Clinical science最新文献

{"title":"Blockade of neddylation through targeted inhibition of DCN1 alleviates renal fibrosis.","authors":"Jin-Ling Huo, Wenjia Fu, Qi Feng, Shaokang Pan, Dongwei Liu, Zhangsuo Liu","doi":"10.1042/CS20243221","DOIUrl":"10.1042/CS20243221","url":null,"abstract":"<p><p>Neddylation is a process of attaching neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) to substrates for the protein function modulation via enzymatic cascades involving NEDD8-activating enzyme (E1), NEDD8-conjugating enzyme (E2), and NEDD8 ligase (E3). Defective in cullin neddylation 1 (DCN1) serves as a co-E3 ligase, which can simultaneously bind E2 UBE2M and cullin proteins to stabilize the catalytic center of the Cullin-Ring E3 ligase complex, thereby promoting cullin neddylation. Neddylation is reported to be activated in diverse human diseases, and inhibition of protein neddylation has been regarded as a promising anticancer therapy. However, whether neddylation participates in renal fibrosis and whether blockade of neddylation through targeted inhibition of DCN1 play effects on renal fibrosis remains unknown. In the present study, an NEDD8 overexpressed plasmid, DCN1 small interfering RNAs, DCN1-specific inhibitor NAcM-OPT, human renal tubular epithelial cells (HK-2), rat kidney fibroblasts (NRK-49F), RNA sequencing, unilateral ureteral obstruction (UUO), and unilateral ischemia-reperfusion injury (UIRI) mouse renal fibrosis models were used. Herein, we first showed that neddylation was activated in renal fibrosis. Neddylation blockade through DCN1 deficiency alleviated TGFβ1-induced up-regulation of fibronectin and α-SMA in HK-2 and NRK-49F cells. Importantly, DCN1 inhibition attenuated UUO- and UIRI-induced mouse renal fibrosis. Further studies revealed that DCN1 loss selectively inhibited cullin3 neddylation and induced its substrate NRF2 accumulation, thereby inhibiting TGFβ-Smad2/3 signaling pathway. Overall, blockade of neddylation through targeted inhibition of DCN1 contributes to alleviating renal fibrosis in vitro and in vivo, which may constitute a novel therapeutic strategy for renal fibrosis.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045735","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}

{"title":"Restoring lung renin-angiotensin system balance through blood pressure control.","authors":"Gabriela Catão D Braga, Joao Carlos Ribeiro-Silva, Andreia Boaro, Flavia Leticia Martins, Thais Mauad, Caio A M Tavares, Lisete Ribeiro Teixeira, Bruno Caramelli, Adriana C C Girardi","doi":"10.1042/CS20241155","DOIUrl":"https://doi.org/10.1042/CS20241155","url":null,"abstract":"<p><p>Dysregulated renin-angiotensin system (RAS) signaling contributes to elevated blood pressure (BP), inflammation, and organ damage in systemic arterial hypertension (HTN). We have demonstrated that hypertensive humans and rats exhibit higher expression of classic RAS components and lower expression of counterregulatory RAS components in the lungs compared with normotensive counterparts. Here, we investigated whether BP control could restore the balance between classic [angiotensin I-converting enzyme 2 (ACE)/angiotensin II (Ang II)] and counterregulatory [angiotensin I-converting enzyme 2 (ACE2)/Ang (1-7)] RAS, thereby mitigating lung inflammation. Male spontaneously hypertensive rats (SHRs) were treated with either losartan or amlodipine, both of which effectively reduced BP. These interventions up-regulated lung Ace2 and down-regulated Ace gene expression. Pulmonary membrane ACE2 abundance and activity were higher in losartan- and amlodipine-treated SHRs than in vehicle-treated SHRs, whereas ACE protein and function remained unchanged. Drug-treated SHRs exhibited lower levels of lung Ang II and higher levels of Ang (1-7) than vehicle-treated SHRs. Rebalancing the pulmonary RAS remarkably reduced macrophage number and down-regulated pro-inflammatory genes in SHR lungs, with lower expression of lung pro-inflammatory genes correlating with lower circulating levels of ACE2. Serum analysis in healthy and hypertensive individuals supported these findings, showing higher ACE2 levels in uncontrolled compared with controlled hypertension and normotension. Collectively, these findings suggest that high blood pressure may induce lung inflammation via an ACE/ACE2 imbalance. BP control with either an RAS inhibitor or a calcium channel blocker rebalances RAS in SHR lungs and alleviates inflammation. Furthermore, this study provides a mechanistic link between inflammatory lung diseases (such as COVID-19) and hypertension as a major risk factor.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 3","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188549","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}

{"title":"PDCD10/CCM3, a potential target for pancreatic ductal adenocarcinoma?","authors":"Hendrik Ungefroren","doi":"10.1042/CS20241916","DOIUrl":"https://doi.org/10.1042/CS20241916","url":null,"abstract":"<p><p>Malignant progression of pancreatic ductal adenocarcinoma (PDAC) is driven by transforming growth factor (TGF)-β1 through extensive cross-talk with other signalling pathways. Prompted by the observation that the ubiquitous protein programmed cell death 10 (PDCD10) is more abundantly expressed in PDAC tumour tissue compared with normal pancreas and highly correlated with reduced patient survival, authors examined its function as a modulator of TGF-β signalling in PDAC. Cytotoxicity assays with PDAC-derived tumour cell lines, PaTu8902 (DPC4+/+) and PaTu8988t (DPC4-/-) engineered to homozygously lack PDCD10 showed that PDCD10 renders cells more chemoresistant to anticancer drugs. Moreover, PDCD10 promoted TGF-β1-dependent proliferation by inactivating the retinoblastoma 1 protein (pRb) via a SMAD4-dependent pathway, and TGF-β1-driven EMT by increasing ERK1/2 activation via a non-SMAD4 pathway. Phosphorylation of pRB and ERK by PDCD10 is facilitated by binding of PDCD10 to MST4. Targeting PDCD10 in PDAC patients may represent a promising new strategy to improve TGF-β targeted therapies.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 3","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381808","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}

{"title":"Therapeutic strategies to ameliorate mitochondrial oxidative stress in ischaemia-reperfusion injury: A narrative review.","authors":"Khalid Alotaibi, Nishkantha Arulkumaran, Alex Dyson, Mervyn Singer","doi":"10.1042/CS20242074","DOIUrl":"10.1042/CS20242074","url":null,"abstract":"<p><p>Mitochondrial reactive oxygen species (mROS) play a crucial physiological role in intracellular signalling. However, high levels of ROS can overwhelm antioxidant defences and lead to detrimental modifications in protein, lipid and DNA structure and function. Ischaemia-reperfusion injury is a multifaceted pathological state characterised by excessive production of mROS. There is a significant clinical need for therapies mitigating mitochondrial oxidative stress. To date, a variety of strategies have been investigated, ranging from enhancing antioxidant reserve capacity to metabolism reduction. While success has been achieved in non-clinical models, no intervention has yet successfully transitioned into routine clinical practice. In this article, we explore the different strategies investigated and discuss the possible reasons for the lack of translation.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 3","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078791","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}

{"title":"Metabolically stable apelin analogs: development and functional role in water balance and cardiovascular function.","authors":"Pierre Couvineau, Catherine Llorens-Cortes","doi":"10.1042/CS20240955","DOIUrl":"https://doi.org/10.1042/CS20240955","url":null,"abstract":"<p><p>Apelin, a (neuro) vasoactive peptide, plays a prominent role in controlling water balance and cardiovascular functions. Apelin and its receptor co-localize with vasopressin in magnocellular vasopressinergic neurons. Apelin receptors (Apelin-Rs) are also expressed in the collecting ducts of the kidney, where vasopressin type 2 receptors are also present. Apelin and vasopressin interact at the brain and renal levels to maintain body fluid homeostasis by regulating diuresis in opposite directions. Apelin and angiotensin II have opposite effects on the regulation of blood pressure (BP). Angiotensin II, by binding to AT1 receptors present in VSMCs, induces intracellular calcium mobilization and vasoconstriction, while apelin, by binding to Apelin-R present on vascular endothelium, increases nitric oxide production and induces vasodilation. Apelin also plays a crucial role in the regulation of cardiac function. Apelin-deficient and Apelin-R-deficient mice develop progressive myocardial dysfunction with ageing and are susceptible to heart failure in response to pressure overload. Since the half-life of apelin is very short in vivo (in the minute range), several metabolically stable apelin analogs and non-peptidic Apelin-R agonists have been developed, with potential applications in diverse diseases. In this review, we highlight the interaction between apelin and vasopressin in the regulation of water balance and that between apelin and angiotensin II in the regulation of BP. Additionally, we underline the protective effects of apelin in cardiac function. Lastly, we discuss the beneficial effects of Apelin-R activation in different pathological states such as hyponatremia, hypertension, and heart failure.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 2","pages":"131-149"},"PeriodicalIF":6.7,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058271","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}

{"title":"Retraction: Down-regulation of lncRNA XIST inhibits cell proliferation via regulating miR-744/RING1 axis in non-small cell lung cancer.","authors":"","doi":"10.1042/CS20190519_RET","DOIUrl":"https://doi.org/10.1042/CS20190519_RET","url":null,"abstract":"","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 2","pages":"213"},"PeriodicalIF":6.7,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058291","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}

{"title":"A new mechanism of arterial calcification in diabetes: interaction between H3K18 lactylation and CHI3L1.","authors":"Yi Zhu, Jing-Cheng Chen, Jia-Li Zhang, Fang-Fang Wang, Rui-Ping Liu","doi":"10.1042/CS20243122","DOIUrl":"10.1042/CS20243122","url":null,"abstract":"<p><p>Metabolic changes are an important characteristic of vascular complications in diabetes. The accumulation of lactate in the microenvironment can promote vascular smooth muscle cell (VSMC) calcification in diabetes, although the specific mechanism remains to be fully elucidated. In this study, we explored the characteristics of lactylation in diabetic arterial calcification and the underlying molecular mechanism. We found that in high-glucose calcified VSMC, the overall lactylation level was significantly increased. Mass spectrometry analysis revealed a significant up-regulation of H3 histone lactylation. After site-specific point-mutation at K18 to simulate the delactylation modification, VSMC calcification was significantly reduced. Through a combination of H3K18la ChIP-seq, RNA-seq, H3K18la ChIP-qPCR, and point-mutation experiments, we confirmed that H3K18la can up-regulate CHI3L1. CHI3L1 knockout significantly alleviated VSMC osteogenic phenotype transformation and mouse arterial calcification. RNA-seq analysis of the downstream molecular signaling showed that CHI3L1 activates the IL-13-IL-13Ra2-JAK1-STAT3 pathway. Targeted inhibition of IL-13Ra2 reduced VSMC calcification. We conclude that in a diabetic calcification environment, the H3 histone K18 site undergoes lactylation modification in VSMCs, upregulating CHI3L1, which, in turn, regulates the IL-13-IL-13Ra2-JAK1-STAT3 signaling pathway, ultimately exacerbating arterial calcification. Our study elucidates the epigenetic mechanism by which lactate promotes arterial calcification in diabetes.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"115-130"},"PeriodicalIF":6.7,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001441","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}

{"title":"Early detection and progression of insulin resistance revealed by impaired organismal anti-inflammatory heat shock response during ex vivo whole-blood heat challenge.","authors":"Helena Trevisan Schroeder, Carlos Henrique de Lemos Muller, Maria Inês Lavina Rodrigues, Marcela Alves de Azevedo, Thiago Gomes Heck, Mauricio Krause, Paulo Ivo Homem de Bittencourt","doi":"10.1042/CS20243515","DOIUrl":"10.1042/CS20243515","url":null,"abstract":"<p><p>Chronic inflammatory diseases, e.g., obesity, cardiovascular disease and type-2 diabetes, progressively suppress the anti-inflammatory heat shock response (HSR) by impairing the synthesis of key components, perpetuating inflammation. Monitoring HSR progression offers predictive value for countering chronic inflammation. This study quantified HSR in high-fat diet (HFD) and normal chow (NC) mice by measuring 70 kDa heat shock protein (HSP70) expression after heat treatment of whole blood samples. To align with human translational relevance, animals were housed within their thermoneutral zone (TNZ). Whole blood was heat-challenged weekly at 42 °C for 1-2 hours over 22 weeks, and ΔHSP70 was calculated as the difference between HSP70 expressions at 42 °C and 37 °C. Results correlated with fasting glycaemia, oral glucose tolerance test, intraperitoneal insulin tolerance test and 2-hour post-glucose load glycaemia. ΔHSP70 levels >0.2250 indicated normal fasting glycaemia, while levels <0.2125 signalled insulin resistance and type-2 diabetes onset. A logistic model (five-parameter logistic) showed progressive HSR decline, with HFD mice exhibiting earlier ΔHSP70 reduction (t1/2 = 3.14 weeks) compared with NC mice (t1/2 = 8.24 weeks), highlighting compromised anti-inflammatory capacity in both groups of mice maintained at TNZ. Remarkably, even NC mice surpassed insulin resistance thresholds by week 22, relevant as control diets confronted interventions. Observed HSR decline mirrors tissue-level suppression in obese and type-2 diabetic individuals, underscoring HSR failure as a hallmark of obesity-driven inflammation. This study introduces a practical whole-blood assay to evaluate HSR suppression, allowing assessment of glycaemic status during obesity onset before any clinical manifestation.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"85-113"},"PeriodicalIF":6.7,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880969","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}

{"title":"Aging and sex differences in salt sensitivity of blood pressure.","authors":"Mert Demirci, Jeremiah M Afolabi, Annet Kirabo","doi":"10.1042/CS20240788","DOIUrl":"https://doi.org/10.1042/CS20240788","url":null,"abstract":"<p><p>Salt sensitivity of blood pressure (SSBP) is a complex physiological trait characterized by changes in blood pressure in response to dietary salt intake. Aging introduces an additional layer of complexity to the pathophysiology of SSBP, with mitochondrial dysfunction, epigenetic modifications, and alterations in gut microbiota emerging as critical factors. Despite advancements in understanding these mechanisms, the processes driving increased salt sensitivity with age and their differential impacts across sexes remain unclear. This review explores the current understanding of salt sensitivity, delving into its underlying mechanisms, the role of inflammation, and the influence of aging and sex differences on these processes. We also aim to provide insights into the multifaceted nature of salt sensitivity and its implications for personalized treatment strategies in hypertension management.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 2","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051954","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}

{"title":"Heme oxygenase, biliverdin reductase, and bilirubin pathways regulate oxidative stress and insulin resistance: a focus on diabetes and therapeutics.","authors":"Wang-Hsin Lee, Zachary A Kipp, Sally N Pauss, Genesee J Martinez, Evelyn A Bates, Olufunto O Badmus, David E Stec, Terry D Hinds","doi":"10.1042/CS20242825","DOIUrl":"10.1042/CS20242825","url":null,"abstract":"<p><p>Metabolic and insulin-resistant diseases, such as type 2 diabetes mellitus (T2DM), have become major health issues worldwide. The prevalence of insulin resistance in the general population ranges from 15.5% to 44.6%. Shockingly, the global T2DM population is anticipated to double by 2050 compared with 2021. Prior studies indicate that oxidative stress and inflammation are instrumental in causing insulin resistance and instigating metabolic diseases. Numerous methods and drugs have been designed to combat insulin resistance, including metformin, thiazolidinediones (TZDs), sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1RA), and dipeptidyl peptidase 4 inhibitors (DPP4i). Bilirubin is an antioxidant with fat-burning actions by binding to the PPARα nuclear receptor transcription factor, improving insulin sensitivity, reducing inflammation, and reversing metabolic dysfunction. Potential treatment with antioxidants like bilirubin and increasing the enzyme that produces it, heme oxygenase (HMOX), has also gained attention. This review discusses the relationships between bilirubin, HMOX, and insulin sensitivity, how T2DM medications affect HMOX levels and activity, and potentially using bilirubin nanoparticles to treat insulin resistance. We explore the sex differences between these treatments in the HMOX system and how bilirubin levels are affected. We discuss the emerging concept that bilirubin bioconversion to urobilin may have a role in metabolic diseases. This comprehensive review summarizes our understanding of bilirubin functioning as a hormone, discusses the HMOX isoforms and their beneficial mechanisms, analyzes the sex differences that might cause a dichotomy in responses, and examines the potential use of HMOX and bilirubin nanoparticle therapies in treating metabolic diseases.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 2","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051956","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}