Pharmacology最新文献

{"title":"Fisetin Suppresses Atherosclerosis by Inhibiting Ferroptosis-Related Oxidative Stress in Apolipoprotein E Knockout Mice.","authors":"Xiufang Jiang, Yanling Lei, Yajuan Yin, Fangfang Ma, Mingqi Zheng, Gang Liu","doi":"10.1159/000538535","DOIUrl":"10.1159/000538535","url":null,"abstract":"<p><strong>Introduction: </strong>Fisetin has been demonstrated to inhibit the occurrence of atherosclerosis; however, the mechanism of fisetin suppressing atherosclerosis remains elusive.</p><p><strong>Methods: </strong>The function of fisetin in the inhibition of atherosclerosis was evaluated by hematoxylin and eosin and Oil Red O staining in ApoE-/- mice. Molecular biomarkers of atherosclerosis progression were detected by Western blot and qPCR. Moreover, the inhibition of atherosclerosis on oxidative stress and ferroptosis was evaluated by immunofluorescence staining, qPCR, and Western blot assays.</p><p><strong>Results: </strong>The obtained results showed that serum lipid was attenuated and consequentially the formation of atherosclerosis was also suppressed by fisetin in ApoE-/- mice. Exploration of the mechanism revealed that molecular biomarkers of atherosclerosis were decreased under fisetin treatment. The level of reactive oxygen species and malondialdehyde declined, while the activity of superoxide dismutases and glutathione peroxidase was increased under the fisetin treatment. Additionally, the suppressor of ferroptosis, glutathione peroxidase 4 proteins, was elevated. The ferritin was decreased in the aortic tissues treated with fisetin.</p><p><strong>Conclusions: </strong>In summary, fisetin attenuated the formation of atherosclerosis through the inhibition of oxidative stress and ferroptosis in the aortic tissues of ApoE-/- mice.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"169-179"},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140857810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Donor Inhalation of Nebulized Dexmedetomidine Alleviates Ischemia-Reperfusion Injury in Rat Lung Transplantation.","authors":"Jing Wang, Jiaojiao Sun, Huizhi Yu, Chunlan Hu, Jinbo Wu, Chunxiao Hu","doi":"10.1159/000539528","DOIUrl":"10.1159/000539528","url":null,"abstract":"<p><strong>Introduction: </strong>The occurrence of lung ischemia-reperfusion injury (LIRI) after lung transplantation results in primary graft dysfunction (PGD) in more than 50% of cases, which seriously affects the prognosis of recipients. Currently, donor lung protection is the focus of research on improving graft survival in lung transplant recipients. Dexmedetomidine (Dex) is a widely used general anesthesia adjuvant in clinical practice to alleviate ischemia-reperfusion injury in the lungs, liver, heart, kidneys, and brain. However, intravenous infusion of Dex can cause negative effects on the cardiovascular system. Inhaling nebulized Dex can directly act on the alveolar tissue and alleviate its cardiovascular inhibitory effect by reducing drug intake. This study aimed to investigate the effect of donor nebulized Dex inhalation on LIRI after lung transplantation in rats.</p><p><strong>Methods: </strong>We randomly divided the male Sprague-Dawley rats into donor rats and recipient rats, and allowed the donor rats to inhale nebulized Dex or physiological saline 15 min before surgery. The donor lung was refrigerated for 8 h before each single-lung transplant. After 2 h of reperfusion of the transplanted lung, serum and transplanted lung tissue were collected. The wet-to-dry weight ratio of the lung tissue was measured, arterial blood gas was detected, and histopathology changes, oxidative stress, inflammatory reactions, and apoptosis were evaluated.</p><p><strong>Results: </strong>Pretransplant inhalation of Dex through the donor's lung reduced the injury of the transplanted lung, increased the levels of malondialdehyde and myeloperoxidase, and decreased the levels of superoxide dismutase and glutathione in the lung tissue. Moreover, nebulized Dex inhalation of the donor lung inhibited LIRI-induced tumor necrosis factor-α, interleukin-6, and inducible nitric oxide synthase expression and also suppressed nuclear factor kappa B phosphorylation. Nebulized Dex inhalation reduced the rate of cell apoptosis in the transplanted lung tissue by inhibiting the upregulation of Bax, downregulation of Bcl-2, and increase in caspase-3 lysis caused by LIRI.</p><p><strong>Conclusion: </strong>Inhalation of atomized Dex is a potential donor lung protection strategy, which can be used to reduce LIRI after lung transplantation and may be helpful to improve the occurrence of PGD and prognosis of lung transplant recipients.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"293-304"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141160583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MiR-205-5p-Mediated MAGI1 Inhibition Attenuates the Injury Induced by Diabetic Nephropathy.","authors":"Yuanbing Xiang, Min Sun, Yuxi Wu, Yao Hu","doi":"10.1159/000535670","DOIUrl":"10.1159/000535670","url":null,"abstract":"<p><strong>Introduction: </strong>Membrane-associated guanylate kinase with an inverted domain structure-1 (MAGI1) is dysregulated in diabetes; however, its role in diabetic nephropathy (DN) remains unclear. In this study, we determined the function and associated mechanisms of MAGI1 in DN.</p><p><strong>Methods: </strong>Serum samples from 28 patients with DN and 28 normal volunteers were collected. High-glucose (HG)-treated human renal mesangial cells (HRMCs) and streptozotocin-treated rats were used as cell and animal models of DN, respectively. MAGI1 mRNA expression was measured by quantitative reverse transcription polymerase chain reaction. An 5-Ethynyl-2'-deoxyuridine assay was used to assess cell proliferation, whereas Western blot analysis was performed to quantitate the levels of markers associated with proliferation, the extracellular matrix (ECM), and inflammation. These included collagens I, collagen IV, cyclin D1, AKT, phosphorylated-AKT (p-AKT), PI3K, and phosphorylated-PI3K (p-PI3K). The predicted binding of miR-205-5p with the MAGI1 3'UTR was verified using a luciferase assay.</p><p><strong>Results: </strong>MAGI1 expression was increased in serum samples from DN patients and in HRMCs treated with HG. MAGI1 knockdown attenuated excessive proliferation, ECM accumulation, and inflammation in HG-induced HRMCs as well as injury to DN rats. MiR-205-5p potentially interacted with the 3'UTR of MAGI1 and binding was verified using a dual-luciferase reporter assay. Moreover, miR-205-5p repression offset the inhibitory influence of MAGI1 knockdown on proliferation, collagen deposition, and inflammation in HG-treated HRMCs.</p><p><strong>Conclusion: </strong>MAGI1 contributes to injury caused by DN. Furthermore, miR-205-5p binds to MAGI1 and suppresses MAGI1 function. These findings suggest that miR-205-5p-mediates MAGI1 inhibition, which represents a potential treatment for DN.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"98-109"},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139703203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"What Women Want? The State of the Art regarding the Treatment of Young Women with Hypoactive Sexual Desire Disorder.","authors":"Leonor de Oliveira, Linda Vignozzi, Annamaria Giraldi, Shelly Varod, Giovanni Corona, Yacov Reisman","doi":"10.1159/000535587","DOIUrl":"10.1159/000535587","url":null,"abstract":"<p><strong>Background: </strong>Hypoactive sexual desire disorder (HSDD) in premenopausal women involves biological, psychological, and social aspects. In the European Society for Sexual Medicine meeting in Rotterdam in February 2023, several leading experts in the field discussed the multifaceted nature of this disorder and the state of the art regarding treatment at a round table. This review reflects the information discussed at this event and further discusses current controversies.</p><p><strong>Summary: </strong>HSDD is the most prevalent female-estimated sexual disorder reported by 28% of the 40% premenopausal women with sexual dysfunction. Flibanserin and bremelanotide are the only approved medications to treat HSDD in the USA, and none are approved in Europe. Lybrido, Lybridos, and Lorexys are under development. There are several psychological factors with impact in sexual desire, including depression and sexual abuse. Feminine sexual scripts, the pleasure gap, and structural inequalities also affect sexual desire. Evidence strongly supports the value of combining medical and psychological approaches in the treatment of HSDD, but there is ongoing controversy regarding the pharmacological treatment of young women with HSDD. However, some women seem open and would like to have access to drug treatment.</p><p><strong>Key messages: </strong>The treatment of HSDD in young women requires a mixed treatment approach that addresses the disorder's complexity. Despite clinicians seeming to be divided between using pharmacological and/or psychosocial approaches, some women might respond better to one type of intervention over the others. This calls for the development of tools that assess the best approach for each person, including their will and informed choice.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"69-75"},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11006276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139049221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting CK1δ and CK1ε as a New Therapeutic Approach for Clear Cell Renal Cell Carcinoma.","authors":"Yu-Chen Lin, Ding-Ping Sun, Tsung-Han Hsieh, Chun-Han Chen","doi":"10.1159/000540182","DOIUrl":"10.1159/000540182","url":null,"abstract":"<p><strong>Introduction: </strong>Kidney cancer ranks as the ninth most common cancer in men and the fourteenth in women globally, with renal cell carcinoma (RCC) being the most prevalent type. Despite advances in therapeutic strategies targeting angiogenesis and immune checkpoints, the absence of reliable markers for patient selection and limited duration of disease control underline the need for innovative approaches. CK1δ and CK1ε are highly conserved serine/threonine kinases involved in cell cycle regulation, apoptosis, and circadian rhythm. While CK1δ dysregulation is reportedly associated with breast and bladder cancer progression, their role in RCC remains elusive. This study aimed to investigate the feasibility of CK1δ/ε as new therapeutic targets for RCC patients.</p><p><strong>Methods: </strong>The relationship between CK1δ/ε and RCC progression was evaluated by the analysis of microarray dataset and TCGA database. The anticancer activity of CK1δ/ε inhibitor was examined by MTT/SRB assay, and apoptotic cell death was analyzed by flow cytometry and Western blotting.</p><p><strong>Results: </strong>Our data demonstrate that the gene expression of CSNK1D and CSNK1E is significantly higher in clear cell RCC (ccRCC) tissues compared to normal kidney samples, which is correlated with lower survival rates in ccRCC patients. SR3029, a selective inhibitor targeting CK1δ/ε, significantly suppresses the viability and proliferation of ccRCC cell lines regardless of the status of VHL deficiency. Importantly, the inhibitor promotes the population of subG1 cells and induces apoptosis, and ectopically expression of CK1δ partially rescued SR3029-induced apoptosis in ccRCC cells.</p><p><strong>Conclusion: </strong>These findings underscore the crucial role of CK1δ and CK1ε in ccRCC progression, suggesting CK1δ/ε inhibitors as new therapeutic options for ccRCC patients.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"330-340"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141493046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Statement.","authors":"","doi":"10.1159/000538004","DOIUrl":"10.1159/000538004","url":null,"abstract":"","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"127"},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140022473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcription Factor E2F8 Activates PDK1-Mediated DNA Damage Repair to Enhance Cisplatin Resistance in Lung Adenocarcinoma.","authors":"Hongliang Li, Junxia Sun, Haibo Hu, Yi Wang","doi":"10.1159/000537819","DOIUrl":"10.1159/000537819","url":null,"abstract":"<p><strong>Introduction: </strong>Cisplatin (DDP) is the commonest chemo drug in lung adenocarcinoma (LUAD) treatment, and DDP resistance is a significant barrier to therapeutic therapy. This study attempted to elucidate the impact of PDK1 on DDP resistance in LUAD and its mechanism.</p><p><strong>Methods: </strong>Bioinformatics analysis was used to determine the expression and enriched pathways of PDK1 in LUAD tissue. Subsequently, E2F8, the upstream transcription factor of PDK1, was predicted, and the binding relationship between the two was analyzed using dual-luciferase and ChIP experiments. PDK1 and E2F8 levels in LUAD tissues and cells were detected via qRT-PCR. Cell viability, proliferation, and apoptosis levels were assayed by CCK-8, EdU, and flow cytometry experiments, respectively. Comet assay was used to assess DNA damage, and immunofluorescence was used to assess the expression of γ-H2AX. NHEJ reporter assay was to assess DNA repair efficiency. Western blot tested levels of DNA damage repair (DDR)-related proteins. Immunohistochemistry assessed the expression of relevant genes. Finally, an animal model was constructed to investigate the influence of PDK1 expression on LUAD growth.</p><p><strong>Results: </strong>PDK1 was found to be upregulated in LUAD and enhanced DDP resistance by mediating DDR. E2F8 was identified as an upstream transcription factor of PDK1 and was highly expressed in LUAD. Rescue experiments presented that knocking down E2F8 could weaken the promotion of PDK1 overexpression on DDR-mediated DDP resistance in LUAD. In vivo experiments showed that knocking down PDK1 plus DDP significantly reduced the growth of xenograft tumors.</p><p><strong>Conclusion: </strong>Our results indicated that the E2F8/PDK1 axis mediated DDR to promote DDP resistance in LUAD. Our findings lead to an improved treatment strategy after drug resistance.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"341-356"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141176215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progression of Acute Lung Injury in Intratracheal LPS Rat Model: Efficacy of Fluticasone, Dexamethasone, and Pirfenidone.","authors":"Anil H Kadam, Jan E Schnitzer","doi":"10.1159/000534329","DOIUrl":"10.1159/000534329","url":null,"abstract":"<p><strong>Introduction: </strong>We investigated the potential of LPS (10-300 µg/rat) administered intratracheally (i.t.) to induce reproducible features of acute lung injury (ALI) and compared the pharmacological efficacy of anti-inflammatory glucocorticoids and antifibrotic drugs to reduce the disease. Additionally, we studied the time-dependent progression of ALI in this LPS rat model.</p><p><strong>Methods: </strong>We conducted (1) dose effect studies of LPS administered i.t. at 10, 30, 100, and 300 μg/rat on ALI at 4 h timepoint; (2) pharmacological interventions using i.t. fluticasone (100 and 300 μg/rat), i.t. pirfenidone (4,000 μg/rat), and peroral dexamethasone (1 mg/kg) at 4 h timepoint; (3) kinetic studies at 0, 2, 4, 6, 8, 10, and 24 h post-LPS challenge. Phenotype or pharmacological efficacy was assessed using predetermined ALI features such as pulmonary inflammation, edema, and inflammatory mediators.</p><p><strong>Results: </strong>All LPS doses induced a similar increase of inflammation, edema, and inflammatory mediators, e.g., IL6, IL1β, TNFα, and CINC-1. In pharmacological intervention studies, we showed fluticasone and dexamethasone ameliorated ALI by inhibiting inflammation (&gt;60-80%), edema (&gt;70-100%), and the increase of cytokines IL6, IL1β, and TNFα (≥70-90%). We also noticed some inhibition of CINC-1 (25-35%) and TIMP1 (57%) increase with fluticasone and dexamethasone. Conversely, pirfenidone failed to inhibit inflammation, edema, and mediators of inflammation. Last, in ALI kinetic studies, we observed progressive pulmonary inflammation and TIMP1 levels, which peaked at 6 h and remained elevated up to 24 h. Progressive pulmonary edema started between 2 and 4 h and was sustained at later timepoints. On average, levels of IL6 (peak at 6-8 h), IL1β (peak at 2-10 h), TNFα (peak at 2 h), CINC-1 (peak at 2-6 h), and TGFβ1 (peak at 8 h) were elevated between 2 and 10 h and declined toward 24 h post-LPS challenge.</p><p><strong>Conclusion: </strong>Our data show that 10 μg/rat LPS achieved a robust, profound, and reproducible experimental ALI phenotype. Glucocorticoids ameliorated key ALI features at the 4-h timepoint, but the antifibrotic pirfenidone failed. Progressive inflammation and sustained pulmonary edema were present up to 24 h, whereas levels of inflammatory mediators were dynamic during ALI progression. This study's data might be helpful in designing appropriate experiments to test the potential of new therapeutics to cure ALI.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"22-33"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10872444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138047762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholesin and GPR146 in Modulating Cholesterol Biosynthesis.","authors":"Jong-Won Kim, Yu Ji Kim","doi":"10.1159/000540351","DOIUrl":"10.1159/000540351","url":null,"abstract":"<p><strong>Background: </strong>Cholesterol homeostasis in the human body is a crucial process that involves a delicate balance between dietary cholesterol absorption in the intestine and de novo cholesterol synthesis in the liver. Both pathways contribute significantly to the overall pool of cholesterol in the body, influencing plasma cholesterol levels and impacting cardiovascular health. Elevated absorption of cholesterol in the intestines has a suppressive impact on the synthesis of cholesterol in the liver, serving to preserve cholesterol balance. Nonetheless, the precise mechanisms driving this phenomenon remain largely unclear.</p><p><strong>Summary: </strong>This review aimed to discuss the previously unrecognized role of cholesin and GPR146 in the regulation of cholesterol biosynthesis, providing a novel conceptual framework for understanding cholesterol homeostasis.</p><p><strong>Key messages: </strong>The discovery of cholesin, a novel protein implicated in the regulation of cholesterol homeostasis, represents a significant advancement in our understanding of cholesterol biosynthesis and its associated pathways. The cholesin-GPR146 axis could have profound implications across various therapeutic areas concerning abnormal cholesterol metabolism, offering new hope for patients and improving overall healthcare outcomes.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"305-311"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simvastatin Attenuates Cardiac Fibrosis under Pathophysiological Conditions of Heart Failure with Preserved Left Ventricular Ejection Fraction by Inhibiting TGF-β Signaling.","authors":"Tetsuro Marunouchi, Kasumi Matsumura, Eriko Fuji, Akihiro Iwamoto, Kouichi Tanonaka","doi":"10.1159/000534933","DOIUrl":"10.1159/000534933","url":null,"abstract":"<p><strong>Introduction: </strong>There is still no effective treatment for heart failure with preserved left ventricular ejection fraction (HFpEF), and therapies to improve prognosis are urgently needed. Clinical studies in patients with HFpEF have shown that statins and HMG-CoA reductase inhibitors may reduce their mortality rate. However, the mechanisms underlying the effects of statins on HFpEF remain unknown. In the present study, we examined whether simvastatin administration inhibits the development of cardiac fibrosis in HFpEF model mice. We further examined the contribution of the Smad and mitogen-activated protein (MAP) kinase pathways to the transforming growth factor-β (TGF-β) signaling pathway in the development of HFpEF.</p><p><strong>Methods: </strong>HFpEF animals were prepared by feeding C57BL/6 N mice a high-fat diet and providing water containing N[w]-nitro-<sc>l</sc>-arginine methyl ester hydrochloride (<sc>l</sc>-NAME) for 15 weeks. Simvastatin (30 mg/kg/day) or vehicle was administered orally daily during the experimental period. Cardiac function was measured by echocardiography, and cardiac fibrosis was evaluated by Masson's trichrome staining. Changes in the TGF-β signaling proteins in myocardial tissue were examined by Western blotting.</p><p><strong>Results: </strong>A high-fat diet and <sc>l</sc>-NAME solution load induced cardiac diastolic dysfunction with cardiac fibrosis. Simvastatin treatment markedly attenuated cardiac fibrosis and reduced cardiac diastolic dysfunction. In addition, simvastatin prevented the increase in phosphorylation levels of Smad (Smad2 and Smad3) and MAPK (c-Raf, Erk1/2) pathway proteins downstream of the TGF-β receptor in cardiac tissue.</p><p><strong>Conclusions: </strong>Our present study demonstrated that simvastatin attenuated diastolic dysfunction by reducing cardiac fibrosis in HFpEF hearts. Furthermore, our findings suggest that the mechanisms by which simvastatin attenuates HFpEF development involve, at least in part, inhibition of the TGF-β signaling pathway, which is activated in the HFpEF heart.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"43-51"},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138452260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}