Pharmacological research最新文献

{"title":"Correspondence: Reply to commentary on \"Omega-3 PUFAs slow organ aging through promoting energy metabolism\".","authors":"Yabing Xiong, Lili Zhou","doi":"10.1016/j.phrs.2024.107479","DOIUrl":"10.1016/j.phrs.2024.107479","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107479"},"PeriodicalIF":9.1,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564614","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":"USP14 inhibition enhances Parkin-independent mitophagy in iNeurons","authors":"Greta Bernardo ,&nbsp;Miguel A. Prado ,&nbsp;Anna Roshani Dashtmian ,&nbsp;Mariavittoria Favaro ,&nbsp;Sofia Mauri ,&nbsp;Alice Borsetto ,&nbsp;Elena Marchesan ,&nbsp;Joao A. Paulo ,&nbsp;Steve P. Gygi ,&nbsp;Daniel J. Finley ,&nbsp;Elena Ziviani","doi":"10.1016/j.phrs.2024.107484","DOIUrl":"10.1016/j.phrs.2024.107484","url":null,"abstract":"<div><div>Loss of proteostasis is well documented during physiological aging and depends on the progressive decline in the activity of two major degradative mechanisms: the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway. This decline in proteostasis is exacerbated in age-associated neurodegenerative diseases, such as Parkinson’s Disease (PD). In PD, patients develop an accumulation of aggregated proteins and dysfunctional mitochondria, which leads to ROS production, neuroinflammation and neurodegeneration. We recently reported that inhibition of the deubiquitinating enzyme USP14, which is known to enhance both the UPS and autophagy, increases lifespan and rescues the pathological phenotype of two <em>Drosophila</em> models of PD. Studies on the effects of USP14 inhibition in mammalian neurons have not yet been conducted. To close this gap, we exploited iNeurons differentiated from human embryonic stem cells (hESCs), and investigated the effect of inhibiting USP14 in these cultured neurons. Quantitative global proteomics analysis performed following genetic ablation or pharmacological inhibition of USP14 demonstrated that USP14 loss of function specifically promotes mitochondrial autophagy in iNeurons. Biochemical and imaging data also showed that USP14 inhibition enhances mitophagy. The mitophagic effect of USP14 inhibition proved to be PINK1/Parkin- independent, instead relying on expression of the mitochondrial E3 Ubiquitin Ligase MITOL/MARCH5. Notably, USP14 inhibition normalized the mitochondrial defects of Parkin KO human neurons.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"210 ","pages":"Article 107484"},"PeriodicalIF":9.1,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methodological considerations in assessing GLP-1 receptor agonists and gastrointestinal cancer risk","authors":"Cheng-Hsien Hung ,&nbsp;Chun-Ting Lin ,&nbsp;James Cheng-Chung Wei","doi":"10.1016/j.phrs.2024.107481","DOIUrl":"10.1016/j.phrs.2024.107481","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"210 ","pages":"Article 107481"},"PeriodicalIF":9.1,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clarifying methodological approaches in the assessment of GLP-1 RAs and gastrointestinal cancer risk","authors":"Gisella Figlioli,&nbsp;Daniele Piovani,&nbsp;Spyros Peppas,&nbsp;Nicola Pugliese,&nbsp;Cesare Hassan,&nbsp;Alessandro Repici,&nbsp;Ana Lleo,&nbsp;Alessio Aghemo,&nbsp;Stefanos Bonovas","doi":"10.1016/j.phrs.2024.107482","DOIUrl":"10.1016/j.phrs.2024.107482","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"210 ","pages":"Article 107482"},"PeriodicalIF":9.1,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Irisin in degenerative musculoskeletal diseases: Functions in system and potential in therapy","authors":"Yu-tong Wang ,&nbsp;Sheng-yuan Zheng ,&nbsp;Shi-de Jiang ,&nbsp;Yan Luo ,&nbsp;Yu-xiang Wu ,&nbsp;Shinen Naranmandakh ,&nbsp;Yu-sheng Li ,&nbsp;Shu-guang Liu ,&nbsp;Wen-feng Xiao","doi":"10.1016/j.phrs.2024.107480","DOIUrl":"10.1016/j.phrs.2024.107480","url":null,"abstract":"<div><div>Degenerative musculoskeletal diseases are a class of diseases related to the gradual structural and functional deterioration of muscles, joints, and bones, including osteoarthritis (OA), osteoporosis (OP), sarcopenia (SP), and intervertebral disc degeneration (IDD). As the proportion of aging people around the world increases, degenerative musculoskeletal diseases not only have a multifaceted impact on patients, but also impose a huge burden on the medical industry in various countries. Therefore, it is crucial to find key regulatory factors and potential therapeutic targets. Recent studies have shown that irisin plays an important role in degenerative musculoskeletal diseases, suggesting that it may become a key molecule in the prevention and treatment of degenerative diseases of the musculoskeletal system. Therefore, this review provides a comprehensive description of the release and basic functions of irisin, and summarizes the role of irisin in OA, OP, SP, and IDD from a cellular and tissue perspective, providing comprehensive basis for clinical application. In addition, we summarized the many roles of irisin as a key information molecule in bone-muscle-adipose crosstalk and a regulatory molecule involved in inflammation, senescence, and cell death, and proposed the interesting possibility of irisin in degenerative musculoskeletal diseases.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"210 ","pages":"Article 107480"},"PeriodicalIF":9.1,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142552890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Omega-3 PUFAs slow organ aging through promoting energy metabolism.","authors":"Da-Jyun Yan, Chi-Shan Huang, Chi-Ya Yang, Su-Boon Yong, Chin-Yuan Yii","doi":"10.1016/j.phrs.2024.107477","DOIUrl":"10.1016/j.phrs.2024.107477","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107477"},"PeriodicalIF":9.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142505694","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":"Upregulation of ALOX12−12-HETE pathway impairs AMPK-dependent modulation of vascular metabolism in ApoE/LDLR−/− mice","authors":"Mariola Olkowicz ,&nbsp;Agnieszka Karas ,&nbsp;Piotr Berkowicz ,&nbsp;Patrycja Kaczara ,&nbsp;Agnieszka Jasztal ,&nbsp;Zuzanna Kurylowicz ,&nbsp;Filip Fedak ,&nbsp;Hernando Rosales-Solano ,&nbsp;Kanchan Sinha Roy ,&nbsp;Agnieszka Kij ,&nbsp;Elzbieta Buczek ,&nbsp;Janusz Pawliszyn ,&nbsp;Stefan Chlopicki","doi":"10.1016/j.phrs.2024.107478","DOIUrl":"10.1016/j.phrs.2024.107478","url":null,"abstract":"<div><div>Mitochondrial dysfunction and 12-lipoxygenase (ALOX12)-derived 12(S)-HETE production have been associated with vascular inflammation and the pathogenesis of atherosclerosis. However, the role of ALOX12 in regulating vascular energy metabolism in vascular inflammation has not been studied to date. Using mitochondrial and glycolysis functional profiling with the Seahorse extracellular flux analyzer, metabolipidomics, and proteomic analysis (LC-MS/MS), we characterized alterations in vascular energy metabolism in 2- and 6-month-old ApoE/LDLR^−/− vs. control C57BL/6 mice. We identified that aorta of 6-month-old ApoE/LDLR^−/− mice displayed compromised mitochondrial metabolism manifested by the reduced expression of mitochondrial enzymes, impaired mitochondrial respiration, and consequently diminished respiratory reserve capacity. An increased flux through the glycolysis/lactate shuttle, the hexosamine biosynthetic pathway (HBP), and the pentose phosphate pathway (PPP) was also recognized. Interestingly, ALOX12−12-HETE was the most upregulated axis in eicosanoid metabolism and histological examinations indicated that ApoE/LDLR^−/− mice showed increased aortic expression of ALOX12, particularly in early atherosclerotic plaque areas. Remarkably, the joint blocking of ALOX12 and activation of AMPK, but not AMPK activation alone, resulted in the reprogramming of vascular metabolism, with improved mitochondrial respiration and suppressed auxiliary pathways (HBP, PPP, itaconate shunt). In conclusion, excessive activation of the ALOX12–12-HETE pathway in vascular inflammation in early atherosclerosis inhibits AMPK-dependent regulation of vascular metabolism. Consequently, ALOX12 may represent a novel target to boost impaired vascular mitochondrial function in pro-atherosclerotic vascular inflammation.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"210 ","pages":"Article 107478"},"PeriodicalIF":9.1,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142505697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overcoming limitations and advancing the therapeutic potential of antibody-oligonucleotide conjugates (AOCs): Current status and future perspectives","authors":"Jinlan Jiao ,&nbsp;Yun Qian ,&nbsp;Yinhua Lv ,&nbsp;Wenqian Wei ,&nbsp;Yongxuan Long ,&nbsp;Xiaoling Guo ,&nbsp;Anya Buerliesi ,&nbsp;Jiahui Ye ,&nbsp;Hao Han ,&nbsp;Jinbo Li ,&nbsp;Yun Zhu ,&nbsp;Weijie Zhang","doi":"10.1016/j.phrs.2024.107469","DOIUrl":"10.1016/j.phrs.2024.107469","url":null,"abstract":"<div><div>As cancer incidence rises due to an aging population, the importance of precision medicine continues to grow. Antibody-drug conjugates (ADCs) exemplify targeted therapies by delivering cytotoxic agents to specific antigens. Building on this concept, researchers have developed antibody-oligonucleotide conjugates (AOCs), which combine antibodies with oligonucleotides to regulate gene expression. This review highlights the mechanism of AOCs, emphasizing their unique ability to selectively target and modulate disease-causing proteins. It also explores the components of AOCs and their application in tumor therapy while addressing key challenges such as manufacturing complexities, endosomal escape, and immune response. The article underscores the significance of AOCs in precision oncology and discusses future directions, highlighting their potential in treating cancers driven by genetic mutations and abnormal protein expression.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107469"},"PeriodicalIF":9.1,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From exosomes to mitochondria and myocardial infarction: Molecular insight and therapeutic challenge","authors":"Chang Liu ,&nbsp;Dengwen Zhang ,&nbsp;Kekao Long ,&nbsp;Wensheng Qi ,&nbsp;Lei Pang ,&nbsp;Jia Li ,&nbsp;Kenneth King-Yip Cheng ,&nbsp;Yin Cai","doi":"10.1016/j.phrs.2024.107468","DOIUrl":"10.1016/j.phrs.2024.107468","url":null,"abstract":"<div><div>Myocardial infarction (MI) remains a leading cause of mortality worldwide. Despite patients with MI benefit from timely reperfusion therapies, the rates of mortality and morbidity remain substantial, suggesting an enduring need for the development of new approaches. Molecular mechanisms underlying myocardial ischemic injury are associated with both cardiomyocytes and non-cardiomyocytes. Exosomes are nano-sized extracellular vesicles released by almost all eukaryotic cells. They facilitate the communication between various cells by transferring information via their cargo and altering different biological activities in recipient cells. Studies have created great prospects for therapeutic applications of exosomes in MI, as demonstrated through their beneficial effect on heart function and reducing ventricular remodeling in association with fibrosis, angiogenesis, apoptosis, and inflammation. Of note, myocardial ischemic injury is primarily due to restricted blood flow, reducing oxygen availability, and causing inefficient utilization of energy substrates. However, the impact of exosomes on cardiac energy metabolism has not been adequately investigated. Although exosomes have been engineered for targeted delivery to enhance clinical efficacy, challenges must be overcome to utilize them reliably in the clinic. In this review, we summarize the research progress of exosomes for MI with a focus on the known and unknown regarding the role of exosomes in energy metabolism in cardiomyocytes and non-cardiomyocytes; as well as potential research avenues of exosome-mitochondrial energy regulation as well as therapeutic challenges. We aim to help identify more efficient molecular targets that may promote the clinical application of exosomes.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107468"},"PeriodicalIF":9.1,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP9X-enriched MSC-sEV inhibits LSEC angiogenesis in MASH mice by downregulating the IκBα/NF-κB/Ang-2 pathway","authors":"Yanjin Wang ,&nbsp;Chen Wang ,&nbsp;Fuji Yang ,&nbsp;Yifei Chen ,&nbsp;Yujie Shi ,&nbsp;Ruizi Xu ,&nbsp;Zhuan Zhang ,&nbsp;Yongmin Yan","doi":"10.1016/j.phrs.2024.107471","DOIUrl":"10.1016/j.phrs.2024.107471","url":null,"abstract":"<div><div>Pathological angiogenesis of liver sinusoidal endothelial cells (LSEC) plays a crucial role in the progression of metabolic dysfunction-associated steatohepatitis (MASH)-induced liver fibrosis. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have shown promising therapeutic potential against MASH. This study aimed to investigate the impact of MSC-sEV on LSEC angiogenesis and elucidate the underlying molecular mechanisms. The effects of MSC-sEV on LSEC angiogenesis were evaluated in Tumor Necrosis Factor- alpha (TNF-α)-treated LSECs in vitro and in Methionine and Choline Deficient Diet (MCD)-induced MASH mice in vivo. Herein, we found that MSC-sEV effectively suppressed LSEC angiogenesis by targeting the angiogenesis marker Angiogenin 2 (Ang-2) in both TNF-α-treated LSECs and MASH mice. Gene manipulation experiments revealed that the primary mechanism by which MSC-sEV inhibited LSEC angiogenesis was through the modulation of nuclear factor kappa B inhibitor alpha (IκBα) / nuclear factor kappa B (NF-κB) / Ang-2 pathway. Additionally, mass spectrometry and co-immunoprecipitation (Co-IP) data suggested that MSC-sEV delivered the ubiquitin specific peptidase 9 X-linked (USP9X) protein to LSECs, leading to enhanced IκBα deubiquitination and NF-κB in activation, ultimately resulting in the inhibition of Ang-2-mediated LSEC angiogenesis. Knockdown of USP9X attenuated the regulatory effects of MSC-sEV on Ang-2 expression, LSEC angiogenesis, and the progression of MASH. In conclusion, our findings indicate that USP9X delivered via MSC-sEV can suppress LSEC angiogenesis and alleviate MASH-induced liver fibrosis through the IκBα/NF-κB/Ang-2 signaling pathway.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107471"},"PeriodicalIF":9.1,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}