Pharmacological research最新文献

{"title":"Formation of CSE-YAP complex drives FOXD3-mediated transition of neurotoxic astrocytes in Parkinson’s disease","authors":"Rong-Xin Zhu ,&nbsp;Yue-Han Chen ,&nbsp;Xian Xia ,&nbsp;Ting Liu ,&nbsp;Cong Wang ,&nbsp;Lei Cao ,&nbsp;Yang Liu ,&nbsp;Ming Lu","doi":"10.1016/j.phrs.2024.107507","DOIUrl":"10.1016/j.phrs.2024.107507","url":null,"abstract":"<div><div>Astrocytes, constituting the predominant glial cells in the brain, undergo significant morphological and functional transformations amidst the progression of Parkinson’s disease (PD). A majority of these reactive astrocytes display a neurotoxic phenotype, intensifying inflammatory responses. Nonetheless, the molecular underpinnings steering neurotoxic astrocyte reactivity during PD progression remain mostly uncharted. Here, we uncover the unique role of cystathionine γ-lyase (CSE) in shaping astrocyte reactivity, primarily channeling astrocytes towards a neurotoxic phenotype, thereby escalating neuroinflammation in PD. Single-cell sequencing data drawn from PD patients coupled with RNA sequencing data from MPP⁺-treated astrocytes, highlighted a marked positive association between increased expression of <em>Cth</em>, the gene that encodes CSE, and neurotoxic astrocyte reactivity. Employing genetic manipulation of <em>Cth</em> in astrocytes, we evidenced that CSE instigates a transition to a neurotoxic state in PD-afflicted astrocytes under <em>in vitro</em> and <em>in vivo</em> settings. Moreover, we identified a CSE-Yes-associated protein (YAP) complex within astrocytes via label-free mass spectrometry. An increased formation of the CSE-YAP complex was found to facilitate the expression of gene patterns tied to neurotoxic astrocytes, driven by the transcription factor, forkhead box protein D3 (FOXD3). Consequently, our work unveils valuable insights into the cell type-specific function of CSE in the brain, and presents FOXD3 as a novel transcription factor influencing astrocyte phenotypes in PD. These findings lay the groundwork for the development of potential strategies intended to manage conditions associated with neuroinflammation.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"210 ","pages":"Article 107507"},"PeriodicalIF":9.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639443","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":"New TIPARP inhibitor rescues mitochondrial function and brain injury in ischemic stroke.","authors":"Yang Cai, Hongfeng Gu, Lu Li, Xue Liu, Ying Bai, Ling Shen, Bing Han, Yungen Xu, Honghong Yao","doi":"10.1016/j.phrs.2024.107508","DOIUrl":"10.1016/j.phrs.2024.107508","url":null,"abstract":"<p><p>Ischemic stroke is a high-mortality disease that urgently requires new therapeutic strategies. Insufficient cerebral blood supply can induce poly (ADP-ribose) polymerase (PARP) activation and mitochondrial dysfunction, leading to tissue damage and motor dysfunction. We demonstrate that the expression of TCDD inducible PARP (TIPARP) is elevated in ischemic stroke patients and mice. Knockdown of Tiparp reduces brain infarction and promotes recovery of motor function in ischemic stroke mice. A rationally designed TIPARP inhibitor, XG-04-B1, promotes repair of brain injury and recovery of motor function in ischemic stroke mice. Mechanistically, XG-04-B1 increases neuronal plasticity and inhibits astrocyte activation in ischemic stroke mice. In addition, eukaryotic translation initiation factor 3 subunit B (EIF3B) is a direct target of TIPARP. TIPARP interacts with EIF3B through nucleoplasmic redistribution, leading to mitochondrial dysfunction. Knockdown of Tiparp and inhibition of TIPARP via XG-04-B1 restore mitochondrial homeostasis in ischemic stroke mice. Taken together, TIPARP activation contributes to mitochondrial dysfunction and subsequent brain injury, and is therefore a promising therapeutic target for stroke.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107508"},"PeriodicalIF":9.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639402","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":"Pregnane X receptor activation promotes hematopoiesis during liver regeneration by inducing proliferation of hematopoietic stem and progenitor cells in mice","authors":"Shuang Hu ,&nbsp;Chenghua Wu ,&nbsp;Dan Li ,&nbsp;Xiaowen Jiang ,&nbsp;Peng Wang ,&nbsp;Guofang Bi ,&nbsp;Hui Ouyang ,&nbsp;Fengting Liang ,&nbsp;Wenhong Zhou ,&nbsp;Xiao Yang ,&nbsp;Jian-Hong Fang ,&nbsp;Huichang Bi","doi":"10.1016/j.phrs.2024.107504","DOIUrl":"10.1016/j.phrs.2024.107504","url":null,"abstract":"<div><div>Liver regeneration is a complex process that involves the recruitment of bone marrow (BM)-derived hematopoietic stem and progenitor cells (HSPCs). Pregnane X receptor (PXR), also known as NR1I2, is an important regulator for liver enlargement and regeneration. However, the role of PXR activation in hematopoiesis during liver regeneration remains unclear. This study investigates the effects of PXR activation on HSPCs and hematopoiesis during liver regeneration, as well as the underlying mechanisms involved. Using a 70 % partial hepatectomy (PHx) on C57BL/6 wild-type (WT) and <em>Pxr</em>-null mice, we observed a significant correlation between the changes in HSPCs numbers in BM and the process of liver regeneration. PXR activation significantly increased the population of Lineage^- Sca-1⁺ c-Kit⁺ (LSK) cells in the BM, which are key HSPCs involved in hematopoiesis. Additionally, PXR activation increased serum levels of thrombopoietin (TPO) and erythropoietin (EPO), factors known to support HSPCs proliferation and hematopoiesis in the process of liver regeneration. PXR activation does not affect the hematopoietic function of normal mice. Furthermore, mice subjected to irradiation or busulfan-induced hematopoietic dysfunction exhibited impaired liver regeneration, which was alleviated by PXR activation. Importantly, in <em>Pxr</em>-null mice, the promotive effects of PXR activation on liver regeneration and increase of HSPCs were markedly diminished. Moreover, liver-specific <em>Pxr</em> silencing using AAV-<em>Pxr</em> shRNA attenuated the PXR activation-mediated liver regeneration and increase in BM LSK cells, confirming the critical role of hepatic PXR in hematopoiesis during liver regeneration. Collectively, these findings reveal that PXR activation promotes HSPCs proliferation and hematopoiesis during liver regeneration, providing new insights into the molecular mechanisms underlying the role of PXR in liver regeneration and hematopoiesis.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"210 ","pages":"Article 107504"},"PeriodicalIF":9.1,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142625824","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":"Targeting gut microbiota as a therapeutic target in T2DM: A review of multi-target interactions of probiotics, prebiotics, postbiotics, and synbiotics with the intestinal barrier","authors":"Keyu Chen ,&nbsp;Han Wang ,&nbsp;Xiaofei Yang ,&nbsp;Cheng Tang ,&nbsp;Guojie Hu ,&nbsp;Zezheng Gao","doi":"10.1016/j.phrs.2024.107483","DOIUrl":"10.1016/j.phrs.2024.107483","url":null,"abstract":"<div><div>The global epidemic of type 2 diabetes mellitus (T2DM) imposes a substantial burden on public health and healthcare expenditures, thereby driving the pursuit of cost-effective preventive and therapeutic strategies. Emerging evidence suggests a potential association between dysbiosis of gut microbiota and its metabolites with T2DM, indicating that targeted interventions aimed at modulating gut microbiota may represent a promising therapeutic approach for the management of T2DM. In this review, we concentrated on the multifaceted interactions between the gut microbiota and the intestinal barrier in the context of T2DM. We systematically summarized that the imbalance of beneficial gut microbiota and its metabolites may constitute a viable therapeutic approach for the management of T2DM. Meanwhile, the mechanisms by which gut microbiota interventions, such as probiotics, prebiotics, postbiotics, and synbiotics, synergistically improve insulin resistance in T2DM are summarized. These mechanisms include the restoration of gut microbiota structure, upregulation of intestinal epithelial cell proliferation and differentiation, enhancement of tight junction protein expression, promotion of mucin secretion by goblet cells, and the immunosuppressive functions of regulatory T cells (Treg) and M2 macrophages. Collectively, these actions contribute to the amelioration of the body's metabolic inflammatory status. Our objective is to furnish evidence that supports the clinical application of probiotics, prebiotics, and postbiotics in the management of T2DM.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"210 ","pages":"Article 107483"},"PeriodicalIF":9.1,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142625825","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":"Characterization of novel nitazene recreational drugs: Insights into their risk potential from in vitro µ-opioid receptor assays and in vivo behavioral studies in mice","authors":"Marthe M. Vandeputte ,&nbsp;Grant C. Glatfelter ,&nbsp;Donna Walther ,&nbsp;Nathan K. Layle ,&nbsp;Danielle M. St. Germaine ,&nbsp;István Ujváry ,&nbsp;Donna M. Iula ,&nbsp;Michael H. Baumann ,&nbsp;Christophe P. Stove","doi":"10.1016/j.phrs.2024.107503","DOIUrl":"10.1016/j.phrs.2024.107503","url":null,"abstract":"<div><div>2-Benzylbenzimidazole derivatives or ‘nitazenes’ are increasingly present on the recreational drug market. Here, we report the synthesis and pharmacological characterization of 15 structurally diverse nitazenes that might be predicted to emerge or grow in popularity. This work expands the existing knowledge about 2-benzylbenzimidazole structure-activity relationships (SARs), while also helping stakeholders (e.g., forensic toxicologists, clinicians, policymakers) in their risk assessment and preparedness for the potential next generation of nitazenes. <em>In vitro</em> µ-opioid receptor (MOR) affinity was determined via competition radioligand (³[H]DAMGO) binding assays in rat brain tissue. MOR activation (potency and efficacy) was studied by means of a cell-based β-arrestin 2 recruitment assay. For seven nitazenes, including etonitazene, opioid-like pharmacodynamic effects (antinociception, locomotor activity, body temperature changes) were evaluated after subcutaneous administration in male C57BL/6 J mice. The results showed that all nitazenes bound to MOR with nanomolar affinities, and the functional potency of several of them was comparable to or exceeded that of fentanyl. <em>In vivo</em>, dose-dependent effects were observed for antinociception, locomotor activity, and body temperature changes in mice. SAR insights included the high opioid-like activity of methionitazene, iso-butonitazene, sec-butonitazene, and the etonitazene analogues 1-ethyl-pyrrolidinylmethyl <em>N</em>-desalkyl etonitazene and ethylene etonitazene. The most potent analogue of the panel across all functional assays was α’-methyl etonitazene. Taken together, through critical pharmacological evaluation, this work provides a framework for strengthened preparedness and risk assessments of current and future nitazenes that have the potential to cause harm to users.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"210 ","pages":"Article 107503"},"PeriodicalIF":9.1,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142625741","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":"Commentary on: MicroRNAs in Helicobacter pylori-infected gastric cancer: Function and clinical application","authors":"Ya Liu,&nbsp;Zhao Zhao,&nbsp;Haibo Lei","doi":"10.1016/j.phrs.2024.107500","DOIUrl":"10.1016/j.phrs.2024.107500","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"210 ","pages":"Article 107500"},"PeriodicalIF":9.1,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142625743","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":"Cortistatin exerts an immunomodulatory and neuroprotective role in a preclinical model of ischemic stroke","authors":"J. Castillo-González ,&nbsp;L. Buscemi ,&nbsp;P. Vargas-Rodríguez ,&nbsp;I. Serrano-Martínez ,&nbsp;I. Forte-Lago ,&nbsp;M. Caro ,&nbsp;M. Price ,&nbsp;P. Hernández-Cortés ,&nbsp;L. Hirt ,&nbsp;E. González-Rey","doi":"10.1016/j.phrs.2024.107501","DOIUrl":"10.1016/j.phrs.2024.107501","url":null,"abstract":"<div><div>Ischemic stroke is the result of a permanent or transient occlusion of a brain artery, leading to irreversible tissue injury and long-term sequelae. Despite ongoing advancements in revascularization techniques, stroke remains the second leading cause of death worldwide. A comprehensive understanding of the complex and interconnected mechanisms, along with the endogenous mediators that modulate stroke responses is essential for the development of effective interventions. Our study investigates cortistatin, a neuropeptide extensively distributed in the immune and central nervous systems, known for its immunomodulatory properties. With neuroinflammation and peripheral immune deregulation as key pathological features of brain ischemia, cortistatin emerges as a promising therapeutic candidate. To this aim, we evaluated its potential effect in a well-established middle cerebral artery occlusion (MCAO) preclinical stroke model. Our findings indicated that the peripheral administration of cortistatin at 24 h post-stroke significantly reduced neurological damage and enhanced recovery. Importantly, cortistatin-induced neuroprotection was multitargeted, as it modulated the glial reactivity and astrocytic scar formation, facilitated blood-brain barrier recovery, and regulated local and systemic immune dysfunction. Surprisingly, administration of cortistatin at immediate and early post-stroke time points proved to be not beneficial and even detrimental. These results emphasize the importance of understanding the spatio-temporal dynamics of stroke pathology to develop innovative therapeutic strategies with appropriate time windows. Premature interruption of certain neuroinflammatory processes might inadvertently compromise neuroprotective mechanisms. In summary, our study highlights cortistatin as a novel pleiotropic therapeutic approach against ischemic stroke, offering new treatment options for patients who undergo early revascularization intervention but unsuccessful recovery.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"210 ","pages":"Article 107501"},"PeriodicalIF":9.1,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142625744","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":"Chrysophanol: A promising natural compound in cancer therapy – Mechanistic insights and future perspectives","authors":"Dehong Liu ,&nbsp;Kun Zhu ,&nbsp;Tao Guo ,&nbsp;Yao Xiao ,&nbsp;Meijing Wang ,&nbsp;Yanxin Guan ,&nbsp;Junjun Li ,&nbsp;Degui Chang ,&nbsp;Xujun Yu","doi":"10.1016/j.phrs.2024.107502","DOIUrl":"10.1016/j.phrs.2024.107502","url":null,"abstract":"<div><div>Cancer continues to be a leading cause of death worldwide, highlighting the urgent need for the development of new therapeutic strategies. Chrysophanol, a naturally occurring anthraquinone compound, has demonstrated significant potential in cancer treatment due to its diverse biological activities. This review delves into the mechanisms through which chrysophanol exerts its anti-cancer effects, including the induction of cell cycle arrest, promotion of apoptosis, regulation of autophagy, and initiation of necrosis across various cancer cell lines. Additionally, the review discusses chrysophanol's impact on inhibiting cancer cell invasion and metastasis and its role in modulating chemotherapy sensitivity. Despite the promising therapeutic potential of chrysophanol, challenges such as poor water solubility, low bioavailability, and safety concerns remain. Comprehensive clinical trials are essential to validate its efficacy and safety. This review emphasizes chrysophanol as a promising candidate for cancer therapy and underscores the necessity for further research to fully harness its therapeutic potential.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"210 ","pages":"Article 107502"},"PeriodicalIF":9.1,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142625820","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":"Erratum to \"Age-related macular degeneration (AMD) is a detrimental eye disease, and the most common cause of visual loss in many countries around the world\" [Pharmacol. Res. 208 (2024) 107402].","authors":"Torben Lykke Sørensen","doi":"10.1016/j.phrs.2024.107470","DOIUrl":"https://doi.org/10.1016/j.phrs.2024.107470","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107470"},"PeriodicalIF":9.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604928","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":"The ketogenic diet modulates tumor-associated neutrophil polarization via the AMOT-YAP/TAZ axis to inhibit colorectal cancer progression","authors":"Xiuwei Mi ,&nbsp;Yudong Duan ,&nbsp;Jiying Sun ,&nbsp;Qingliang Tai ,&nbsp;Huihui Yao ,&nbsp;Lijun Meng ,&nbsp;Xiaoshan Yang ,&nbsp;Xinyu Shi ,&nbsp;Bo Shi ,&nbsp;Junjie Chen ,&nbsp;Liang Sun ,&nbsp;Diyuan Zhou ,&nbsp;Sheng Xiao ,&nbsp;Yizhou Yao ,&nbsp;Songbing He","doi":"10.1016/j.phrs.2024.107494","DOIUrl":"10.1016/j.phrs.2024.107494","url":null,"abstract":"<div><div>Despite significant advances in the diagnosis and treatment of colorectal cancer (CRC), the prognosis for late-stage patients remains poor, highlighting the urgent need for new preventive and therapeutic strategies. Recent studies have focused on the ketogenic diet (KD) and its metabolite, β-hydroxybutyrate (BHB), for their tumor-suppressive effects and modulation of inflammatory responses. Using the azoxymethane (AOM) / dextran sulfate sodium (DSS)-induced mouse CRC model, we found that the ketogenic diet and BHB inhibit pro-tumor N2-type tumor-associated neutrophils (TANs) while promoting the polarization of TANs towards the anti-tumor N1 type. This shift in TANs polarization affects tumor growth and metastasis. The underlying mechanism involves BHB acting on the intracellular receptor histone deacetylases 3 (HDAC3), which modulates the activation of the AMOT-YAP/TAZ axis, leading to the inhibition of pro-carcinogenic factor transcription and release. Moreover, clinical cohort data corroborate these findings, showing that CRC patients with elevated BHB levels have significantly lower rates of lymph node involvement, which is associated with a higher infiltration ratio of anti-carcinogenic N1-type TANs in the tumor microenvironment (TME). These results suggest that BHB levels could serve as a prognostic biomarker for CRC. In conclusion, our findings indicate that BHB derived from KD regulates TANs polarization in CRC via the HDAC3-AMOT-YAP/TAZ axis, effectively inhibiting tumor growth and metastasis. These insights establish a novel theoretical basis for employing the KD in the treatment of CRC and for developing cancer adjuvant immunotherapy strategy based on the polarization of neutrophils.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"210 ","pages":"Article 107494"},"PeriodicalIF":9.1,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605199","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}