Biochemical pharmacology最新文献

{"title":"An Island of Reil excitation: Mapping glutamatergic (vGlut1+ and vGlut2+) connections in the medial insular cortex.","authors":"Mia Jessica O'Shea, Roberta Goncalves Anversa, Sarah Sulaiman Ch'ng, Erin Jane Campbell, Leigh Clasina Walker, Zane Bruce Andrews, Andrew John Lawrence, Robyn Mary Brown","doi":"10.1016/j.bcp.2024.116637","DOIUrl":"https://doi.org/10.1016/j.bcp.2024.116637","url":null,"abstract":"<p><p>The insular cortex is a multifunctional and richly connected region of the cerebral cortex, critical in the neural integration of external stimuli and internal signals. Well-served for this role by a large network of afferent and efferent connections, the mouse insula can be simplified into an anterior, medial and posterior portion. Here we focus on the medial subregion, a once over-looked area that has gained recent attention for its involvement in an array of behaviours. Although the connections of medial insular cortex neurons have been previously identified, their precise glutamatergic phenotype remains undefined (typically defined by the presence of the subtype of vesicular glutamate transporters). Hence, we combined Cre knock-in mouse lines and adeno-associated viral tracing to distinguish between the expression of the two major vesicular glutamate transporters, type 1 (vGlut1) and 2 (vGlut2), in the subregion's neuronal inputs and outputs. Our results determined that the medial insula has extensive glutamatergic efferents expressing both vGlut1 and vGlut2 throughout the neuraxis. In contrast, a more conservative number of glutamatergic inputs were observed, with exclusively vGlut2+ projections received from hypothalamic and thalamic regions. Taken together, we demonstrate that vGlut1- and vGlut2-expressing networks of this insular subdivision have distinct connectivity patterns, including a greater abundance of vGlut1+ fibres innervating hypothalamic regions and the extended amygdala. These findings provide insight into the distinct chemo-architecture of this region, which may facilitate further investigation into the role of the medial insula in complex behaviour.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116637"},"PeriodicalIF":5.3,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674925","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":"Exploring heat shock proteins as therapeutic targets for Parkinson's disease.","authors":"Xiang Li, Wenjun Wang, Shi Pan, Xueqin Cao, Elizabeth Rosalind Thomas, Mingyu Xie, Chunxiang Zhang, Jianming Wu","doi":"10.1016/j.bcp.2024.116633","DOIUrl":"https://doi.org/10.1016/j.bcp.2024.116633","url":null,"abstract":"<p><p>Parkinson's disease (PD) is characterized by the accumulation of misfolded α-synuclein (α-syn). Promoting the degradation of misfolded proteins has been shown to be an effective approach to alleviate PD. This review highlights the roles of specific heat shock proteins (HSPs) in modulating α-syn aggregation and neuronal survival. HSP27 prevents glycosylation-induced α-syn aggregation, disrupts copper ion interactions, inhibits mitochondrial apoptosis, and prevents dopaminergic neuronal cell death. HSP70 alleviates dopaminergic neuronal damage by promoting mitophagy and preventing neuronal apoptosis. HSC70 plays a critical role in chaperone-mediated autophagy and facilitates lysosomal degradation. GRP78 mitigates abnormal protein aggregation. The HSP70-HSP40-HSP110 system is capable of degrading α-syn amyloid fibers. Inhibition of HSP90 expression protects neurons. Further research should prioritize developing regulators of HSPs as treatments for PD. While HSPs offer promise in PD management, their complex roles necessitate cautious therapeutic development to harness their potential. Understanding the specific roles of different HSPs will be essential to developing effective therapies for α-syn clearance.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116633"},"PeriodicalIF":5.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646758","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":"Role of Relaxin Signaling in Cancer: A Review","authors":"Anupam Kotwal ,&nbsp;Whitney S. Goldner ,&nbsp;Robert G. Bennett","doi":"10.1016/j.bcp.2024.116634","DOIUrl":"10.1016/j.bcp.2024.116634","url":null,"abstract":"<div><div>The investigation into relaxin (RLN), additional RLN-like proteins, and RLN family peptide receptors (RXFP) has demonstrated their role in modulating the extracellular matrix (ECM), immune cells, specifically macrophages, and angiogenesis, with recent evidence showing an effect on signaling pathways in tumor cells. These findings serve as the basis for our narrative review to collate pertinent studies in this field and provide our perspective on their clinical and investigational significance. In the article, we discuss findings from pertinent studies focusing on evaluating the expression or effect of RLN1, RLN2, or RXFP1 in various cancers. We also briefly discuss the potential role that other RLN family peptides and their receptors play in cancer. Specifically, we delve into questions regarding RLN signaling in terms of parity/pregnancy-associated protection from mammary tumors, expression in tumors, detection in serum in the setting of cancers, effect on tumor-adjacent cells, effect on tumorigenesis depending on endogenous expression or delivery, and last, but not the least, impact on the effectiveness of anti-cancer therapies. We expect that summarizing the available literature to answer these questions will allow readers to understand the role of RLN-receptor interaction in cancer as well as identify areas of uncertainty and avenues for future investigation.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116634"},"PeriodicalIF":5.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638331","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":"Interactions between glucagon like peptide 1 (GLP-1) and estrogens regulates lipid metabolism","authors":"Jorge F.A. Model ,&nbsp;Rafaella S. Normann ,&nbsp;Éverton L. Vogt ,&nbsp;Maiza Von Dentz ,&nbsp;Marjoriane de Amaral ,&nbsp;Rui Xu ,&nbsp;Tsvetan Bachvaroff ,&nbsp;Poli Mara Spritzer ,&nbsp;J. Sook Chung ,&nbsp;Anapaula S. Vinagre","doi":"10.1016/j.bcp.2024.116623","DOIUrl":"10.1016/j.bcp.2024.116623","url":null,"abstract":"<div><div>Obesity, characterized by excessive fat accumulation in white adipose tissue (WAT), is linked to numerous health issues, including insulin resistance (IR), and type 2 diabetes mellitus (DM2). The distribution of adipose tissue differs by sex, with men typically exhibiting android adiposity and pre-menopausal women displaying gynecoid adiposity. After menopause, women have an increased risk of developing android-type obesity, IR, and DM2. Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) are important in treating obesity and DM2 by regulating insulin secretion, impacting glucose and lipid metabolism. GLP-1Rs are found in various tissues including the pancreas, brain, and adipose tissue. Studies suggest GLP-1RAs and estrogen replacement therapies have similar effects on tissues like the liver, central nervous system, and WAT, probably by converging pathways involving protein kinases.</div><div>To investigate these interactions, female rats underwent ovariectomy (OVR) to promote a state of estrogen deficiency. After 20 days, the rats were euthanized and the tissues were incubated with 10 μM of liraglutide, a GLP-1RA. Results showed significant changes in metabolic parameters: OVR increased lipid catabolism in perirenal WAT and basal lipolysis in subcutaneous WAT, while liraglutide treatment enhanced stimulated lipolysis in subcutaneous WAT. Liver responses included increased stimulated lipolysis with liraglutide. Transcriptome analysis revealed distinct gene expression patterns in WAT of OVR rats and those treated with GLP-1RA, highlighting pathways related to lipid and glucose metabolism. Functional enrichment analysis showed estrogen’s pivotal role in these pathways, influencing genes involved in lipid metabolism regulation.</div><div>Overall, the study underscores GLP-1RA acting directly on adipose tissues and highlights the complex interactions between GLP-1 and estrogen in regulating metabolism, suggesting potential synergistic therapeutic effects in treating metabolic disorders like obesity and DM2.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116623"},"PeriodicalIF":5.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613949","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":"3,4,5-trimethoxycinnamic acid methyl ester isolated from Polygala tenuifolia enhances hippocampal LTP through PKA and calcium-permeable AMPA receptor","authors":"Yehee Lee ,&nbsp;Jieun Jeon ,&nbsp;So-Ri Son ,&nbsp;Eunbi Cho ,&nbsp;Somin Moon ,&nbsp;A Young Park ,&nbsp;Hye Ji Chae ,&nbsp;Ho Jung Bae ,&nbsp;Minho Moon ,&nbsp;Se Jin Jeon ,&nbsp;Dae Sik Jang ,&nbsp;Dong Hyun Kim","doi":"10.1016/j.bcp.2024.116622","DOIUrl":"10.1016/j.bcp.2024.116622","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is a degenerative brain disorder characterized by progressive cognitive decline and neuronal death due to extracellular deposition of amyloid β (Aβ) and intracellular deposition of tau proteins. Recently approved antibody drugs targeting Aβ have been shown to slow the progression of the disease, but they have minimal effects on cognitive improvement. Therefore, there is a need to develop drugs with cognitive-enhancing effects that can be used in conjunction with these antibody treatments. In this study, we investigated whether <em>Polygala tenuifolia</em> (PT), traditionally known for its cognitive-enhancing effects, can improve synaptic plasticity and identified its active components and mechanisms. PT demonstrated a dose-dependent effect in enhancing long-term potentiation (LTP), and among its components, 3,4,5-trimethoxycinnamic acid methyl ester (TMCA) showed a similar LTP-enhancing effect. TMCA increased the phosphorylation of the GluA1 subunit of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and increased the amount of GluA1 on the synapse without affecting the amount of GluA2. Additionally, the increase in GluA1 induced by TMCA was inhibited by a PKA inhibitor. Consistent with these results, the enhancement of LTP by TMCA was inhibited by a GluA1 antagonist and a PKA inhibitor. <em>In silico</em> molecular docking experiments confirmed that TMCA binds to PKA. Finally, we confirmed the LTP-enhancing effect of TMCA in hippocampal slices from 5XFAD mice. These results suggest that PT and its active component, TMCA, can interact with PKA to enhance LTP, indicating the potential for improving cognitive function in AD patients.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116622"},"PeriodicalIF":5.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613793","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":"Crosstalk between non-coding RNA and apoptotic signaling in diabetic nephropathy","authors":"Kejia Zhang,&nbsp;Di Wu,&nbsp;Chunjie Huang","doi":"10.1016/j.bcp.2024.116621","DOIUrl":"10.1016/j.bcp.2024.116621","url":null,"abstract":"<div><div>Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in diabetes mellitus. It is also a significant contributor to cardiovascular morbidity and mortality in diabetic patients Thereby, Innovative therapeutic approaches are needed to retard the initiation and advancement of DN. Hyperglycemia can induce apoptosis, a regulated form of cell death, in multiple renal cell types, such as podocytes, mesangial cells, and proximal tubule epithelial cells, ultimately contributing to the pathogenesis of DN. Recent genome-wide investigations have revealed the widespread transcription of the human genome, resulting in the production of numerous regulatory non-protein-coding RNAs (ncRNAs), including microRNAs (miRNAs) and diverse categories of long non-coding RNAs (lncRNAs). They play a critical role in preserving physiological homeostasis, while their dysregulation has been implicated in a broad spectrum of disorders, including DN. Considering the established association between apoptotic processes and the expression of ncRNAs in DN, a thorough understanding of their intricate interplay is essential. Therefore, the current work thoroughly analyzes the intricate interplay among miRNAs, lncRNAs, and circular RNAs in the context of apoptosis within the pathogenesis of DN. Additionally, in the final section, we demonstrated that ncRNA-mediated modulation of apoptosis can be achieved through stem cell-derived exosomes and herbal medicines, presenting potential avenues for the treatment of DN.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116621"},"PeriodicalIF":5.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613822","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":"C1QTNF Related protein 8 (CTRP8) is a marker of myeloid derived innate immune cell populations in the human breast cancer microenvironment.","authors":"Leanne Arreza, Thatchawan Thanasupawat, Sai Nivedita Krishnan, Matthew Kraljevic, Thomas Klonisch, Sabine Hombach-Klonisch","doi":"10.1016/j.bcp.2024.116624","DOIUrl":"10.1016/j.bcp.2024.116624","url":null,"abstract":"<p><p>Innate immune cells in the tumor microenvironment (TME) play an important role in breast cancer (BC) metastatic spread and influence patient survival. Macrophages differentiate along a proinflammatory M1 to protumorigenic M2 phenotype spectrum which affects distinct functions, like angiogenesis and cytokine production, and modulates BC aggressiveness and affects patient survival. Mast cells (MCs) are myeloid derived cells that serve as the first line of innate immune defense but their role in the TME of BC is not well understood. In this study, we have identified a subpopulation of innate immune cells that shows strong immunopositivity for the least studied adipokine CTRP8. Using a new and highly specific polyclonal antiserum on patient BC tissues, we identify a subset of tryptase + MCs and CD68 + macrophages co-expressing immunoreactive CTRP8. In M1 polarized THP-1 myeloid cells, this adipokine stimulated increased secretion of pro-inflammatory cytokines and elevated expression of the relaxin/ CTRP8 receptor RXFP1. Comparative analysis of secreted cytokine profiles in THP-1 M1 macrophages exposed to either CTRP8, relaxin-2 (RLN2), or the small molecule RXFP1 agonist ML-290 revealed ligand-specific cytokine signatures. Our study identified novel subsets of CTRP8 + myeloid derived innate immune cells and links this adipokine to pro-inflammatory events in the TME of BC.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116624"},"PeriodicalIF":5.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613821","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":"3,3′-Diindolylmethane promotes bone formation – A assessment in MC3T3-E1 cells and zebrafish","authors":"Ying Ma ,&nbsp;Yin Zhu ,&nbsp;Feng Wang ,&nbsp;Guoyang Zhao ,&nbsp;Lianlian Huang ,&nbsp;Rongzhu Lu ,&nbsp;Dongxu Wang ,&nbsp;Xinyu Tian ,&nbsp;Yang Ye","doi":"10.1016/j.bcp.2024.116618","DOIUrl":"10.1016/j.bcp.2024.116618","url":null,"abstract":"<div><div>Osteoporosis is a common degenerative bone disease in middle-aged and elderly people. The current drugs used to treat osteoporosis have many side effects and low patient compliance. Phytochemotherapy may be safer and more effective. 3,3′-diindolemethane (DIM) is the digestive product of indole-3-methanol in cruciferous vegetables in the stomach, which is a kind of anti-tumor and anti-oxidation phytochemical. However, the effects of DIM on osteoblasts and the mechanism by which DIM regulates bone formation are not fully understood. The aim of this study was to investigate the effects of DIM on the bone formation of mouse preosteoblasts MC3T3-E1 and zebrafish. DIM promotes proliferation and osteogenic differentiation of MC3T3-E1 cells in vitro, and also plays a bone promoting role by increasing the interaction between BRCA1-Associated Protein 1(BAP1) and Inositol 1,4,5-Trisphosphate Receptor(IP3R), up-regulating the expression of BAP1 and IP3R and downstream storage operation calcium entry (SOCE) related protein Recombinant Stromal Interaction Molecule 1(STIM1). The effect of DIM on osteoporosis was confirmed in zebrafish osteoporosis model, and its molecular mechanism may be related to BAP1/IP3R/SOCE signaling pathway. These findings highlight the potential therapeutic value of DIM in the prevention and treatment of osteoporosis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116618"},"PeriodicalIF":5.3,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613979","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":"Unveiling the potential of intranasal delivery of renin-angiotensin system drugs: Insights on the pharmacokinetics of irbesartan.","authors":"Filipa Gouveia, Andreia Carona, Mariana Lacerda, Joana Bicker, Antoni Camins, M Teresa Cruz, Miren Ettcheto, Amílcar Falcão, Ana Fortuna","doi":"10.1016/j.bcp.2024.116616","DOIUrl":"https://doi.org/10.1016/j.bcp.2024.116616","url":null,"abstract":"<p><p>The therapeutic interest of renin-angiotensin system (RAS) drugs for the treatment of neuroinflammation has been recently acknowledged. Nevertheless, most RAS drugs display limited passage across the blood-brain barrier (BBB). Therefore, this study investigated the potential of intranasal (IN) delivery of six RAS drugs to circumvent the BBB and attain the brain, envisioning its future use in central nervous system (CNS) neuroinflammatory diseases, such as Alzheimer's disease (AD). Captopril, enalaprilat, irbesartan, lisinopril, losartan and valsartan were firstly screened based on their impact on the viability of nasal, lung, and neuronal cell lines and their apparent permeability (Papp) across porcine olfactory mucosa. Irbesartan, identified as the one with the best safety and permeability balance, was selected for pharmacokinetic characterization following single and multidose IN administration to CD-1 mice. The results were compared to those obtained by intravenous (IV) injection to assess direct nose-to-brain drug delivery. Olfactory toxicity and anxiety were also evaluated after multidose IN treatment. Irbesartan IN administration significantly enhanced brain targeting, with a 3-fold increase in the maximum concentration (C_max) and a 2.5-fold increase in the area under the curve (AUC_t) in the brain compared to IV route. The drug exhibited a t_max of 15 min post-IN administration and achieved a brain targeting efficiency of 239.56%, with a significant direct transport percentage of 58.26%. Multidose administration indicated no systemic or tissue accumulation, with accumulation ratio (R_ac) values below 1.0, and no significant olfactory toxicity. Overall, the study highlights the potential of IN delivery of irbesartan as a promising strategy to improve brain targeting and therapeutic outcomes in CNS diseases such as AD, providing an effective approach to bypass BBB limitations.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116616"},"PeriodicalIF":5.3,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613966","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":"Andrographolide prevents renal fibrosis via decelerating lipotoxicity-mediated premature senescence of tubular epithelial cells","authors":"Meng Yang ,&nbsp;Shengquan Wu ,&nbsp;Qihui Dai ,&nbsp;Weihong Qin ,&nbsp;Yujie Zhang ,&nbsp;Yiting Lei ,&nbsp;Haochang Song ,&nbsp;Tingting Zheng ,&nbsp;Min Guan ,&nbsp;Gonghua Huang ,&nbsp;Xinguang Liu","doi":"10.1016/j.bcp.2024.116615","DOIUrl":"10.1016/j.bcp.2024.116615","url":null,"abstract":"<div><div>Excessive lipid accumulation often occurs in the early stage of chronic kidney disease (CKD) which is prone to induce oxidative stress and mitochondrial damage, promoting the progression of kidney fibrosis. Andrographolide (AP), a multifunctional natural terpenoids derived from <em>Andrographis paniculate</em>, has been suggested to play beneficial roles in metabolic disorders-associated disease. Here, we reported that AP effectively counteracts tubule injury and interstitial fibrosis in mice fed with a long-term high-fat diet (HFD). AP treatment decreased HFD-induced lipid accumulation in kidney parenchyma and attenuated lipotoxicity-mediated oxidative stress and mitochondrial dysfunction, resulting in a marked decrease in tubular cell senescence. Importantly, AP inhibited senescence-associated secretory phenotype (SASP) secretion by senescent tubular cells, and in turn suppressed proliferation and activation of fibroblasts in a paracrine effect. Furthermore, we revealed that AP functions as an AMP-activated protein kinase (AMPK) activator to ameliorate renal lipid accumulation through coordinately modulating AMP-activated protein kinase AMPK target genes. By stimulation of AMPK activity, AP protects injured kidney against tubular cell senescence and fibroblast activation. These results suggest the potential therapeutic application of AP in the prevention and treatment of CKD, highlighting the promising drug strategy of targeting the lipotoxicity-mediated premature senescence in tubular cells.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116615"},"PeriodicalIF":5.3,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613998","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}