Clinical science最新文献_第3页

Sex-mediated effects of transglutaminase 2 inhibition on endothelial function in human resistance arteries from diabetic and non-diabetic patients. 转谷氨酰胺酶2抑制对糖尿病和非糖尿病人抵抗动脉内皮功能的性别介导影响。

IF 6.7 2区医学

Clinical science Pub Date : 2025-01-15 DOI: 10.1042/CS20242001

Khatera Saii, Judit Prat-Duran, Ulf Simonsen, Anders Riegels Knudsen, Jonas Amstrup Funder, Niels Henrik Buus, Estéfano Pinilla

{"title":"Sex-mediated effects of transglutaminase 2 inhibition on endothelial function in human resistance arteries from diabetic and non-diabetic patients.","authors":"Khatera Saii, Judit Prat-Duran, Ulf Simonsen, Anders Riegels Knudsen, Jonas Amstrup Funder, Niels Henrik Buus, Estéfano Pinilla","doi":"10.1042/CS20242001","DOIUrl":"10.1042/CS20242001","url":null,"abstract":"Transglutaminase 2 (TG2) is an enzyme with multiple conformations. In its open conformation, TG2 exhibits transamidase activity linked to fibrosis, arterial remodeling, and endothelial dysfunction, a process enhanced by high glucose in endothelial cells. However, the closed conformation of TG2 contributes to transmembrane signaling and nitric oxide (NO)-dependent vasorelaxation. LDN 27219, a reversible allosteric inhibitor, stabilizes TG2 in its closed conformation. We examined whether pharmacological modulation of TG2 into its closed conformation induces vasorelaxation and enhances endothelium-dependent and independent relaxation in resistance arteries from age-matched diabetic (n = 14) and non-diabetic patients (n = 14) (age 71 (Standard Error of the Mean: ± 2)). Subcutaneous arteries (diameter 133-1013 µm) were isolated from abdominal fat biopsies. TG2 mRNA expression and transamidase activity were assessed via RT-qPCR and 5-biotin(amido)pentylamine (5-BP) incorporation, while vascular reactivity was measured using wire myography. TG2 mRNA was highly expressed without significant differences between the groups and LDN 27219 induced concentration-dependent vasorelaxation in arteries from both groups. Sex-specific analysis revealed that potentiation of acetylcholine-induced vasorelaxation by LDN 27219 was driven by increased TG2 expression in non-diabetic females, whereas no effect was observed in arteries from non-diabetic males. Among diabetic patients, LDN 27219 increased maximal acetylcholine-induced vasorelaxation in males only. LDN 27219 did not affect endothelium-independent relaxation to sodium nitroprusside in either group. In conclusion, TG2 is expressed in human resistance arteries, and LDN 27219 induced vasorelaxation, selectively enhancing ACh relaxation in non-diabetic females, likely owing to increased TG2 expression. This finding underscores the importance of sex differences in TG2 modulation of vasorelaxation.","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"1-14"},"PeriodicalIF":6.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811954","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

Distinct effects of obesity and diabetes on the action potential waveform and inward currents in rat ventricular myocytes. 肥胖和糖尿病对大鼠心室肌细胞动作电位波形和内向电流的不同影响。

IF 6.7 2区医学

Clinical science Pub Date : 2025-01-15 DOI: 10.1042/CS20242144

Anatoliy Shmygol, Gilles Bru-Mercier, Ahmed S Sultan, Frank C Howarth

{"title":"Distinct effects of obesity and diabetes on the action potential waveform and inward currents in rat ventricular myocytes.","authors":"Anatoliy Shmygol, Gilles Bru-Mercier, Ahmed S Sultan, Frank C Howarth","doi":"10.1042/CS20242144","DOIUrl":"10.1042/CS20242144","url":null,"abstract":"Obesity is a significant global health challenge, increasing the risk of developing type 2 diabetes mellitus (T2DM) and cardiovascular disease. Research indicates that obese individuals, regardless of their diabetic status, have an increased risk of cardiovascular complications. Studies suggest that these patients experience impaired electrical conduction in the heart, although the underlying cause-whether due to obesity-induced fat toxicity or diabetes-related factors-remains uncertain. This study investigated ventricular action potential parameters, as well as sodium (INa) and calcium (ICa, L) currents, in Zucker fatty (ZF) rats and Zucker diabetic fatty (ZDF) rats, which serve as models for obesity and T2DM, respectively. Ventricular myocytes were isolated from 25- to 30-week-old Zucker rats. Resting and action potentials were recorded using a β-escin perforated patch clamp, while INa and ICa,L were assessed with whole-cell patch clamp methods. ZF rats exhibited higher excitability and faster upstroke velocity with greater INa density, whereas ZDF rats showed decreased INa and slower action potential upstroke. No differences in ICa,L density or voltage sensitivity were found among the groups. In summary, obesity, with or without accompanying T2DM, distinctly impacts the action potential waveform, INa density, and excitability of ventricular myocytes in this rat model of T2DM.","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"55-67"},"PeriodicalIF":6.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853144","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

Arterial effects of anthracycline: structural and inflammatory assessments in non-human primates and lymphoma patients. 蒽环类药物的动脉效应：非人灵长类动物和淋巴瘤患者的结构和炎症评估。

IF 6.7 2区医学

Clinical science Pub Date : 2025-01-15 DOI: 10.1042/CS20241529

Stephen Rankin, Caitlin Fountain, Alastair J Gemmell, Daire Quinn, Alasdair Henderson, John McClure, Sandy Small, Balaji Venugopal, Pamela McKay, Piotr J Slomka, David Colville, Mark C Petrie, Giselle C Meléndez, Ninian N Lang

{"title":"Arterial effects of anthracycline: structural and inflammatory assessments in non-human primates and lymphoma patients.","authors":"Stephen Rankin, Caitlin Fountain, Alastair J Gemmell, Daire Quinn, Alasdair Henderson, John McClure, Sandy Small, Balaji Venugopal, Pamela McKay, Piotr J Slomka, David Colville, Mark C Petrie, Giselle C Meléndez, Ninian N Lang","doi":"10.1042/CS20241529","DOIUrl":"10.1042/CS20241529","url":null,"abstract":"Anthracyclines, such as doxorubicin, are important anti-cancer therapies but are associated with arterial injury. Histopathological insights have been limited to small animal models, and the role of inflammation in the arterial toxic effects of anthracycline is unclear in humans. Our aims were (1) to evaluate aortic media fibrosis and injury in non-human primates treated with anthracyclines; (2) to assess the effect of anthracycline on aortic inflammation in patients treated for lymphoma. African Green monkeys (AGMs) received doxorubicin (30-60 mg/m2/biweekly intravenously, cumulative dose: 240 mg/m2). Blinded histopathologic analyses of the ascending aorta were performed 15 weeks after the last doxorubicin dose and compared to five age- and gender-matched healthy, untreated AGMs. Analysis of the thoracic aorta of patients with diffuse large B-cell lymphoma (DLBCL), at baseline and after doxorubicin exposure, was performed using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in this observational study by maximal tissue-to-background ratio (TBRmax). In AGMs, doxorubicin exposure was associated with greater aortic fibrosis (collagen deposition: doxorubicin 6.23 ± 0.88% vs. controls 4.67 ± 0.54%; P=0.01) and intracellular vacuolization (doxorubicin 66.3 ± 10.1 vs. controls 11.5 ± 4.2 vacuoles/field, P<0.0001) than untreated controls. In 101 patients with DLBCL, there was no change in aortic TBRmax after anthracycline exposure (TBRmax 1.46 ± 0.16 vs. 1.44 ± 0.14, respectively, P=0.14). Univariate analyses yielded similar results. In a large animal model, anthracycline exposure was associated with aortic fibrosis. In patients with lymphoma, anthracycline exposure was not associated with aortic inflammation. Further research is required to elucidate the mechanisms of anthracycline-related vascular harm.","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"29-41"},"PeriodicalIF":6.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827576","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

SMAD5 as a novel gene for familial pulmonary arterial hypertension. SMAD5作为家族性肺动脉高压的新基因。

IF 6.7 2区医学

Clinical science Pub Date : 2025-01-15 DOI: 10.1042/CS20241340

Ding Cao, Ekkehard Grünig, Yuriy Sirenko, Ganna Radchenko, Henning Gall, Ayat Ahmed, Susanne Theiß, Mareike Lankeit, Benjamin Meder, Magdalena Laugsch, Christina A Eichstaedt

{"title":"SMAD5 as a novel gene for familial pulmonary arterial hypertension.","authors":"Ding Cao, Ekkehard Grünig, Yuriy Sirenko, Ganna Radchenko, Henning Gall, Ayat Ahmed, Susanne Theiß, Mareike Lankeit, Benjamin Meder, Magdalena Laugsch, Christina A Eichstaedt","doi":"10.1042/CS20241340","DOIUrl":"10.1042/CS20241340","url":null,"abstract":"Genetic diagnostic testing of 325 pulmonary arterial hypertension (PAH) patients using a PAH specific gene panel including 18 known PAH genes revealed mutations in 23%. Further PAH candidate genes were sequenced in the remaining patients exposing two SMAD5 variants, which were clinically and functionally characterized. We first recorded familial cosegregation and clinical parameters. Functional tests were performed following transient over-expression of the two SMAD5 variants in pulmonary artery smooth muscle cells (PASMCs). Expression of these variants was confirmed by quantitative PCR, Sanger sequencing, and Western blotting. Cell viability was evaluated using cell counting kit 8, cell proliferation by bromodeoxyuridine (BrdU), and apoptosis by annexin V assay. Both SMAD5 missense variants were absent in healthy controls and predicted to be pathogenic. The variant c.1175T>C p.(Leu392Pro) was identified in a heritable PAH patient and her healthy son. The mother had died of suspected PAH at age 42. The expression of this variant in PASMCs led to significantly higher cell viability due to higher proliferation in comparison with SMAD5 wild-type cells. The second variant c.277T>A p.(Trp93Arg) was identified in a patient with congenital heart disease associated PAH with a surgically repaired ventricular septal defect. Its expression led to significantly lower cell viability due to increased apoptosis in comparison with wild-type SMAD5 cells. Taking into account familial aggregation, clinical findings, and functional evidence, both variants could be classified as likely pathogenic. This is the first description of SMAD5 as a potential novel PAH gene for genetic diagnostic testing.","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"15-27"},"PeriodicalIF":6.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779561","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

RNA-binding protein HuR regulates the transition of septic AKI to CKD by modulating CD147. rna结合蛋白HuR通过调节CD147调控脓毒性AKI向CKD的转变。

IF 6.7 2区医学

Clinical science Pub Date : 2025-01-15 DOI: 10.1042/CS20241756

Simeng Liu, Renfei Luo, Davey Li, Anna Tang, Yuli Qiu, Ryan P Sherrier, Jeffrey Aube, Xiaoqing Wu, Liang Xu, Yufeng Huang

{"title":"RNA-binding protein HuR regulates the transition of septic AKI to CKD by modulating CD147.","authors":"Simeng Liu, Renfei Luo, Davey Li, Anna Tang, Yuli Qiu, Ryan P Sherrier, Jeffrey Aube, Xiaoqing Wu, Liang Xu, Yufeng Huang","doi":"10.1042/CS20241756","DOIUrl":"10.1042/CS20241756","url":null,"abstract":"Septic acute kidney injury (AKI) is an important risk factor for developing chronic kidney disease (CKD). Hu antigen R (HuR) is recognized as a crucial modulator in inflammation. We hypothesized that elevated HuR contributes to the transition from septic AKI to CKD by promoting persistent inflammation and fibrosis, and inhibition of HuR may reverse septic kidney injury. Mice subjected to lipopolysaccharide (LPS) injections every other day were concurrently treated without or with either KH39 or niclosamide (NCS) for 7 days. Control mice received saline injections. Repeated LPS injections led to a significant increase in HuR expression in the kidneys, which was effectively suppressed by KH39 or NCS treatment. LPS-induced kidney injury was characterized by elevated plasma blood urea nitrogen levels and urinary albuminuria, along with histological signs of inflammatory cell infiltration and fibrosis, as determined by periodic acid-Schiff and Masson's trichrome staining, and immunofluorescent staining for markers such as α-smooth muscle actin, fibronectin, collagen III, and F4/80. Treatment with either KH39 or NCS mitigated these changes observed in LPS-injured kidneys. Additionally, increased expression of CD147, a molecule implicated in inflammatory cell recruitment and tubular injury, was inhibited by KH39 or NCS treatment. These effects on HuR and CD147 expression were further validated in vitro in cultured macrophages and tubular cells. This study suggests that HuR elevation in LPS-stimulated macrophages and kidney cells contributes to the progression of septic kidney injury, possibly through HuR-CD147 interactions, underscoring the therapeutic potential of HuR inhibitors for this condition.","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"69-84"},"PeriodicalIF":6.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Higher circulating ACE2 and DPP3 but reduced ACE and angiotensinogen in hyperreninemic sepsis patients. 高肾素血症脓毒症患者循环ACE2和DPP3升高但ACE和血管紧张素原降低。

IF 6.7 2区医学

Clinical science Pub Date : 2025-01-15 DOI: 10.1042/CS20242168

Mark C Chappell, Christopher L Schaich, Laurence W Busse, D Clark Files, Greg S Martin, Jonathan E Sevransky, Jeremiah S Hinson, Richard E Rothman, Ashish K Khanna

{"title":"Higher circulating ACE2 and DPP3 but reduced ACE and angiotensinogen in hyperreninemic sepsis patients.","authors":"Mark C Chappell, Christopher L Schaich, Laurence W Busse, D Clark Files, Greg S Martin, Jonathan E Sevransky, Jeremiah S Hinson, Richard E Rothman, Ashish K Khanna","doi":"10.1042/CS20242168","DOIUrl":"10.1042/CS20242168","url":null,"abstract":"Sepsis and septic shock are global healthcare problems associated with high mortality rates. Activation of the renin-angiotensin-aldosterone system (RAAS) is an early event in sepsis, and elevated renin may be predictive of worse outcomes. In a subset of sepsis patients enrolled in the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial, elevated levels of active renin (median value > 189 pg/mL or 5.1 pM) at baseline (day 0) were strongly associated with mortality; however, corresponding plasma levels of the vasopressor hormone Angiotensin II were not substantially increased nor was Angiotensin II associated with disease severity. The current study assessed RAAS components that may impact the Angiotensin II response in control subjects, normal renin sepsis (NRS, renin < 5.1 pM) and high renin sepsis (HRS, renin > 5.1 pM) patients. NRS and HRS subjects exhibited a similar reduction in ACE (40%), but increased levels of ACE2 and DPP3. The ACE to DPP3 ratio was higher in controls but this relationship was reversed in both NRS and HRS subjects. Intact angiotensinogen was 50% lower in the HRS than control or NRS subjects, whereas the intact angiotensinogen to renin ratio was <10% of control or NRS subjects. We conclude that altered expression of ACE, ACE2, DPP3 and angiotensinogen may attenuate the expected increase in Angiotensin II, particularly in sepsis subjects with high renin concentrations.","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"43-53"},"PeriodicalIF":6.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863568","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

Insight into the roles of lactylation in macrophages: functions and clinical implications.

IF 6.7 2区医学

Clinical science Pub Date : 2025-01-13 DOI: 10.1042/CS20242737

Min Shu, Dingci Lu, Ziyi Zhu, Fei Yang, Zhaowu Ma

{"title":"Insight into the roles of lactylation in macrophages: functions and clinical implications.","authors":"Min Shu, Dingci Lu, Ziyi Zhu, Fei Yang, Zhaowu Ma","doi":"10.1042/CS20242737","DOIUrl":"https://doi.org/10.1042/CS20242737","url":null,"abstract":"Lactylation, a post-translational modification, has been linked to gene transcription regulation through epigenetic modulation in various pathophysiological processes. The lactylation regulatory proteins, known as writers, erasers, and readers, govern their dynamics by adding, removing, and recognizing lactyl groups on proteins. Macrophages, as cells of the immune system, maintain homeostasis, responding dynamically to diverse internal and external stimuli. Emerging researches unveil that lactylation, through inducing macrophage activation and polarization, affects their functionality in pathological conditions such as inflammation, tumor microenvironment, and fibrosis. Evidence progressively indicates that lactate-driven alterations in lactylation levels within macrophages can influence the pathogenesis of numerous diseases. This review aims to systematically summarize the research progress of lactylation in macrophages, explore its functions and mechanisms by which lactylation contributes to the pathology of different disease phenotypes, and propose future research directions along with potential diagnostic and therapeutic strategies.","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 2","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058260","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

Muscle mass, muscle strength and the renin-angiotensin system. 肌肉质量，肌肉力量和肾素-血管紧张素系统。

IF 6.7 2区医学

Clinical science Pub Date : 2024-12-24 DOI: 10.1042/CS20220501

Hikari Takeshita, Koichi Yamamoto, Masaki Mogi, Hiromi Rakugi

{"title":"Muscle mass, muscle strength and the renin-angiotensin system.","authors":"Hikari Takeshita, Koichi Yamamoto, Masaki Mogi, Hiromi Rakugi","doi":"10.1042/CS20220501","DOIUrl":"https://doi.org/10.1042/CS20220501","url":null,"abstract":"The renin-angiotensin system (RAS) is a classically known circulatory regulatory system. In addition to the previously known multi-organ circulatory form of the RAS, the existence of tissue RASs in individual organs has been well established. Skeletal muscle has also been identified as an organ with a distinct RAS. In recent years, the effects of RAS activation on skeletal muscle have been elucidated from several perspectives: differences in motor function due to genetic polymorphisms of RAS components, skeletal muscle dysfunction under conditions of excessive RAS activation such as heart failure, and the effects of the use of RAS inhibitors on muscle strength. In addition, the concept of the RAS itself has recently been expanded with the discovery of a 'protective arm' of the RAS formed by factors such as angiotensin-converting enzyme 2 and angiotensin 1-7. This has led to a new understanding of the physiological function of the RAS in skeletal muscle. This review summarizes the diverse physiological functions of the RAS in skeletal muscle and considers the potential of future therapeutic strategies targeting the RAS to overcome problems such as sarcopenia and muscle weakness associated with chronic disease.","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"138 24","pages":"1561-1577"},"PeriodicalIF":6.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881430","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

Serpina3c Deficiency Promotes Obesity-related Hypertriglyceridemia and Inflammation through Activation of the Hif1α-glycolysis Axis in Adipose Tissue. Serpina3c缺乏通过激活脂肪组织中hif1 α-糖酵解轴促进肥胖相关的高甘油三酯血症和炎症

IF 6.7 2区医学

Clinical science Pub Date : 2024-12-18 DOI: 10.1042/CS20242610

Jiaqi Guo, Zhenjun Ji, Yu Jiang, Ya Wu, Shaofan Wang, Peng Zheng, Mengchen Yang, Yongjun Li, Genshan Ma, Yuyu Yao

{"title":"Serpina3c Deficiency Promotes Obesity-related Hypertriglyceridemia and Inflammation through Activation of the Hif1α-glycolysis Axis in Adipose Tissue.","authors":"Jiaqi Guo, Zhenjun Ji, Yu Jiang, Ya Wu, Shaofan Wang, Peng Zheng, Mengchen Yang, Yongjun Li, Genshan Ma, Yuyu Yao","doi":"10.1042/CS20242610","DOIUrl":"https://doi.org/10.1042/CS20242610","url":null,"abstract":"Adipose tissue dysfunction leads to abnormal lipid metabolism and high inflammation levels. This research aims to explore the role of Serpina3c, which is highly expressed in adipocytes, in obesity-related hypertriglyceridemia and metaflammation. Serpina3c global knockout (KO) mice, adipocyte-specific Serpina3c overexpressing mice, Serpina3c knockdown (KD) mice, and hypoxia-inducible factor 1 alpha (Hif1α) KD mice were fed a high-fat diet (HFD) for 16 weeks to generate obesity-related hypertriglyceridemia mice models. In the present study, Serpina3c KO mice and adipocyte-specific Serpina3c KD mice exhibited more severe obesity-related hypertriglyceridemia and metaflammation under HFD conditions. Serpina3c KO epididymal white adipose tissue (eWAT) primary stromal vascular fraction (SVF)-derived adipocytes exhibited higher lipid (triglyceride and non-esterified fatty acid) levels and higher fatty acid synthase expression after palmitic acid stimulation. Adipocyte-specific Serpina3c overexpression in KO mice prevented the KO group phenotype. The RNA-seq and in vitro validation revealed that Hif1α and the glycolysis pathways were upregulated in Serpina3c KD adipocytes, which were all validated by in vitro and in vivo reverse experiments. Co-immunoprecipitation (co-IP) provided evidence that Serpina3c bound nuclear factor erythroid 2-related factor 2 (Nrf2) to regulate Hif1α. Nrf2 KD reduced Hif1α and Fasn expression, decreased lipid content, and reduced the extracellular acidification rate in Serpina3c KO adipocytes. Metabolomics revealed that lactic acid (LD) levels in eWAT were responsible for adipose-associated macrophage inflammation. In summary, Serpina3c inhibits the Hif1α-glycolysis pathway and reduces de novo lipogenesis and LD secretion in adipocytes by binding to Nrf2, thereby improving HFD-induced lipid metabolism disorders and alleviating adipose tissue macrophage inflammation.","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853148","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

Protective effect of mesenchymal stromal cells in diabetic nephropathy: the In vitro and In vivo role of the M-Sec-tunneling nanotubes. 间充质基质细胞对糖尿病肾病的保护作用：M-Sec-隧道纳米管在体外和体内的作用

IF 6.7 2区医学

Clinical science Pub Date : 2024-12-04 DOI: 10.1042/CS20242064

Federica Barutta, Beatrice Corbetta, Stefania Bellini, Roberto Gambino, Stefania Bruno, Shunsuke Kimura, Koji Hase, Hiroshi Ohno, Gabriella Gruden

{"title":"Protective effect of mesenchymal stromal cells in diabetic nephropathy: the In vitro and In vivo role of the M-Sec-tunneling nanotubes.","authors":"Federica Barutta, Beatrice Corbetta, Stefania Bellini, Roberto Gambino, Stefania Bruno, Shunsuke Kimura, Koji Hase, Hiroshi Ohno, Gabriella Gruden","doi":"10.1042/CS20242064","DOIUrl":"10.1042/CS20242064","url":null,"abstract":"Mitochondrial dysfunction plays an important role in the development of podocyte injury in diabetic nephropathy (DN). Tunnelling nanotubes (TNTs) are long channels that connect cells and allow organelle exchange. Mesenchymal stromal cells (MSCs) can transfer mitochondria to other cells through the M-Sec-TNTs system. However, it remains unexplored whether MSCs can form heterotypic TNTs with podocytes, thereby enabling the replacement of diabetes-damaged mitochondria. In this study, we analysed TNT formation, mitochondrial transfer, and markers of cell injury in podocytes that were pre-exposed to diabetes-related insults and then co-cultured with diabetic or non-diabetic MSCs. Furthermore, to assess the in vivo relevance, we treated DN mice with exogenous MSCs, either expressing or lacking M-Sec, carrying fluorescent-tagged mitochondria. MSCs formed heterotypic TNTs with podocytes, allowing mitochondrial transfer, via a M-Sec-dependent mechanism. This ameliorated mitochondrial function, nephrin expression, and reduced apoptosis in recipient podocytes. However, MSCs isolated from diabetic mice failed to confer cytoprotection due to Miro-1 down-regulation. In experimental DN, treatment with exogenous MSCs significantly improved DN, but no benefit was observed in mice treated with MSCs lacking M-Sec. Mitochondrial transfer from exogenous MSCs to podocytes occurred in vivo in a M-Sec-dependent manner. These findings demonstrate that the M-Sec-TNT-mediated transfer of mitochondria from healthy MSCs to diabetes-injured podocytes can ameliorate podocyte damage. Moreover, M-Sec expression in exogenous MSCs is essential for providing renoprotection in vivo in experimental DN.","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"1537-1559"},"PeriodicalIF":6.7,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0