血管生成能力显著增加。我们的研究结果对糖尿病影响下的肺部病理进行了全面的探索，并解释了影响糖尿病患者肺部免疫的多种因素。

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引用次数: 0