Pub Date : 2024-08-30DOI: 10.1016/j.phrs.2024.107356
Recent advances in genetic diagnosis identified variants in genes encoding GABAA receptors as causative for genetic epilepsy. Here, we selected eight disease-associated variants in the α1 subunit of GABAA receptors causing mild to severe clinical phenotypes and showed that they are loss of function, mainly by reducing the folding and surface trafficking of the α1 protein. Furthermore, we sought client protein-specific pharmacological chaperones to restore the function of pathogenic receptors. Applications of positive allosteric modulators, including Hispidulin and TP003, increase the functional surface expression of the α1 variants. Mechanism of action study demonstrated that they enhance the folding, assembly, and trafficking and reduce the degradation of GABAA variants without activating the unfolded protein response in HEK293T cells and human iPSC-derived neurons. Since these compounds cross the blood-brain barrier, such a pharmacological chaperoning strategy holds great promise to treat genetic epilepsy in a GABAA receptor-specific manner.
{"title":"Pharmacological chaperones restore proteostasis of epilepsy-associated GABAA receptor variants","authors":"","doi":"10.1016/j.phrs.2024.107356","DOIUrl":"10.1016/j.phrs.2024.107356","url":null,"abstract":"<div><p>Recent advances in genetic diagnosis identified variants in genes encoding GABA<sub>A</sub> receptors as causative for genetic epilepsy. Here, we selected eight disease-associated variants in the α1 subunit of GABA<sub>A</sub> receptors causing mild to severe clinical phenotypes and showed that they are loss of function, mainly by reducing the folding and surface trafficking of the α1 protein. Furthermore, we sought client protein-specific pharmacological chaperones to restore the function of pathogenic receptors. Applications of positive allosteric modulators, including Hispidulin and TP003, increase the functional surface expression of the α1 variants. Mechanism of action study demonstrated that they enhance the folding, assembly, and trafficking and reduce the degradation of GABA<sub>A</sub> variants without activating the unfolded protein response in HEK293T cells and human iPSC-derived neurons. Since these compounds cross the blood-brain barrier, such a pharmacological chaperoning strategy holds great promise to treat genetic epilepsy in a GABA<sub>A</sub> receptor-specific manner.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003013/pdfft?md5=737b2d5ff82d045c1e90ffb1f07d48f8&pid=1-s2.0-S1043661824003013-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142110745","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}
Pub Date : 2024-08-30DOI: 10.1016/j.phrs.2024.107375
The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) is a growing concern for the high incidence rate of hepatocellular carcinoma (HCC) globally. The progression of NAFLD to HCC is heterogeneous and non-linear, involving intermediate stages of non-alcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. There is a high unmet clinical need for appropriate diagnostic, prognostic, and therapeutic options to tackle this emerging epidemic. Unfortunately, at present, there is no validated marker to identify the risk of developing HCC in patients suffering from NAFLD or NASH. Additionally, the current treatment protocols for HCC don’t differentiate between viral infection or NAFLD-specific etiology of the HCC and have a limited success rate. The mammalian target of rapamycin complex 1 (mTORc1) is an important protein involved in many vital cellular processes like lipid metabolism, glucose homeostasis, and inflammation. These cellular processes are highly implicated in NAFLD and its progression to severe liver manifestations. Additionally, hyperactivation of mTORc1 is known to promote cell proliferation, which can contribute to the genesis and progression of tumors. Many mTORc1 inhibitors are being evaluated for different types of cancers under various phases of clinical trials. This paper deliberates on the strong pathological implication of the mTORc1 signaling pathway in NAFLD and its progression to NASH and HCC and advocates for a systematic investigation of known mTORc1 inhibitors in suitable pre-clinical models of HCC having NAFLD/NASH-specific etiology.
{"title":"NAFLD-associated hepatocellular carcinoma (HCC) – A compelling case for repositioning of existing mTORc1 inhibitors","authors":"","doi":"10.1016/j.phrs.2024.107375","DOIUrl":"10.1016/j.phrs.2024.107375","url":null,"abstract":"<div><p>The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) is a growing concern for the high incidence rate of hepatocellular carcinoma (HCC) globally. The progression of NAFLD to HCC is heterogeneous and non-linear, involving intermediate stages of non-alcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. There is a high unmet clinical need for appropriate diagnostic, prognostic, and therapeutic options to tackle this emerging epidemic. Unfortunately, at present, there is no validated marker to identify the risk of developing HCC in patients suffering from NAFLD or NASH. Additionally, the current treatment protocols for HCC don’t differentiate between viral infection or NAFLD-specific etiology of the HCC and have a limited success rate. The mammalian target of rapamycin complex 1 (mTORc1) is an important protein involved in many vital cellular processes like lipid metabolism, glucose homeostasis, and inflammation. These cellular processes are highly implicated in NAFLD and its progression to severe liver manifestations. Additionally, hyperactivation of mTORc1 is known to promote cell proliferation, which can contribute to the genesis and progression of tumors. Many mTORc1 inhibitors are being evaluated for different types of cancers under various phases of clinical trials. This paper deliberates on the strong pathological implication of the mTORc1 signaling pathway in NAFLD and its progression to NASH and HCC and advocates for a systematic investigation of known mTORc1 inhibitors in suitable pre-clinical models of HCC having NAFLD/NASH-specific etiology.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003207/pdfft?md5=6bdb1381ac1b3d70f38cf02a0329affa&pid=1-s2.0-S1043661824003207-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142110744","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}
Pub Date : 2024-08-30DOI: 10.1016/j.phrs.2024.107380
Giorgia Bresciani, Federico Manai, Szabolcs Felszeghy, Adrian Smedowski, Kai Kaarniranta, Marialaura Amadio
Age-related macular degeneration (AMD) is a common retinal pathology characterized by degeneration of macula's retinal pigment epithelium (RPE) and photoreceptors, visual impairment, or loss. Compared to wet AMD, dry AMD is more common, but lacks cures; therefore, identification of new potential therapeutic targets and treatments is urgent. Increased oxidative stress and declining antioxidant, detoxifying systems contribute to the pathophysiologic mechanisms underlying AMD. The present work shows that the Embryonic Lethal Abnormal Vision-Like 1/Human antigen R (ELAVL1/HuR) and the Vascular Endothelial Growth Factor (VEGF) protein levels are higher in the RPE of both dry and wet AMD patients compared to healthy subjects. Moreover, increased HuR protein levels are detected in the retina, and especially in the RPE layer, of a dry AMD model, the nuclear factor erythroid 2-related factor 2 (Nrf2) / peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) double knock-out mouse. The crosstalk among Nrf2, HuR and VEGF has been also studied in ARPE-19 cells in basal and stressful conditions related to the AMD context (i.e., oxidative stress, autophagy impairment, Nrf2 deficit), offering new evidence of the mutual influence between Nrf2 and HuR, of the dependence of VEGF expression and secretion by these two factors, and of the increased susceptibility of cells to stressful conditions in Nrf2- or HuR-impaired contexts. Overall, this study shows evidence of the interplay among Nrf2, HuR and VEGF, essential factors for RPE homeostasis, and represents an additional piece in the understanding of the complex pathophysiologic mechanisms underlying AMD.
{"title":"VEGF and ELAVL1/HuR protein levels are increased in dry and wet AMD patients. A new tile in the pathophysiologic mechanisms underlying RPE degeneration?","authors":"Giorgia Bresciani, Federico Manai, Szabolcs Felszeghy, Adrian Smedowski, Kai Kaarniranta, Marialaura Amadio","doi":"10.1016/j.phrs.2024.107380","DOIUrl":"10.1016/j.phrs.2024.107380","url":null,"abstract":"<p><p>Age-related macular degeneration (AMD) is a common retinal pathology characterized by degeneration of macula's retinal pigment epithelium (RPE) and photoreceptors, visual impairment, or loss. Compared to wet AMD, dry AMD is more common, but lacks cures; therefore, identification of new potential therapeutic targets and treatments is urgent. Increased oxidative stress and declining antioxidant, detoxifying systems contribute to the pathophysiologic mechanisms underlying AMD. The present work shows that the Embryonic Lethal Abnormal Vision-Like 1/Human antigen R (ELAVL1/HuR) and the Vascular Endothelial Growth Factor (VEGF) protein levels are higher in the RPE of both dry and wet AMD patients compared to healthy subjects. Moreover, increased HuR protein levels are detected in the retina, and especially in the RPE layer, of a dry AMD model, the nuclear factor erythroid 2-related factor 2 (Nrf2) / peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) double knock-out mouse. The crosstalk among Nrf2, HuR and VEGF has been also studied in ARPE-19 cells in basal and stressful conditions related to the AMD context (i.e., oxidative stress, autophagy impairment, Nrf2 deficit), offering new evidence of the mutual influence between Nrf2 and HuR, of the dependence of VEGF expression and secretion by these two factors, and of the increased susceptibility of cells to stressful conditions in Nrf2- or HuR-impaired contexts. Overall, this study shows evidence of the interplay among Nrf2, HuR and VEGF, essential factors for RPE homeostasis, and represents an additional piece in the understanding of the complex pathophysiologic mechanisms underlying AMD.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142110747","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}
Pub Date : 2024-08-30DOI: 10.1016/j.phrs.2024.107379
Tuberculosis (TB), a deadly disease caused by Mycobacterium tuberculosis (Mtb) infection, remains one of the top killers among infectious diseases worldwide. How to increase targeting effects of current anti-TB chemotherapeutics and enhance anti-TB immunological responses remains a big challenge in TB and drug-resistant TB treatment. Here, mannose functionalized and polyetherimide protected graphene oxide system (GO-PEI-MAN) was designed for macrophage-targeted antibiotic (rifampicin) and autophagy inducer (carbamazepine) delivery to achieve more effective Mtb killings by combining targeted drug killing and host immunological clearance. GO-PEI-MAN system demonstrated selective uptake by in vitro macrophages and ex vivo macrophages from macaques. The endocytosed GO-PEI-MAN system would be transported into lysosomes, where the drug loaded Rif@Car@GO-PEI-MAN system would undergo accelerated drug release in acidic lysosomal conditions. Rif@Car@GO-PEI-MAN could significantly promote autophagy and apoptosis in Mtb infected macrophages, as well as induce anti-bacterial M1 polarization of Mtb infected macrophages to increase anti-bacterial IFN-γ and nitric oxide production. Collectively, Rif@Car@GO-PEI-MAN demonstrated effectively enhanced intracellular Mtb killing effects than rifampicin, carbamazepine or GO-PEI-MAN alone in Mtb infected macrophages, and could significantly reduce mycobacterial burdens in the lung of infected mice with alleviated pathology and inflammation without systemic toxicity. This macrophage targeted nanosystem synergizing increased drug killing efficiency and enhanced host immunological defense may be served as more effective therapeutics against TB and drug-resistant TB.
{"title":"Macrophage targeted graphene oxide nanosystem synergize antibiotic killing and host immune defense for Tuberculosis Therapy","authors":"","doi":"10.1016/j.phrs.2024.107379","DOIUrl":"10.1016/j.phrs.2024.107379","url":null,"abstract":"<div><p>Tuberculosis (TB), a deadly disease caused by <em>Mycobacterium tuberculosis</em> (Mtb) infection, remains one of the top killers among infectious diseases worldwide. How to increase targeting effects of current anti-TB chemotherapeutics and enhance anti-TB immunological responses remains a big challenge in TB and drug-resistant TB treatment. Here, mannose functionalized and polyetherimide protected graphene oxide system (GO-PEI-MAN) was designed for macrophage-targeted antibiotic (rifampicin) and autophagy inducer (carbamazepine) delivery to achieve more effective Mtb killings by combining targeted drug killing and host immunological clearance. GO-PEI-MAN system demonstrated selective uptake by <em>in vitro</em> macrophages and <em>ex vivo</em> macrophages from macaques. The endocytosed GO-PEI-MAN system would be transported into lysosomes, where the drug loaded Rif@Car@GO-PEI-MAN system would undergo accelerated drug release in acidic lysosomal conditions. Rif@Car@GO-PEI-MAN could significantly promote autophagy and apoptosis in Mtb infected macrophages, as well as induce anti-bacterial M1 polarization of Mtb infected macrophages to increase anti-bacterial IFN-γ and nitric oxide production. Collectively, Rif@Car@GO-PEI-MAN demonstrated effectively enhanced intracellular Mtb killing effects than rifampicin, carbamazepine or GO-PEI-MAN alone in Mtb infected macrophages, and could significantly reduce mycobacterial burdens in the lung of infected mice with alleviated pathology and inflammation without systemic toxicity. This macrophage targeted nanosystem synergizing increased drug killing efficiency and enhanced host immunological defense may be served as more effective therapeutics against TB and drug-resistant TB.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003244/pdfft?md5=4aa5ccb131a64c818f3cfdcc918df90a&pid=1-s2.0-S1043661824003244-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142110742","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}
Pub Date : 2024-08-30DOI: 10.1016/j.phrs.2024.107381
Natural polyphenols, abundant in the human diet, are derived from a wide variety of sources. Numerous preclinical studies have demonstrated their significant anticancer properties against various malignancies, making them valuable resources for drug development. However, traditional experimental methods for developing anticancer therapies from natural polyphenols are time-consuming and labor-intensive. Recently, artificial intelligence has shown promising advancements in drug discovery. Integrating AI technologies into the development process for natural polyphenols can substantially reduce development time and enhance efficiency. In this study, we review the crucial roles of natural polyphenols in anticancer treatment and explore the potential of AI technologies to aid in drug development. Specifically, we discuss the application of AI in key stages such as drug structure prediction, virtual drug screening, prediction of biological activity, and drug-target protein interaction, highlighting the potential to revolutionize the development of natural polyphenol-based anticancer therapies.
{"title":"The role of artificial intelligence in the development of anticancer therapeutics from natural polyphenols: Current advances and future prospects","authors":"","doi":"10.1016/j.phrs.2024.107381","DOIUrl":"10.1016/j.phrs.2024.107381","url":null,"abstract":"<div><p>Natural polyphenols, abundant in the human diet, are derived from a wide variety of sources. Numerous preclinical studies have demonstrated their significant anticancer properties against various malignancies, making them valuable resources for drug development. However, traditional experimental methods for developing anticancer therapies from natural polyphenols are time-consuming and labor-intensive. Recently, artificial intelligence has shown promising advancements in drug discovery. Integrating AI technologies into the development process for natural polyphenols can substantially reduce development time and enhance efficiency. In this study, we review the crucial roles of natural polyphenols in anticancer treatment and explore the potential of AI technologies to aid in drug development. Specifically, we discuss the application of AI in key stages such as drug structure prediction, virtual drug screening, prediction of biological activity, and drug-target protein interaction, highlighting the potential to revolutionize the development of natural polyphenol-based anticancer therapies.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003268/pdfft?md5=a01c8d95dd22c6cd2ec3bde07b10d0cd&pid=1-s2.0-S1043661824003268-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142110746","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}
Pub Date : 2024-08-29DOI: 10.1016/j.phrs.2024.107378
Dual antiplatelet therapy (DAPT), comprising both aspirin and the P2Y12 receptor inhibitor, is crucial in managing patients with coronary artery disease following percutaneous coronary intervention (PCI). The optimal duration for DAPT in patients with angiography-detected moderate-to-severe calcified coronary (MSCC) lesions who underwent PCI with drug-eluting stents (DES) implantation remains uncertain. We recruited patients with angiography-detected MSCC lesions who received DES implantation from the prospective Fuwai Percutaneous Coronary Intervention Registry. Patients were classified into two groups according to the duration of DAPT: those with a DAPT duration of one year or less, and those with a DAPT duration of more than one year. The primary endpoint was the major adverse cardiovascular and cerebrovascular event, which was defined as composed of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. The key-safety endpoint was bleeding type 2, 3, or 5 according to the Bleeding Academic Research Consortium criteria. There were 1730 patients included in the study, and 470 (27.17 %) continued DAPT for more than one year after undergoing MSCC-PCI with DES implantation. The median follow-up time was 2.5 years. DAPT>1-year versus ≤1-year DAPT was significantly associated with a reduced risk of the primary outcome (1.59 % versus 3.19 %; adjusted hazard ratio=0.44; 95 % CI: 0.22–0.88). Similar trends were observed for all-cause death (0.16 % versus 1.91 %; P<0.001) and cardiovascular death (0.08 % versus 1.06 %; P=0.001). There was no significant difference in the key-safety endpoint between 2 regimens (1.75 % versus 0.85 %; adjusted hazard ratio=1.95; 95 % CI: 0.65–5.84). In conclusion, long-term DAPT after DES implantation in patients with MSCC lesions resulted in improved clinical outcomes at 2.5 years. This was achieved by reducing the risk of ischemia without increasing clinically significant bleeding.
{"title":"Novel insights on dual antiplatelet therapy duration following stenting for angiography-detected moderate-to-severe calcified coronary lesions","authors":"","doi":"10.1016/j.phrs.2024.107378","DOIUrl":"10.1016/j.phrs.2024.107378","url":null,"abstract":"<div><p>Dual antiplatelet therapy (DAPT), comprising both aspirin and the P2Y<sub>12</sub> receptor inhibitor, is crucial in managing patients with coronary artery disease following percutaneous coronary intervention (PCI). The optimal duration for DAPT in patients with angiography-detected moderate-to-severe calcified coronary (MSCC) lesions who underwent PCI with drug-eluting stents (DES) implantation remains uncertain. We recruited patients with angiography-detected MSCC lesions who received DES implantation from the prospective Fuwai Percutaneous Coronary Intervention Registry. Patients were classified into two groups according to the duration of DAPT: those with a DAPT duration of one year or less, and those with a DAPT duration of more than one year. The primary endpoint was the major adverse cardiovascular and cerebrovascular event, which was defined as composed of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. The key-safety endpoint was bleeding type 2, 3, or 5 according to the Bleeding Academic Research Consortium criteria. There were 1730 patients included in the study, and 470 (27.17 %) continued DAPT for more than one year after undergoing MSCC-PCI with DES implantation. The median follow-up time was 2.5 years. DAPT>1-year versus ≤1-year DAPT was significantly associated with a reduced risk of the primary outcome (1.59 % versus 3.19 %; adjusted hazard ratio=0.44; 95 % CI: 0.22–0.88). Similar trends were observed for all-cause death (0.16 % versus 1.91 %; <em>P</em><0.001) and cardiovascular death (0.08 % versus 1.06 %; <em>P</em>=0.001). There was no significant difference in the key-safety endpoint between 2 regimens (1.75 % versus 0.85 %; adjusted hazard ratio=1.95; 95 % CI: 0.65–5.84). In conclusion, long-term DAPT after DES implantation in patients with MSCC lesions resulted in improved clinical outcomes at 2.5 years. This was achieved by reducing the risk of ischemia without increasing clinically significant bleeding.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003232/pdfft?md5=79bc4c939c53c86b257ff30bf3e21180&pid=1-s2.0-S1043661824003232-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142096911","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}
Pub Date : 2024-08-28DOI: 10.1016/j.phrs.2024.107369
Cardiac diseases encompass a wide range of conditions that affect the structure and function of the heart. These conditions are a leading cause of morbidity and mortality worldwide. The serum- and glucocorticoid-inducible kinase 1 (SGK1) is a serine/threonine kinase that plays a significant role in various cellular processes, including cell survival and stress response. Alterations in SGK1 activity can have significant impacts on health and disease. Multiple research findings have indicated that SGK1 is associated with heart disease due to its involvement in cardiac hypertrophy and fibrosis. This article reviews different signaling pathways associated with SGK1 activity in various heart conditions, including the SGK1/NF-κB and PI3K/SGK1 pathways.
{"title":"Serum and glucocorticoid-regulated kinase 1 (SGK1) as an emerging therapeutic target for cardiac diseases","authors":"","doi":"10.1016/j.phrs.2024.107369","DOIUrl":"10.1016/j.phrs.2024.107369","url":null,"abstract":"<div><p>Cardiac diseases encompass a wide range of conditions that affect the structure and function of the heart. These conditions are a leading cause of morbidity and mortality worldwide. The serum- and glucocorticoid-inducible kinase 1 (SGK1) is a serine/threonine kinase that plays a significant role in various cellular processes, including cell survival and stress response. Alterations in SGK1 activity can have significant impacts on health and disease. Multiple research findings have indicated that SGK1 is associated with heart disease due to its involvement in cardiac hypertrophy and fibrosis. This article reviews different signaling pathways associated with SGK1 activity in various heart conditions, including the SGK1/NF-κB and PI3K/SGK1 pathways.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003141/pdfft?md5=2bf3a63ffcacc3591296836ff82e339d&pid=1-s2.0-S1043661824003141-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142089028","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}
Pub Date : 2024-08-28DOI: 10.1016/j.phrs.2024.107377
The bromodomain and extraterminal domain (BET) family proteins serve as primary readers of acetylated lysine residues and play crucial roles in cell proliferation and differentiation. Dysregulation of BET proteins has been implicated in tumorigenesis, making them important therapeutic targets. BET-bromodomain (BD) inhibitors and BET-targeting degraders have been developed to inhibit BET proteins. In this study, we found that the BET inhibitor MS645 exhibited superior antiproliferative activity than BET degraders including ARV771, AT1, MZ1 and dBET1 in triple-negative breast cancer (TNBC) cells. Treatment with MS645 led to the dissociation of BETs, MED1 and RNA polymerase II from the E2F1–3 promoter, resulting in the suppression of E2F1–3 transcription and subsequent inhibition of cell growth in TNBC. In contrast, while ARV771 displaced BET proteins from chromatin, it did not significantly alter E2F1–3 expression. Mechanistically, ARV771 induced BRD4 depletion at protein level, which markedly increased EGR1 expression. This elevation of EGR1 subsequently recruited septin 2 and septin 9 to E2F1–3 promoters, enhancing E2F1–3 transcription and promoting cell proliferation rate in vitro and in vivo. Our findings provide valuable insights into differential mechanisms of BET inhibition and highlight potential of developing BET-targeting molecules as therapeutic strategies for TNBC.
溴化结构域和外基质结构域(BET)家族蛋白是乙酰化赖氨酸残基的主要阅读器,在细胞增殖和分化过程中发挥着至关重要的作用。BET 蛋白的失调与肿瘤发生有关,因此成为重要的治疗靶标。目前已开发出抑制 BET 蛋白的 BET-溴结构域(BD)抑制剂和 BET 靶向降解剂。在这项研究中,我们发现在三阴性乳腺癌(TNBC)细胞中,BET抑制剂MS645比BET降解剂(包括ARV771、AT1、MZ1和dBET1)具有更强的抗增殖活性。用 MS645 处理会导致 BET、MED1 和 RNA 聚合酶 II 与 E2F1-3 启动子分离,从而抑制 E2F1-3 的转录,进而抑制 TNBC 细胞的生长。相反,虽然 ARV771 将 BET 蛋白从染色质中移出,但并没有显著改变 E2F1-3 的表达。从机理上讲,ARV771 在蛋白水平上诱导了 BRD4 的耗竭,从而显著增加了 EGR1 的表达。EGR1 的升高随后将 septin 2 和 septin 9 募集到 E2F1-3 启动子上,增强了 E2F1-3 的转录,促进了体外和体内细胞的增殖率。我们的研究结果为了解 BET 抑制的不同机制提供了有价值的见解,并凸显了开发 BET 靶向分子作为 TNBC 治疗策略的潜力。
{"title":"BET degrader exhibits lower antiproliferative activity than its inhibitor via EGR1 recruiting septins to promote E2F1-3 transcription in triple-negative breast cancer","authors":"","doi":"10.1016/j.phrs.2024.107377","DOIUrl":"10.1016/j.phrs.2024.107377","url":null,"abstract":"<div><p>The bromodomain and extraterminal domain (BET) family proteins serve as primary readers of acetylated lysine residues and play crucial roles in cell proliferation and differentiation. Dysregulation of BET proteins has been implicated in tumorigenesis, making them important therapeutic targets. BET-bromodomain (BD) inhibitors and BET-targeting degraders have been developed to inhibit BET proteins. In this study, we found that the BET inhibitor MS645 exhibited superior antiproliferative activity than BET degraders including ARV771, AT1, MZ1 and dBET1 in triple-negative breast cancer (TNBC) cells. Treatment with MS645 led to the dissociation of BETs, MED1 and RNA polymerase II from the E2F1–3 promoter, resulting in the suppression of E2F1–3 transcription and subsequent inhibition of cell growth in TNBC. In contrast, while ARV771 displaced BET proteins from chromatin, it did not significantly alter E2F1–3 expression. Mechanistically, ARV771 induced BRD4 depletion at protein level, which markedly increased EGR1 expression. This elevation of EGR1 subsequently recruited septin 2 and septin 9 to E2F1–3 promoters, enhancing E2F1–3 transcription and promoting cell proliferation rate in <em>vitro</em> and in <em>vivo</em>. Our findings provide valuable insights into differential mechanisms of BET inhibition and highlight potential of developing BET-targeting molecules as therapeutic strategies for TNBC.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003220/pdfft?md5=8da53eb109d867e7270ef708992883a2&pid=1-s2.0-S1043661824003220-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142096912","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}
Pub Date : 2024-08-28DOI: 10.1016/j.phrs.2024.107384
Energy metabolism disorder, mainly exhibiting the inhibition of fatty acid degradation and lipid accumulation, is highly related with aging acceleration. However, the intervention measures are deficient. Here, we reported Omega-3 polyunsaturated fatty acids (Omega-3 PUFAs), especially EPA, exerted beneficial effects on maintaining energy metabolism and lipid homeostasis to slow organ aging. As the endogenous agonist of peroxisome proliferator–activated receptor α (PPARα), Omega-3 PUFAs significantly boosted fatty acid β-oxidation and ATP production in multiple aged organs. Consequently, Omega-3 PUFAs effectively inhibited age-related pathological changes, preserved organ function, and retarded aging process. The beneficial effects of Omega-3 PUFAs were also testified in mfat-1 transgenic mice, which spontaneously generate abundant endogenous Omega-3 PUFAs. In conclusion, our study innovatively demonstrated Omega-3 PUFAs administration in diet slow aging through promoting energy metabolism. The supplement of Omega-3 PUFAs or fat-1 transgene provides a promising therapeutic approach to promote healthy aging in the elderly.
{"title":"Omega-3 PUFAs slow organ aging through promoting energy metabolism","authors":"","doi":"10.1016/j.phrs.2024.107384","DOIUrl":"10.1016/j.phrs.2024.107384","url":null,"abstract":"<div><p>Energy metabolism disorder, mainly exhibiting the inhibition of fatty acid degradation and lipid accumulation, is highly related with aging acceleration. However, the intervention measures are deficient. Here, we reported Omega-3 polyunsaturated fatty acids (Omega-3 PUFAs), especially EPA, exerted beneficial effects on maintaining energy metabolism and lipid homeostasis to slow organ aging. As the endogenous agonist of peroxisome proliferator–activated receptor α (PPARα), Omega-3 PUFAs significantly boosted fatty acid β-oxidation and ATP production in multiple aged organs. Consequently, Omega-3 PUFAs effectively inhibited age-related pathological changes, preserved organ function, and retarded aging process. The beneficial effects of Omega-3 PUFAs were also testified in mfat-1 transgenic mice, which spontaneously generate abundant endogenous Omega-3 PUFAs. In conclusion, our study innovatively demonstrated Omega-3 PUFAs administration in diet slow aging through promoting energy metabolism. The supplement of Omega-3 PUFAs or <em>fat-1</em> transgene provides a promising therapeutic approach to promote healthy aging in the elderly.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003293/pdfft?md5=87e8b82a8e1cff0c6806d4f9440f9748&pid=1-s2.0-S1043661824003293-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142096913","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}
Pub Date : 2024-08-28DOI: 10.1016/j.phrs.2024.107383
Mitochondria exhibit heterogeneous shapes and networks within and among cell types and tissues, also in normal or osteoporotic bone tissues with complex cell types. This dynamic characteristic is determined by the high plasticity provided by mitochondrial dynamics and is stemmed from responding to the survival and functional requirements of various bone cells in a specific microenvironments. In contrast, mitochondrial dysfunction, induced by dysregulation of mitochondrial dynamics, may act as a trigger of cell death signals, including common apoptosis and other forms of programmed cell death (PCD). These PCD processes consisting of tightly structured cascade gene expression events, can further influence the bone remodeling by facilitating the death of various bone cells. Mitochondrial dynamics, therefore, drive the bone cells to stand at the crossroads of life and death by integrating external signals and altering metabolism, shape, and signal-response properties of mitochondria. This implies that targeting mitochondrial dynamics displays significant potential in treatment of osteoporosis. Considerable effort has been made in osteoporosis to emphasize the parallel roles of mitochondria in regulating energy metabolism, calcium signal transduction, oxidative stress, inflammation, and cell death. However, the emerging field of mitochondrial dynamics-related PCD is not well understood. Herein, to bridge the gap, we outline the latest knowledge on mitochondrial dynamics regulating bone cell life or death during normal bone remodeling and osteoporosis.
{"title":"Cell life-or-death events in osteoporosis: All roads lead to mitochondrial dynamics","authors":"","doi":"10.1016/j.phrs.2024.107383","DOIUrl":"10.1016/j.phrs.2024.107383","url":null,"abstract":"<div><p>Mitochondria exhibit heterogeneous shapes and networks within and among cell types and tissues, also in normal or osteoporotic bone tissues with complex cell types. This dynamic characteristic is determined by the high plasticity provided by mitochondrial dynamics and is stemmed from responding to the survival and functional requirements of various bone cells in a specific microenvironments. In contrast, mitochondrial dysfunction, induced by dysregulation of mitochondrial dynamics, may act as a trigger of cell death signals, including common apoptosis and other forms of programmed cell death (PCD). These PCD processes consisting of tightly structured cascade gene expression events, can further influence the bone remodeling by facilitating the death of various bone cells. Mitochondrial dynamics, therefore, drive the bone cells to stand at the crossroads of life and death by integrating external signals and altering metabolism, shape, and signal-response properties of mitochondria. This implies that targeting mitochondrial dynamics displays significant potential in treatment of osteoporosis. Considerable effort has been made in osteoporosis to emphasize the parallel roles of mitochondria in regulating energy metabolism, calcium signal transduction, oxidative stress, inflammation, and cell death. However, the emerging field of mitochondrial dynamics-related PCD is not well understood. Herein, to bridge the gap, we outline the latest knowledge on mitochondrial dynamics regulating bone cell life or death during normal bone remodeling and osteoporosis.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003281/pdfft?md5=f38b9f3dd2ea707ff789171d4e220b0c&pid=1-s2.0-S1043661824003281-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142096914","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}