Pub Date : 2025-01-15DOI: 10.1016/j.ejphar.2024.177208
Zhenjiang Li , Yulian Wang , Zhewei Yang , Jiayun Pang , Lin Song , Chunyan Liu , Junfeng Zhang , Lei Dong
Full-thickness skin grafts often face challenges related to inefficient vascularization in clinical settings. Senescent cells, known for secreting various growth factors, have demonstrated excellent effects on angiogenesis. In this study, we induced senescence in a subset of fibroblasts in the donor dermis by co-administering trametinib and palbociclib before harvesting the skin grafts for transplantation. Grafts containing these senescent fibroblasts showed significant promotion of vascularization when surgically transplanted into recipient animals. This approach resulted in a 100% survival rate of the transplanted skin. Additionally, the senescent fibroblasts optimized wound healing and matrix remodeling, subsequently reducing inflammation and scar hyperplasia. Importantly, these senescent fibroblasts disappeared 14 days post-grafting, preventing excessive accumulation of senescent cells. Overall, our study indicates that inducing senescence in the donor dermis prior to transplantation is an effective strategy to enhance vascularization and increase the success rate of skin grafting.
{"title":"Drug-induced senescence of donor dermal fibroblasts enhances revascularization and graft success in skin transplantation","authors":"Zhenjiang Li , Yulian Wang , Zhewei Yang , Jiayun Pang , Lin Song , Chunyan Liu , Junfeng Zhang , Lei Dong","doi":"10.1016/j.ejphar.2024.177208","DOIUrl":"10.1016/j.ejphar.2024.177208","url":null,"abstract":"<div><div>Full-thickness skin grafts often face challenges related to inefficient vascularization in clinical settings. Senescent cells, known for secreting various growth factors, have demonstrated excellent effects on angiogenesis. In this study, we induced senescence in a subset of fibroblasts in the donor dermis by co-administering trametinib and palbociclib before harvesting the skin grafts for transplantation. Grafts containing these senescent fibroblasts showed significant promotion of vascularization when surgically transplanted into recipient animals. This approach resulted in a 100% survival rate of the transplanted skin. Additionally, the senescent fibroblasts optimized wound healing and matrix remodeling, subsequently reducing inflammation and scar hyperplasia. Importantly, these senescent fibroblasts disappeared 14 days post-grafting, preventing excessive accumulation of senescent cells. Overall, our study indicates that inducing senescence in the donor dermis prior to transplantation is an effective strategy to enhance vascularization and increase the success rate of skin grafting.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"987 ","pages":"Article 177208"},"PeriodicalIF":4.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-15DOI: 10.1016/j.ejphar.2024.177183
Anish Sharma , Sahil Kapur , Priyal Kancharla , Tao Yang
The intricate ecosystem of the gut microbiome exhibits sex-specific differences, influencing the susceptibility to cardiovascular diseases (CVD). Imbalance within the gut microbiome compromises the gut barrier, activates inflammatory pathways, and alters the production of metabolites, all of which initiate chronic diseases including CVD. In particular, the interplay between lifestyle choices, hormonal changes, and metabolic byproducts uniquely affects sex-specific gut microbiomes, potentially shaping the risk profiles for hypertension and CVD differently in men and women. Understanding the gut microbiome's role in CVD risk offers informative reasoning behind the importance of developing tailored preventative strategies based on sex-specific differences in CVD risk. Furthermore, insight into the differential impact of social determinants and biological factors on CVD susceptibility emphasizes the necessity for more nuanced approaches. This review also outlines specific dietary interventions that may enhance gut microbiome health, offering a glimpse into potential therapeutic avenues for reducing CVD risk that require greater awareness. Imbalance in natural gut microbiomes may explain etiologies of chronic diseases; we advocate for future application to alter the gut microbiome as possible treatment of the aforementioned diseases. This review mentions the idea of altering the gut microbiome through interventions such as fecal microbiota transplantation (FMT), a major application of microbiome-based therapy that is first-line for Clostridium difficile infections and patient-specific probiotics highlights more innovative approaches to hypertension and CVD prevention. Through increased analysis of gut microbiota compositions along with patient-centric probiotics and microbiome transfers, this review advocates for future preventative strategies for hypertension.
{"title":"Sex differences in gut microbiota, hypertension, and cardiovascular risk","authors":"Anish Sharma , Sahil Kapur , Priyal Kancharla , Tao Yang","doi":"10.1016/j.ejphar.2024.177183","DOIUrl":"10.1016/j.ejphar.2024.177183","url":null,"abstract":"<div><div>The intricate ecosystem of the gut microbiome exhibits sex-specific differences, influencing the susceptibility to cardiovascular diseases (CVD). Imbalance within the gut microbiome compromises the gut barrier, activates inflammatory pathways, and alters the production of metabolites, all of which initiate chronic diseases including CVD. In particular, the interplay between lifestyle choices, hormonal changes, and metabolic byproducts uniquely affects sex-specific gut microbiomes, potentially shaping the risk profiles for hypertension and CVD differently in men and women. Understanding the gut microbiome's role in CVD risk offers informative reasoning behind the importance of developing tailored preventative strategies based on sex-specific differences in CVD risk. Furthermore, insight into the differential impact of social determinants and biological factors on CVD susceptibility emphasizes the necessity for more nuanced approaches. This review also outlines specific dietary interventions that may enhance gut microbiome health, offering a glimpse into potential therapeutic avenues for reducing CVD risk that require greater awareness. Imbalance in natural gut microbiomes may explain etiologies of chronic diseases; we advocate for future application to alter the gut microbiome as possible treatment of the aforementioned diseases. This review mentions the idea of altering the gut microbiome through interventions such as fecal microbiota transplantation (FMT), a major application of microbiome-based therapy that is first-line for <em>Clostridium difficile</em> infections and patient-specific probiotics highlights more innovative approaches to hypertension and CVD prevention. Through increased analysis of gut microbiota compositions along with patient-centric probiotics and microbiome transfers, this review advocates for future preventative strategies for hypertension.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"987 ","pages":"Article 177183"},"PeriodicalIF":4.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-15DOI: 10.1016/j.ejphar.2024.177162
Akira Takaguri, Sari Shinohe, Ryuta Noro, Mei Sakuraba, Chihiro Satoh, Runa Ohashi, Kumi Satoh
The circadian clock protein reverse erythroblastosis virus (REV)-ERBα is implicated in the pathogenesis of various diseases, including cancer and myocardial infarction. Emerging evidence suggests that SR9009, an agonist of REV-ERBα, regulates multiple signaling molecules independent or dependent of REV-ERBα. However, the impact of SR9009 on renal fibrosis remains largely unevaluated. In this study, we investigated the effects of SR9009 on transforming growth factor (TGF)-β1-induced fibrotic responses and elucidated the mechanisms involved. Masson's trichome staining revealed that in the unilateral ureteral obstruction groups, there was a decrease in REV-ERBα expression, accompanied by increased levels of the profibrotic factor TGF-β1 and the fibrosis marker α-smooth muscle actin (α-SMA). REV-ERBα knockdown significantly increased α-SMA expression in NRK-49F cells. SR9009 significantly attenuated unilateral ureteral obstruction-induced fibrosis and TGF-β1-induced fibrotic responses in normal rat kidney fibroblasts (NRK-49F cells). Conversely, the REV-ERBα antagonist SR8278 did not affect TGF-β1-induced fibrotic responses. Mechanistic studies revealed that SR9009 significantly inhibited the phosphorylation of ERK and p38, concomitant with reduced α-SMA levels, suppressing TGF-β1-induced NADPH oxidase 4 (NOX4) mRNA expression in NRK-49F cells. Notably, SR9009 did not influence the expression of dual specificity phosphatase 4, which dephosphorylates MAPKs, including p38. Furthermore, REV-ERBα knockdown did not affect the ability of SR9009 to inhibit TGF-β1-induced fibrotic responses and NOX4 expression in NRK-49F cells. In conclusion, SR9009 exerts a protective role against renal fibrosis independent of REV-ERBα. Therefore, SR9009 is a promising therapeutic agent for the prevention and treatment of renal fibrosis associated with renal failure.
{"title":"SR9009 attenuates TGF-β1-induced renal fibrotic responses by inhibiting the NOX4/p38 signaling pathway in NRK-49F cells","authors":"Akira Takaguri, Sari Shinohe, Ryuta Noro, Mei Sakuraba, Chihiro Satoh, Runa Ohashi, Kumi Satoh","doi":"10.1016/j.ejphar.2024.177162","DOIUrl":"10.1016/j.ejphar.2024.177162","url":null,"abstract":"<div><div>The circadian clock protein reverse erythroblastosis virus (REV)-ERBα is implicated in the pathogenesis of various diseases, including cancer and myocardial infarction. Emerging evidence suggests that SR9009, an agonist of REV-ERBα, regulates multiple signaling molecules independent or dependent of REV-ERBα. However, the impact of SR9009 on renal fibrosis remains largely unevaluated. In this study, we investigated the effects of SR9009 on transforming growth factor (TGF)-β1-induced fibrotic responses and elucidated the mechanisms involved. Masson's trichome staining revealed that in the unilateral ureteral obstruction groups, there was a decrease in REV-ERBα expression, accompanied by increased levels of the profibrotic factor TGF-β1 and the fibrosis marker α-smooth muscle actin (α-SMA). REV-ERBα knockdown significantly increased α-SMA expression in NRK-49F cells. SR9009 significantly attenuated unilateral ureteral obstruction-induced fibrosis and TGF-β1-induced fibrotic responses in normal rat kidney fibroblasts (NRK-49F cells). Conversely, the REV-ERBα antagonist SR8278 did not affect TGF-β1-induced fibrotic responses. Mechanistic studies revealed that SR9009 significantly inhibited the phosphorylation of ERK and p38, concomitant with reduced α-SMA levels, suppressing TGF-β1-induced NADPH oxidase 4 (NOX4) mRNA expression in NRK-49F cells. Notably, SR9009 did not influence the expression of dual specificity phosphatase 4, which dephosphorylates MAPKs, including p38. Furthermore, REV-ERBα knockdown did not affect the ability of SR9009 to inhibit TGF-β1-induced fibrotic responses and NOX4 expression in NRK-49F cells. In conclusion, SR9009 exerts a protective role against renal fibrosis independent of REV-ERBα. Therefore, SR9009 is a promising therapeutic agent for the prevention and treatment of renal fibrosis associated with renal failure.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"987 ","pages":"Article 177162"},"PeriodicalIF":4.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diabetes is known to increase the risk of kidney stones, but the influence of antidiabetic drugs on this risk remains uncertain. Genetic instruments for antidiabetic drugs were identified as variants, which were associated with both the expression of genes encoding target proteins of drugs and glycated hemoglobin level (HbA1c). Here, we investigated the effect of antidiabetic drugs on kidney stones in a mendelian randomization (MR) framework, and further explore the potential effect on CaOx stone rat models induced by glyoxylic acid. Genetically proxied thiazolidinediones (PPARG agonists) significantly reduced the risk of kidney stones (OR = 0.42; P=0.004) per 1-SD decrement in HbA1c, while no significant association was noted in sulfonylureas, SGLT2 inhibitors, or GLP-1 analogs. Other antidiabetic drugs were not analyzed due to unclear pharmacological targets or no identified instruments. Additionally, PPARG agonists pioglitazone ameliorated CaOx nephrocalcinosis in glyoxylic acid-induced rats. The summary-data-based MR (SMR) results showed that PPARG mRNA expression in blood or kidney was not associated with kidney stone risk, and thus we performed mediation MR of PPARG agonists, circulating metabolites, and kidney stones. Among 249 circulating metabolites, we identified an indirect effect of PPARG agonists on kidney stones through increasing phospholipids to total lipids ratio in very large VLDL, with a mediated proportion of 6.87% (P = 0.018). Our study provided evidence that PPARG agonists reduced the risk of kidney stones partially via regulating lipid metabolism, and PPARG agonists may be a promising study subject in clinical studies for the prevention of kidney stones.
{"title":"Therapeutic targets of antidiabetic drugs and kidney stones: A druggable mendelian randomization study and experimental study in rats","authors":"Maolan Wu , Cheng He , Hao Yu , Youjie Zhang , Liang Tang , Minghui Liu , Meng Gao , Jian Wu , Feng Zeng , Hequn Chen , Shilong Jiang , Zewu Zhu","doi":"10.1016/j.ejphar.2024.177197","DOIUrl":"10.1016/j.ejphar.2024.177197","url":null,"abstract":"<div><div>Diabetes is known to increase the risk of kidney stones, but the influence of antidiabetic drugs on this risk remains uncertain. Genetic instruments for antidiabetic drugs were identified as variants, which were associated with both the expression of genes encoding target proteins of drugs and glycated hemoglobin level (HbA1c). Here, we investigated the effect of antidiabetic drugs on kidney stones in a mendelian randomization (MR) framework, and further explore the potential effect on CaOx stone rat models induced by glyoxylic acid. Genetically proxied thiazolidinediones (PPARG agonists) significantly reduced the risk of kidney stones (OR = 0.42; <em>P=</em>0.004) per 1-SD decrement in HbA1c, while no significant association was noted in sulfonylureas, SGLT2 inhibitors, or GLP-1 analogs. Other antidiabetic drugs were not analyzed due to unclear pharmacological targets or no identified instruments. Additionally, PPARG agonists pioglitazone ameliorated CaOx nephrocalcinosis in glyoxylic acid-induced rats. The summary-data-based MR (SMR) results showed that PPARG mRNA expression in blood or kidney was not associated with kidney stone risk, and thus we performed mediation MR of PPARG agonists, circulating metabolites, and kidney stones. Among 249 circulating metabolites, we identified an indirect effect of PPARG agonists on kidney stones through increasing phospholipids to total lipids ratio in very large VLDL, with a mediated proportion of 6.87% (<em>P</em> = 0.018). Our study provided evidence that PPARG agonists reduced the risk of kidney stones partially via regulating lipid metabolism, and PPARG agonists may be a promising study subject in clinical studies for the prevention of kidney stones.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"987 ","pages":"Article 177197"},"PeriodicalIF":4.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-15DOI: 10.1016/j.ejphar.2024.177175
Olga Gawrys , Petr Kala , Janusz Sadowski , Vojtěch Melenovský , Peter Sandner , Luděk Červenka
Nitric oxide (NO)-stimulated cyclic guanosine monophosphate (cGMP) is a key regulator of cardiovascular health, as NO-cGMP signalling is impaired in diseases like pulmonary hypertension, heart failure and chronic kidney disease. The development of NO-independent sGC stimulators and activators provide a novel therapeutic option to restore altered NO signalling. sGC stimulators have been already approved for the treatment of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and chronic heart failure (HFrEF), while sGC activators are currently in phase-2 clinical trials for CKD.
The best characterized effect of increased cGMP via the NO-sGC-cGMP pathway is vasodilation. However, to date, none of the sGC agonists are in development for hypertension (HTN). According to WHO, the global prevalence of uncontrolled HTN continues to rise, contributing significantly to cardiovascular mortality. While there are effective antihypertensive treatments, many patients require multiple drugs, and some remain resistant to all therapies. Thus, in addition to improved diagnosis and lifestyle changes, new pharmacological strategies remain in high demand.
In this review we explore the potential of sGC stimulators and activators as novel antihypertensive agents, starting with the overview of NO-sGC-cGMP signalling, followed by potential mechanisms by which the increase in cGMP may regulate vascular tone and BP. These effects may encompass not only acute vasodilation, but also mid-term and chronic effects, such as the regulation of salt and water balance, as well as mitigation of vascular ageing and remodelling. The main section summarizes the preclinical and clinical evidence supporting the BP-lowering efficacy of sGC agonists.
{"title":"Soluble guanylyl cyclase stimulators and activators: Promising drugs for the treatment of hypertension?","authors":"Olga Gawrys , Petr Kala , Janusz Sadowski , Vojtěch Melenovský , Peter Sandner , Luděk Červenka","doi":"10.1016/j.ejphar.2024.177175","DOIUrl":"10.1016/j.ejphar.2024.177175","url":null,"abstract":"<div><div>Nitric oxide (NO)-stimulated cyclic guanosine monophosphate (cGMP) is a key regulator of cardiovascular health, as NO-cGMP signalling is impaired in diseases like pulmonary hypertension, heart failure and chronic kidney disease. The development of NO-independent sGC stimulators and activators provide a novel therapeutic option to restore altered NO signalling. sGC stimulators have been already approved for the treatment of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and chronic heart failure (HFrEF), while sGC activators are currently in phase-2 clinical trials for CKD.</div><div>The best characterized effect of increased cGMP via the NO-sGC-cGMP pathway is vasodilation. However, to date, none of the sGC agonists are in development for hypertension (HTN). According to WHO, the global prevalence of uncontrolled HTN continues to rise, contributing significantly to cardiovascular mortality. While there are effective antihypertensive treatments, many patients require multiple drugs, and some remain resistant to all therapies. Thus, in addition to improved diagnosis and lifestyle changes, new pharmacological strategies remain in high demand.</div><div>In this review we explore the potential of sGC stimulators and activators as novel antihypertensive agents, starting with the overview of NO-sGC-cGMP signalling, followed by potential mechanisms by which the increase in cGMP may regulate vascular tone and <span>BP</span>. These effects may encompass not only acute vasodilation, but also mid-term and chronic effects, such as the regulation of salt and water balance, as well as mitigation of vascular ageing and remodelling. The main section summarizes the preclinical and clinical evidence supporting the BP-lowering efficacy of sGC agonists.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"987 ","pages":"Article 177175"},"PeriodicalIF":4.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
β-asarone, an effective volatile oil component of Acorus chinensis, has been found to hold beneficial effects on Parkinson's disease (PD), but its mechanism remains incompletely understood. Drosophila melanogaster with PTEN induced kinase 1 (PINK1) mutations, a prototype PD model, was used in this study. We found that calcium chelation profoundly alleviated a spectrum of PD symptoms. Whereas, calcium supplementation made the case worse, suggesting accumulated calcium contributes to progression of PD. β-asarone administration decreased Ca2+ level in PD flies, accompanied by alleviated behavioral and neural defects. Further study demonstrated that β-asarone downregulated L-type Ca2+ channels (Dmca1D), which was increased in PD flies. Besides, β-asarone decreased expression of 1,4,5 - trisphosphate receptor (Itpr), which is responsible for calcium release from endoplasmic reticulum (ER). Knockdown of either Dmca1D or Itpr specifically in dopaminergic neurons alleviated behavioral and neural defects in PD flies. While overexpression of Itpr aggravated PD symptoms. The results indicated that increased intracellular calcium influx and release triggers dysregulation of calcium homeostasis in PD flies. And β-asarone prevents PD by restoring Ca2+ homeostasis. Overall, the study demonstrated that β-asarone can serve as a new prospective medication against PD or other diseases associated with dysregulation of Ca2+ homeostasis.
{"title":"β-asarone relieves Parkinson's disease through reducing intracellular Ca2+ in PINK1 mutant Drosophila melanogaster","authors":"Lanxiang Yin , Xintong Yuan , Jiahui Yu , Xuemin Ren , Hongqin Zhang , Yunyan Ye , Zixuan Wang , Xiangtao Chen","doi":"10.1016/j.ejphar.2024.177155","DOIUrl":"10.1016/j.ejphar.2024.177155","url":null,"abstract":"<div><div>β-asarone, an effective volatile oil component of Acorus chinensis, has been found to hold beneficial effects on Parkinson's disease (PD), but its mechanism remains incompletely understood. Drosophila melanogaster with PTEN induced kinase 1 (PINK1) mutations, a prototype PD model, was used in this study. We found that calcium chelation profoundly alleviated a spectrum of PD symptoms. Whereas, calcium supplementation made the case worse, suggesting accumulated calcium contributes to progression of PD. β-asarone administration decreased Ca<sup>2+</sup> level in PD flies, accompanied by alleviated behavioral and neural defects. Further study demonstrated that β-asarone downregulated L-type Ca<sup>2+</sup> channels (Dmca1D), which was increased in PD flies. Besides, β-asarone decreased expression of 1,4,5 - trisphosphate receptor (Itpr), which is responsible for calcium release from endoplasmic reticulum (ER). Knockdown of either Dmca1D or Itpr specifically in dopaminergic neurons alleviated behavioral and neural defects in PD flies. While overexpression of Itpr aggravated PD symptoms. The results indicated that increased intracellular calcium influx and release triggers dysregulation of calcium homeostasis in PD flies. And β-asarone prevents PD by restoring Ca<sup>2+</sup> homeostasis. Overall, the study demonstrated that β-asarone can serve as a new prospective medication against PD or other diseases associated with dysregulation of Ca<sup>2+</sup> homeostasis.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"987 ","pages":"Article 177155"},"PeriodicalIF":4.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-15DOI: 10.1016/j.ejphar.2024.177154
Meng Wu , Wenyan Wang , Zhicheng Yang , Guangfeng Long , Yan Zhang , Daheng Yang
Kawasaki disease (KD) primarily affects the pediatric population and exhibits a notable incidence of drug resistance, resulting in coronary artery damage and thrombosis. This study aimed to identify innovative therapeutic targets for KD treatment. By harnessing single-cell data derived from peripheral blood mononuclear cells, we identified differentially expressed genes. Through the integration of eQTL data and Mendelian randomization analysis, we identified FCGR3B and S100A12 were causally linked to KD. The DrugBank database showed their potential as drug target candidates. GSEA further elucidated their roles on coronary artery damage and thrombosis. Furthermore, we have confirmed that the ligand-FCGR3B complex enhances the intracellular calcium concentration (Ca2+) within the cytoplasm, which in turn accelerates the secretion of S100A12, a pro-inflammatory cytokine that targets endothelial cells, from neutrophils. By integrating existing research, we proposed a synergistic effect that FCGR3B-S100A12 pathway positively modulates the development of coronary artery damage and thrombus formation, suggesting their perspectives in clinical treatment.
{"title":"Illuminating the enigmatic pathogenesis of Kawasaki disease: Unveiling novel therapeutic avenues by targeting FCGR3B-S100A12 pathway","authors":"Meng Wu , Wenyan Wang , Zhicheng Yang , Guangfeng Long , Yan Zhang , Daheng Yang","doi":"10.1016/j.ejphar.2024.177154","DOIUrl":"10.1016/j.ejphar.2024.177154","url":null,"abstract":"<div><div>Kawasaki disease (KD) primarily affects the pediatric population and exhibits a notable incidence of drug resistance, resulting in coronary artery damage and thrombosis. This study aimed to identify innovative therapeutic targets for KD treatment. By harnessing single-cell data derived from peripheral blood mononuclear cells, we identified differentially expressed genes. Through the integration of eQTL data and Mendelian randomization analysis, we identified FCGR3B and S100A12 were causally linked to KD. The DrugBank database showed their potential as drug target candidates. GSEA further elucidated their roles on coronary artery damage and thrombosis. Furthermore, we have confirmed that the ligand-FCGR3B complex enhances the intracellular calcium concentration (Ca<sup>2+</sup>) within the cytoplasm, which in turn accelerates the secretion of S100A12, a pro-inflammatory cytokine that targets endothelial cells, from neutrophils. By integrating existing research, we proposed a synergistic effect that FCGR3B-S100A12 pathway positively modulates the development of coronary artery damage and thrombus formation, suggesting their perspectives in clinical treatment.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"987 ","pages":"Article 177154"},"PeriodicalIF":4.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-15DOI: 10.1016/j.ejphar.2024.177176
Chanon Kunasol , Nipon Chattipakorn , Siriporn C. Chattipakorn
Calcineurin Inhibitors (CNIs), including tacrolimus and cyclosporine A, are the most widely used immunosuppressive drugs in solid organ transplantation. Those drugs play a pivotal role in preventing graft rejection and reducing autoimmunity. However, recent studies indicate that CNIs can disrupt the composition of gut microbiota or result in “gut dysbiosis”. This dysbiosis has been shown to be a significant factor in reducing host immunity by decreasing innate immune cells and impairing metabolic regulation, leading to lipid and glucose accumulation. Several in vivo and clinical studies have demonstrated a mechanistic link between gut dysbiosis and the side effects of CNI. Those studies have unveiled that gut dysbiosis induced by CNIs contributes to adverse effects such as hyperglycemia, nephrotoxicity, and diarrhea. These adverse effects of the induced gut dysbiosis require interventions to restore microbial balance. Probiotics and dietary supplements have emerged as potential interventions to mitigate the side effects of gut dysbiosis caused by CNIs. In this complex relationship between CNI treatment, gut dysbiosis, and interventions, several types of gut microbiota and host immunity are involved. However, the mechanisms underlying these relationships remain elusive. Therefore, the aim of this review is to comprehensively summarize and discuss the major findings from in vivo and clinical data regarding the impact of treatment with CNIs on gut microbiota. This review also explores interventions to mitigate dysbiosis for therapeutic approaches of the side effects of CNIs. The possible underlying mechanisms of CNIs-induced gut dysbiosis with or without interventions are also presented and discussed.
{"title":"Impact of calcineurin inhibitors on gut microbiota: Focus on tacrolimus with evidence from in vivo and clinical studies","authors":"Chanon Kunasol , Nipon Chattipakorn , Siriporn C. Chattipakorn","doi":"10.1016/j.ejphar.2024.177176","DOIUrl":"10.1016/j.ejphar.2024.177176","url":null,"abstract":"<div><div>Calcineurin Inhibitors (CNIs), including tacrolimus and cyclosporine A, are the most widely used immunosuppressive drugs in solid organ transplantation. Those drugs play a pivotal role in preventing graft rejection and reducing autoimmunity. However, recent studies indicate that CNIs can disrupt the composition of gut microbiota or result in “gut dysbiosis”. This dysbiosis has been shown to be a significant factor in reducing host immunity by decreasing innate immune cells and impairing metabolic regulation, leading to lipid and glucose accumulation. Several <em>in vivo</em> and clinical studies have demonstrated a mechanistic link between gut dysbiosis and the side effects of CNI. Those studies have unveiled that gut dysbiosis induced by CNIs contributes to adverse effects such as hyperglycemia, nephrotoxicity, and diarrhea. These adverse effects of the induced gut dysbiosis require interventions to restore microbial balance. Probiotics and dietary supplements have emerged as potential interventions to mitigate the side effects of gut dysbiosis caused by CNIs. In this complex relationship between CNI treatment, gut dysbiosis, and interventions, several types of gut microbiota and host immunity are involved. However, the mechanisms underlying these relationships remain elusive. Therefore, the aim of this review is to comprehensively summarize and discuss the major findings from <em>in vivo</em> and clinical data regarding the impact of treatment with CNIs on gut microbiota. This review also explores interventions to mitigate dysbiosis for therapeutic approaches of the side effects of CNIs. The possible underlying mechanisms of CNIs-induced gut dysbiosis with or without interventions are also presented and discussed.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"987 ","pages":"Article 177176"},"PeriodicalIF":4.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-15DOI: 10.1016/j.ejphar.2024.177160
Rajat Atre , Alexander G. Obukhov , Chinmay Y. Majmudar , Krishnaprasad Nair , Fletcher A. White , Rahul Sharma , Faaiza Siddiqi , Syed M. Faisal , Vivek P. Varma , Md Imtaiyaz Hassan , Taj Mohammad , Gajanan N. Darwhekar , Mirza S. Baig
Dorzolamide (DZD), a Carbonic anhydrase (CA) inhibitor clinically used to lower intraocular pressure, exhibits anti-inflammatory effects owing to the drug's ability to inhibit the TIR domain-containing adaptor protein (TIRAP)-mediated signalling in macrophages. Here, we investigated whether DZD intermediates also demonstrate any anti-inflammatory property like DZD but with a reduced inhibition of CA. We found that several intermediates of DZD show increased binding to TIRAP at the common interface of kinases, such as Protein kinase C-delta (PKCδ) and Bruton's tyrosine kinase (BTK). Such binding results in a decreased activity of TIRAP, p38 Mitogen-activating protein kinases (MAPK), and p65, which are essential for major inflammatory signaling pathways. Remarkably, the DZD intermediates were more effective than DZD in decreasing the mRNA expression levels of pro-inflammatory cytokines in Lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. The DZD intermediates also exhibit a reduced binding energy to CA II and CA IV, highlighting their improved specificity as anti-inflammatory compounds with decreased unwanted biological effects. Furthermore, we validated the anti-inflammatory effect of the most efficient DZD intermediate, DRZ V, in a model of mouse sepsis. DRZ V-treated septic mice exhibited improved survival compared to DZD-treated septic mice. Our data indicate that the tested DZD intermediates are more effectual in dampening TIRAP-mediated inflammatory signaling as compared to DZD. Thus, DZD intermediates may be a promising option for developing novel anti-inflammatory therapeutics.
{"title":"Dorzolamide intermediates with potential anti-inflammatory activity","authors":"Rajat Atre , Alexander G. Obukhov , Chinmay Y. Majmudar , Krishnaprasad Nair , Fletcher A. White , Rahul Sharma , Faaiza Siddiqi , Syed M. Faisal , Vivek P. Varma , Md Imtaiyaz Hassan , Taj Mohammad , Gajanan N. Darwhekar , Mirza S. Baig","doi":"10.1016/j.ejphar.2024.177160","DOIUrl":"10.1016/j.ejphar.2024.177160","url":null,"abstract":"<div><div>Dorzolamide (DZD), a Carbonic anhydrase (CA) inhibitor clinically used to lower intraocular pressure, exhibits anti-inflammatory effects owing to the drug's ability to inhibit the TIR domain-containing adaptor protein (TIRAP)-mediated signalling in macrophages. Here, we investigated whether DZD intermediates also demonstrate any anti-inflammatory property like DZD but with a reduced inhibition of CA. We found that several intermediates of DZD show increased binding to TIRAP at the common interface of kinases, such as Protein kinase C-delta (PKCδ) and Bruton's tyrosine kinase (BTK). Such binding results in a decreased activity of TIRAP, p38 Mitogen-activating protein kinases (MAPK), and p65, which are essential for major inflammatory signaling pathways. Remarkably, the DZD intermediates were more effective than DZD in decreasing the mRNA expression levels of pro-inflammatory cytokines in Lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. The DZD intermediates also exhibit a reduced binding energy to CA II and CA IV, highlighting their improved specificity as anti-inflammatory compounds with decreased unwanted biological effects. Furthermore, we validated the anti-inflammatory effect of the most efficient DZD intermediate, DRZ V, in a model of mouse sepsis. DRZ V-treated septic mice exhibited improved survival compared to DZD-treated septic mice. Our data indicate that the tested DZD intermediates are more effectual in dampening TIRAP-mediated inflammatory signaling as compared to DZD. Thus, DZD intermediates may be a promising option for developing novel anti-inflammatory therapeutics.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"987 ","pages":"Article 177160"},"PeriodicalIF":4.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Corrigendum to “Role of the ventral tegmental area in general anesthesia” [986(2025) 177145]","authors":"Jia Li , Yiyong Wei , Jiaxin Xiang , Donghang Zhang","doi":"10.1016/j.ejphar.2024.177209","DOIUrl":"10.1016/j.ejphar.2024.177209","url":null,"abstract":"","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"987 ","pages":"Article 177209"},"PeriodicalIF":4.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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