Pharmacological research最新文献

{"title":"Role for the F-box Proteins in Heart Diseases.","authors":"Sa Liu, Yuanying Yang, Xingyuan Hou, Ni Zhou, Bikui Zhang, Wenqun Li","doi":"10.1016/j.phrs.2024.107514","DOIUrl":"https://doi.org/10.1016/j.phrs.2024.107514","url":null,"abstract":"<p><p>The maintenance of cardiac homeostasis necessitates proper protein turnover, which is regulated by the ubiquitin-proteasome system. F-box proteins are one type of E3 ubiquitin ligases, and accumulating evidence suggests that dysregulation of FBPs exacerbates heart diseases. Therefore, in this review, we summarized the F-box proteins present in the heart, which can be divided into three types based on their repeated sequences, namely FBXO (Fbxo32, Fbxo25, Fbxo44, Fbxo27 and Fbxo28), FBXW (Fbxw7 and Fbxw5), and FBXL (Fbxl1, Fbxl10, Fbxl16 and Fbxl2). Moreover, the physiological and pathological roles and the functional mechanisms of these F-box proteins were elucidated within the cardiac context, providing new theories and strategies for the prevention and treatment of heart diseases.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107514"},"PeriodicalIF":9.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693089","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":"Corrigendum to \"Overcoming limitations and advancing the therapeutic potential of antibody-oligonucleotide conjugates (AOCs): Current status and future perspectives\" [Pharmacol. Res. 209 (2024) 107469].","authors":"Jinlan Jiao, Yun Qian, Yinhua Lv, Wenqian Wei, Yongxuan Long, Xiaoling Guo, Anya Buerliesi, Jiahui Ye, Hao Han, Jinbo Li, Yun Zhu, Weijie Zhang","doi":"10.1016/j.phrs.2024.107513","DOIUrl":"https://doi.org/10.1016/j.phrs.2024.107513","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107513"},"PeriodicalIF":9.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142688070","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":"Effect of anthocyanins on metabolic syndrome through interacting with gut microbiota.","authors":"Lanlan Du, Xiaoqin Ding, Yuwen Tian, Jian Chen, Weilin Li","doi":"10.1016/j.phrs.2024.107511","DOIUrl":"https://doi.org/10.1016/j.phrs.2024.107511","url":null,"abstract":"<p><p>Metabolic syndrome, as a complex pathological condition, is caused by a series of pathogenic factors and has become a global public health challenge. Anthocyanins, a natural water-soluble flavonoid pigment, have attracted much attention due to their antioxidant, anti-inflammatory, and anticancer biological activities. After ingestion, a majority of anthocyanins is not directly absorbed but rather reaches the colon. Hence, the exertion of their biological benefits is closely intertwined with the role played by gut microbiota. In this review, we introduce the pathogenesis and intervention methods of metabolic syndrome, as well as the interaction between anthocyanins and gut microbiota. We also discuss the therapeutic potential of anthocyanins through gut microbiota in addressing a range of metabolic syndrome conditions, including obesity, type 2 diabetes mellitus, cardiovascular diseases, non-alcoholic fatty liver disease, inflammatory bowel disease, polycystic ovary syndrome, osteoporosis, and cancer.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107511"},"PeriodicalIF":9.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692931","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":"PPARβ/δ prevents inflammation and fibrosis during diabetic cardiomyopathy.","authors":"Adel Rostami, Xavier Palomer, Javier Pizarro-Delgado, Emma Barroso, Brenda Valenzuela-Alcaraz, Fátima Crispi, J Francisco Nistal, María A Hurlé, Raquel García, Walter Wahli, Manuel Vázquez-Carrera","doi":"10.1016/j.phrs.2024.107515","DOIUrl":"https://doi.org/10.1016/j.phrs.2024.107515","url":null,"abstract":"<p><p>Diabetic cardiomyopathy (DCM) is a specific type of myocardial disease that often develops in patients suffering from diabetes, which has become the foremost cause of death among them. It is an insidious multifactorial disease caused by complex and partially unknown mechanisms that include metabolic dysregulation, local inflammation, fibrosis, and cardiomyocyte apoptosis. Despite its severity and poor prognosis, it often goes undiagnosed, and there are currently no approved specific drugs to prevent or even treat it. Peroxisome proliferator-activated receptor (PPAR)β/δ is a key metabolic regulator that has been proposed as a potential target for DCM due to its pleiotropic anti-inflammatory properties. Diabetes was induced by multiple low-dose streptozotocin (STZ) administration in wild-type and PPARβ/δ knockout male mice treated with the PPARβ/δ agonist GW0742 or vehicle. Human cardiomyocytes (AC16) and mouse atrial myocytes (HL-1) exposed to hyperglycemia and treated with PPARβ/δ agonists were also used. PPARβ/δ deletion in mice negatively impacted cardiac morphology and function, which was accompanied by interstitial fibrosis and structural remodeling of the heart. This phenotype was further exacerbated in knockout diabetic mice. At the molecular level, PPARβ/δ suppression resulted in increased expression of pro-inflammatory and pro-fibrotic markers. Some of these markers were also induced by diabetes in wild-type mice and were exacerbated in diabetic knockout mice. The activity of the transcription factors nuclear factor κB (NF-κB) and activator protein-1 (AP-1) correlated with most of these changes. Remarkably, PPARβ/δ activation partially prevented inflammation and fibrosis in the heart, as well as cardiac atrophy, induced during diabetes in mice, and also in cultured cardiomyocytes exposed to hyperglycemia. Finally, our results suggest that the beneficial effects of PPARβ/δ activation are mediated by the inhibition of mitogen-activated protein kinases (MAPK) activity and subsequent downregulation of the transcriptional activities of NF-κB and AP-1. Overall, the data suggest that PPARβ/δ agonists might be useful in preventing inflammation and fibrosis progression in DCM.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107515"},"PeriodicalIF":9.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692952","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":"Comparative effectiveness and safety of imported and domestic immune checkpoint inhibitors in China: a systematic review and pairwise and network meta-analyses.","authors":"Jilin Peng, Yixu Wang, Zhenye Chi, Shichao Li, Yuan Zhang, Ling Li, Di Bian, Ziyu Zhai, Sijie Yuan, Yulin Zhang, Weijie Li, Fanglei Ye, Le Wang","doi":"10.1016/j.phrs.2024.107475","DOIUrl":"https://doi.org/10.1016/j.phrs.2024.107475","url":null,"abstract":"<p><strong>Background: </strong>Multiple brands of immune checkpoint inhibitors (ICIs), including domestic and imported agents, have been approved as front-line therapy in China. However, little is known about the difference in efficacy and safety of these agents of different origins. This study aims to systematically compare the difference between National Medical Products Administration (NMPA) approved domestic and imported ICIs regarding their efficacy, safety, and price.</p><p><strong>Methods: </strong>We systematically searched PubMed, Embase, and Cochrane Central, from inception to July 1^st, 2023, for phase III trials evaluating ICIs as first- or second-line settings that have available hazard ratio (HR) for Asians or non-Asians. Studies of domestic and imported ICIs were screened and paired by the matching clinical characteristics as mirror groups. The primary endpoint was to assess the difference in efficacy between domestic and imported ICIs regarding overall survival. An effect size was derived from each mirror group and then pooled across all groups using a random-effects model. Heterogeneity was assessed by I² statistics. Monthly treatment costs for each drug were calculated based on dosing information on National Medical Products Administration (NMPA) label and prices extracted from INSIGHT database. The difference in monthly treatment costs was compared by unpaired T-test. The protocol is registered on PROSPERO, CRD42024580753.</p><p><strong>Results: </strong>Overall, domestic ICIs exhibited better efficacy regarding overall survival (HR, 0.87; 95% CI, 0.79-0.97; P < 0.05; I² = 0) compared with imported agents. No difference was observed regarding benefits in progression free survival (HR, 0.95; 95% CI, 0.82-1.09; P > 0.05; I² = 0). Consistent results were obtained through frequentists and Bayesian approaches. The differences in safety; measured by relative risk of treatment-related adverse events (TARE) of any grade, TARE of grade 3 or higher, immune-related adverse events(irAE) of any grade, irAE of grade 3 or higher, discontinuation due to treatment, and death due to treatment; were also similar between domestic and imported ICIs. Moreover, in current Chinese market, the monthly treatment prices of domestic ICIs was statistically lower than that of imported ICIs (P < 0.01).</p><p><strong>Conclusions: </strong>Our research provides an essential reference of cost-effectiveness of ICIs manufactured in China for clinicians in routine practice of cancer care as well as public health authorities for decision making process.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107475"},"PeriodicalIF":9.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687665","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":"IUPHAR Review on muscarinic M1 and M4 receptors as drug treatment targets relevant to the molecular pathology of schizophrenia.","authors":"Brian Dean","doi":"10.1016/j.phrs.2024.107510","DOIUrl":"https://doi.org/10.1016/j.phrs.2024.107510","url":null,"abstract":"<p><p>Cobenfy, a co-formulation of xanomeline and trospium, is the first drug not acting on the dopaminergic system of the CNS approved for the treatment of schizophrenia by the FDA. Xanomeline is a muscarinic M1 and M4 receptor (CHRM1 and CHRM4) agonist whilst trospium is a peripherally active CHRM antagonist that reduces the unwanted peripheral side-effects of xanomeline. Relevant to this exciting development, this review details the human CNS cholinergic systems and how those systems are affected by the molecular pathology of schizophrenia in a way suggesting activating the CHRM1 and 4 would be beneficial in treating the disorder. The CNS distribution of CHRMs is presented along with findings using CHRM knockout mice and mice treated with drugs that activate the CHRM1 and / or M4, these data explain why these CHRMs could be involved in the genesis of the symptoms of schizophrenia. Next, the process leading to the formulation of Cobenfy and the preclinical data on xanomeline are reviewed showing why Cobenfy was expected to be useful in treating schizophrenia. The pipeline of drugs targeting CHRM1 and /or M4 receptors to treat schizophrenia are discussed. Finally, the molecular pathology of two sub-groups within schizophrenia, separated based on the presence or absence of a deficit of cortical CHRM1, are reviewed to show how such approaches could identify new drug targets. In conclusion, developing Cobenfy highlights why fully understanding the pathophysiology of schizophrenia will suggest new treatment targets for the disorder and that pharmacologists can synthesise drugs to target these sites.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107510"},"PeriodicalIF":9.1,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682392","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":"METTL14-mediated m⁶A modification enhances USP22-ERα axis to drive breast cancer malignancy.","authors":"Xuefen Zhuang, Shusha Yin, Ji Cheng, Wenshuang Sun, Zesen Fang, Yujie Xiang, E-Ying Peng, Yu Yao, Yuting Li, Xiaoyue He, Li Lu, Yuanfei Deng, Hongbiao Huang, Gengxi Cai, Yuning Liao","doi":"10.1016/j.phrs.2024.107509","DOIUrl":"10.1016/j.phrs.2024.107509","url":null,"abstract":"<p><p>The abundance and activity of estrogen receptor alpha (ERα) are tightly regulated by ubiquitin-specific peptidase 22 (USP22) during the progression of breast cancer (BCa). However, the post-transcriptional modifications on the USP22-ERα axis remain elusive. N6-methyladenosine (m⁶A) is critical to modulate RNA status in eukaryotic cells. Here, we find that METTL14 positively regulates the mRNA expression of USP22 and ERα. Mechanistically, METTL14 potently binds to the USP22 and ERα mRNA, and thereby enhancing their stability through m⁶A modification. YTHDC1 and YTHDF1 function as readers for m⁶A-modified USP22 and ERα, respectively. Additionally, METTL14 promotes the growth and migration of ERα⁺ BCa via the USP22-ERα-Cyclin D1 axis. Enforced expression of USP22/ERα significantly reverses the METTL14 depletion-induced growth and migration inhibition in BCa. Moreover, our analysis of clinical samples shows that the expression of METTL14, USP22, and ERα is upregulated and correlated in BCa tissues. Overall, our findings reveal the key role of the METTL14-USP22-ERα axis in BCa progression, which further provides a druggable target to treat BCa.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107509"},"PeriodicalIF":9.1,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668484","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":"Ectopic expression of NKG7 enhances CAR-T function and improves the therapeutic efficacy in liquid and solid tumors.","authors":"Yuxin Chen, Meng Wang, Shuxin Huang, Lulu Han, Ying Cai, Xiaodi Xu, Shuwen Sun, Zhaokai Chen, Junze Chen, Jiatian Yu, Hongwei Du, Huizhong Li, Junnian Zheng, Bo Ma, Gang Wang","doi":"10.1016/j.phrs.2024.107506","DOIUrl":"10.1016/j.phrs.2024.107506","url":null,"abstract":"<p><p>Lack of biopsies after treatment, especially in solid tumors, restricts the understanding of chimeric antigen receptor (CAR)-T cells -related characteristic in vivo, thus hindering the development of strategies to improve CAR-T cells efficacy. Here, we applied nineteen individual single-cell RNA sequencing (scRNA-seq) data from clinical samples of digestive cancers to explore the characteristics of tumor-infiltrating T cells (TILs) to identify effective targets which might be benefit for enhancing the function of CAR-T cells. The data showed that natural killer cell granule protein 7 (NKG7) was overexpressed in TILs and positively associated with anti-PD1 or anti-CTLA4 therapy in digestive cancers. Subsequently, we found that ectopic expression of NKG7 significantly improved the cytotoxicity of B7H3-targeting CAR-T cells to B7H3-positive digestive cancer cells (MKN45, Huh7, HuCCT-1, SW620 and PANC-1 cells), as well as promoted the TNF-α and IL-2 expression. Furthermore, in a CD19-targeting CAR-T model, the therapeutic efficacy was also found increased after NKG7 overexpression. Mechanically, NKG7 preserved surface CAR expression and promoted CAR-T cell proliferation after exposing to relative tumor antigen. These results indicated that it may be feasible to explore single-cell sequencing data of clinical tumor samples to find strategies to improve CAR-T function, and that ectopic expression of NKG7 is an effective strategy to improve the therapeutic efficacy of CAR-T cells against tumors.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107506"},"PeriodicalIF":9.1,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648737","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":"ARID1A is a coactivator of STAT5 that contributes to CD8⁺ T cell dysfunction and anti-PD-1 resistance in gastric cancer.","authors":"Fangqi Ma, Mingming Ren, Zhongqiu Li, Yujing Tang, Xiaoyu Sun, Yi Wang, Nida Cao, Xiaohong Zhu, Yan Xu, Rui Wang, Yumiao Shen, Ruohan Zhao, Zhaoyan Li, Milad Ashrafizadeh, Gautam Sethi, Furong Wang, Aiguang Zhao","doi":"10.1016/j.phrs.2024.107499","DOIUrl":"10.1016/j.phrs.2024.107499","url":null,"abstract":"<p><p>ARID1A deletion mutation contributes to improved treatment of several malignancies with immune checkpoint inhibitors (ICIs). However, its role in modulating of tumor immune microenvironment (TIME) of gastric cancer (GC) remains unclear. Here, we report an increase of CD8⁺ T cells infiltration in GC patients with ARID1A-mutation (MUT), which enhances sensitivity to ICIs. Kaplan-Meier survival analysis showed that ARID1A-mutation patients with gastrointestinal malignancies benefit from immunotherapy. Transcriptome analysis implicated that ARID1A regulates STAT5 downstream targets to inhibit T-cell mediated toxicity. Integrated dual luciferase assay and ChIP-qPCR analyses indicated that ARID1A coordinated with STAT5 to facilitate the transcription of the immunosuppressive factors TGF-β1 and NOX4. ARID1A recruited canonical BAF complex (cBAF) subunits, including SMARCB1 and SMARCD1, to sustain DNA accessibility. Downregulation of ARID1A reduced chromatin remodeling into configurations which make GC more sensitive to ICIs. In addition, targeting STAT5 effectively improved anti-PD-1 efficiency in ARID1A-wild type (WT) GC patients. Taken together, ARID1A is a coactivator of STAT5, function as a chromatin organizer in GC ICIs resistance, and targeting STAT5 is an effective strategy to improve the efficiency of ICIs in GC.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107499"},"PeriodicalIF":9.1,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644361","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":"Mechanism and therapeutic targets of circulating immune cells in diabetic retinopathy.","authors":"Bowen Zhao, Yin Zhao, Xufang Sun","doi":"10.1016/j.phrs.2024.107505","DOIUrl":"10.1016/j.phrs.2024.107505","url":null,"abstract":"<p><p>Diabetic retinopathy (DR) continues to be the leading cause of preventable vision loss among working-aged adults, marked by immune dysregulation within the retinal microenvironment. Typically, the retina is considered as an immune-privileged organ, where circulating immune cells are restricted from entry under normal conditions. However, during the progression of DR, this immune privilege is compromised as circulating immune cells breach the barrier and infiltrate the retina. Increasing evidence suggests that vascular and neuronal degeneration in DR is largely driven by the infiltration of immune cells, particularly neutrophils, monocyte-derived macrophages, and lymphocytes. This review delves into the mechanisms and therapeutic targets associated with these immune cell populations in DR, offering a promising and innovative approach to managing the disease.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107505"},"PeriodicalIF":9.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639401","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}