Biochemical pharmacology最新文献_第4页

FABP4 inhibition protects renal tubular cells and ameliorates renal inflammation in diabetic kidney disease

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-31 DOI: 10.1016/j.bcp.2025.116899

Yen‐Wen Wu , Jaw‐Wen Chen , Liang-Yu Lin , Jih-Hsin Huang , Chia‐Chi Chang , Ting‐Ting Chang

{"title":"FABP4 inhibition protects renal tubular cells and ameliorates renal inflammation in diabetic kidney disease","authors":"Yen‐Wen Wu , Jaw‐Wen Chen , Liang-Yu Lin , Jih-Hsin Huang , Chia‐Chi Chang , Ting‐Ting Chang","doi":"10.1016/j.bcp.2025.116899","DOIUrl":"10.1016/j.bcp.2025.116899","url":null,"abstract":"<div><div>Diabetic kidney disease (DKD) is a common complication associated with diabetes mellitus (DM). Fatty acid binding protein (FABP) 4 is a small cytoplasmic lipid chaperone that is up-regulated in DKD. This study aims to elucidate whether FABP4 could play a critical role and serve as a potential therapeutic target in DKD. In a clinical observational study, DKD patients and non-DKD subjects were enrolled and their circulating FABP4 levels were analyzed. The renoprotective effects of FABP4 inhibition were evaluated <em>in vivo</em> and <em>in vitro</em> using db/db mice and high glucose-induced human kidney proximal tubular epithelial cells, respectively. Circulating FABP4 was up-regulated in clinical patients and mice with DKD. The inhibition of FABP4 with an orally administered inhibitor ameliorated insulin resistance and renal function in DKD mice, as evidenced by decreased systemic inflammation as well as improved serum creatinine and BUN levels, kidney weight to body weight ratio, and urine albumin-to-creatinine ratio. FABP4 inhibition also reduced renal tubular injury, fibrosis, and macrophage infiltration in DKD mice. Furthermore, FABP4 inhibition down-regulated the inflammatory, fibrotic, and cell apoptotic protein expressions in kidney tissues of DKD mice and in high glucose-induced renal proximal tubular epithelial cells. On the other hand, FABP4 directly caused cellular inflammation, fibrosis, and apoptosis via NF-κB activation in renal tubular epithelial cells. Altogether, FABP4 might induce renal inflammation and renal tubular epithelial cell damage during the pathological process of DKD. Future clinical studies may be required to validate whether FABP4 inhibition can serve as a novel therapeutic strategy for DKD.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116899"},"PeriodicalIF":5.3,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759063","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}

引用次数: 0

Unveiling the roles of HIPK2 in atherosclerosis: Insights into the β-catenin/STAT1 signaling cascade and the involvement of SENP1

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-29 DOI: 10.1016/j.bcp.2025.116911

Yanhua Zhen , Dongdong Li , Yulu Meng , Zeyu Xing , Jiahe Zheng

{"title":"Unveiling the roles of HIPK2 in atherosclerosis: Insights into the β-catenin/STAT1 signaling cascade and the involvement of SENP1","authors":"Yanhua Zhen , Dongdong Li , Yulu Meng , Zeyu Xing , Jiahe Zheng","doi":"10.1016/j.bcp.2025.116911","DOIUrl":"10.1016/j.bcp.2025.116911","url":null,"abstract":"<div><div>Atherosclerosis is a disorder of lipid metabolism, but its pathogenesis has not yet been fully elucidated. This study aimed to clarify the roles of homeodomain interacting protein kinase 2 (HIPK2) in atherosclerosis. Atherosclerotic model was constructed by feeding apolipoprotein E knockout (ApoE<sup>-/-</sup>) mice with a high-fat diet. Human THP-1 macrophages and mouse RAW 264.7 macrophages were stimulated with IFN-γ to establish an in vitro model. We showed an upregulation of HIPK2 in the aorta of atherosclerotic mice. HIPK2 knockdown reduced macrophage infiltration, M1 polarization, and attenuates atherosclerosis development. Downregulation of HIPK2 in macrophages led to a significant suppression in the expression of pro-inflammatory factors, which was accompanied by an enhancement in the phosphorylation and degradation of β-catenin, as well as the activation of the signal transducer and activator of transcription 1 (STAT1) signaling pathway. Silencing of HIPK2 alone in THP-1 macrophages resulted in anti-inflammatory effects and suppression of M1 macrophage polarization. However, simultaneous silencing of HIPK2 and β-catenin (CTNNB1) reversed these effects, counteracting the outcomes observed with HIPK2 silencing alone. We validated that small ubiquitin-like modifier (SUMO)-specific peptidase 1 (SENP1) regulated HIPK2 function by affecting the SUMOylation of HIPK2 at the K32 site. SENP1 knockdown promoted HIPK2 SUMOylation, impairing its protein stability. In the rescue experiments, IFN-γ-induced inflammation and M1 polarization were resumed upon restoration of HIPK2 expression in SENP1-silenced macrophages. Our work demonstrated that HIPK2 accelerated the progression of atherosclerosis by regulating β-catenin/STAT1 signaling cascade to promote macrophage infiltration and M1 polarization. HIPK2 was regulated by SENP1-mediated de-SUMOylation.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116911"},"PeriodicalIF":5.3,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750943","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}

引用次数: 0

A non-bactericidal glycine-rich peptide enhances cutaneous wound healing in mice via the activation of the TLR4/MAPK/NF-κB pathway

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-29 DOI: 10.1016/j.bcp.2025.116912

Guizhu Feng , Xiaoyan Zhou , Xiaojie Fang , Yanmei He, Ting Lin, Lixian Mu, Hailong Yang, Jing Wu

{"title":"A non-bactericidal glycine-rich peptide enhances cutaneous wound healing in mice via the activation of the TLR4/MAPK/NF-κB pathway","authors":"Guizhu Feng , Xiaoyan Zhou , Xiaojie Fang , Yanmei He, Ting Lin, Lixian Mu, Hailong Yang, Jing Wu","doi":"10.1016/j.bcp.2025.116912","DOIUrl":"10.1016/j.bcp.2025.116912","url":null,"abstract":"<div><div>Although the antibacterial properties of glycine-rich peptides from prokaryotes to eukaryotes have been well characterized, their role in skin wound healing remains poorly understood, especially non-bactericidal glycine-rich peptides. Herein, a novel glycine-rich (46.5%) peptide (Smaragin, SRGSRGGRGGRGGGGRGGRGRSGSGSSIAGGGSRGSRGGSQYA) was identified from the skin of the tree frog <em>Zhangixalus smaragdinus</em>. Unlike other glycine-rich peptides, Smaragin showed no antimicrobial activity <em>in vitro</em> but significantly enhance wound healing in full-thickness dermal wounds in mice. In comparison with other wound healing-promoting peptides, Smaragin did not directly affect the proliferation and migration of keratinocytes, vascular endothelial cells, and fibroblasts. However, it notably increased phagocytes infiltration at the wound site by 0.5-day post-injury. Smaragin was not a direct chemoattractant for phagocytes, but it stimulated macrophages to secrete chemokines CXCL1 and CXCL2, which indirectly enhanced the migration of phagocytes, keratinocytes and vascular endothelial cells. Moreover, Smaragin promoted the polarization of macrophages from a pro-inflammatory M1-type to an anti-inflammatory M2 phenotype at the wound, which is associated with angiogenic activity. As expected, CD31, the most common analyzed marker of angiogenesis, showed a significant increase in vascular network area. Subsequent studies revealed that Smaragin promoted the chemokine level and polarization of macrophages via the TLR4/MAPK/NF-κB pathway, which enhanced the number of phagocytes and the regeneration of the epidermis and blood vessels at the wound, thereby accelerating skin wound healing in mice. These findings highlight the skin healing properties of non-bactericidal glycine-rich peptides and display the potential of Smaragin as a promising candidate for developing effective wound healing therapies.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116912"},"PeriodicalIF":5.3,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750915","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}

引用次数: 0

Acetylation of H3K18 activated by p300 promotes osteogenesis in human adipose-derived mesenchymal stem cells

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-29 DOI: 10.1016/j.bcp.2025.116901

Liping Zeng , Chen Chen , Yafei Xiong , Yinan Liu , Miao Huang , Junsong Ye , Jianing Zhong , Weijie Peng

{"title":"Acetylation of H3K18 activated by p300 promotes osteogenesis in human adipose-derived mesenchymal stem cells","authors":"Liping Zeng , Chen Chen , Yafei Xiong , Yinan Liu , Miao Huang , Junsong Ye , Jianing Zhong , Weijie Peng","doi":"10.1016/j.bcp.2025.116901","DOIUrl":"10.1016/j.bcp.2025.116901","url":null,"abstract":"<div><div>Human adipose-derived mesenchymal stem cells (hAD-MSCs) have garnered significant interest as a viable alternative source of stem cells for applications in bone tissue engineering due to their high and ease availability. At present, the limited studies on potential epigenetic regulatory mechanism in hAD-MSCs greatly hinders its clinical application in bone repair. Histone acetylation has been identified as a critical regulator of the osteogenic differentiation of mesenchymal stem cells (MSCs), with increased levels of histone acetylation sites frequently correlating with enhanced osteogenic differentiation. However, their specific roles in MSCs osteogenesis remain unclear. In this study, we observed a significant up-regulation of H3K18 acetylation (H3K18ac) during the osteogenic induction of hAD-MSCs. This modification was notably enriched in the promoter regions of genes associated with osteogenesis, thereby facilitating osteogenic differentiation. Furthermore, the treatment of histone acetyltransferases p300 inhibitor A-485 in hAD-MSCs resulted in a reduction of H3K18 acetylation levels during the osteogenic differentiation, which corresponded with a diminished osteoblast phenotype and function. These results indicated that p300-mediated acetylation of H3K18 enhances the osteogenic differentiation of hAD-MSCs. It provides a novel insight into understanding the mechanism of osteogenic differentiation of hAD-MSCs and promoting its application in bone tissue engineering.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116901"},"PeriodicalIF":5.3,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750953","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}

引用次数: 0

IDO1-mediated AhR activation up-regulates pentose phosphate pathway via NRF2 to inhibit ferroptosis in lung cancer

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-29 DOI: 10.1016/j.bcp.2025.116913

Jiani Zhan , Yijia Chen , Yuying Liu , Yunqiu Chen , Zhiyao Li , Xuewen Li , Zhenning He , Fangzhou Meng , Xiaoyang Qian , Lili Yang , Qing Yang

{"title":"IDO1-mediated AhR activation up-regulates pentose phosphate pathway via NRF2 to inhibit ferroptosis in lung cancer","authors":"Jiani Zhan , Yijia Chen , Yuying Liu , Yunqiu Chen , Zhiyao Li , Xuewen Li , Zhenning He , Fangzhou Meng , Xiaoyang Qian , Lili Yang , Qing Yang","doi":"10.1016/j.bcp.2025.116913","DOIUrl":"10.1016/j.bcp.2025.116913","url":null,"abstract":"<div><div>Ferroptosis is a type of cell death marked by iron-dependent lipid peroxide accumulation. Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in the catabolism of tryptophan through kynurenine pathway, participates in the development of multiple tumor types. However, the role of IDO1 in tumor ferroptosis is unclear. In this study, we identified IDO1 as a key regulator of ferroptosis in lung cancer. With Erastin-treated lung cancer cells, we found that IDO1 inhibited ferroptosis, reduced the generation of lipid peroxide and ROS. Mechanistically, IDO1 promoted the expression of nuclear factor erythroid 2-related factor 2 (NRF2) through activating aryl hydrocarbon receptor (AhR) pathway. IDO1 up-regulated the expression of solute carrier family 7 member 11 (SLC7A11) and the activity of pentose phosphate pathway (PPP) via AhR-NRF2 axis, promoted the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thereby inhibiting ferroptosis. Moreover, combined treatment with IDO1 inhibitor and Erastin inhibited tumor growth, down-regulated SLC7A11 expression and PPP activity, promoted tumor ferroptosis in lung cancer-bearing mice. In conclusion, this study revealed the function of IDO1 in lung cancer ferroptosis and provided a new strategy for lung cancer therapy.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116913"},"PeriodicalIF":5.3,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750940","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}

引用次数: 0

Discovery of targeting USP10-mediated proline metabolism arrangement to inhibit hepatocellular carcinoma progression

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-28 DOI: 10.1016/j.bcp.2025.116904

Yinze Han , Weili Kong , Qixin Shang , Yuanzhi Liu , Xincheng Ni , Lin Yang , Jian Lei

{"title":"Discovery of targeting USP10-mediated proline metabolism arrangement to inhibit hepatocellular carcinoma progression","authors":"Yinze Han , Weili Kong , Qixin Shang , Yuanzhi Liu , Xincheng Ni , Lin Yang , Jian Lei","doi":"10.1016/j.bcp.2025.116904","DOIUrl":"10.1016/j.bcp.2025.116904","url":null,"abstract":"<div><div>Metabolic dysregulation is closely related to hepatocellular carcinoma (HCC) progression. Aberrant proline metabolism plays crucial roles in HCC onset and development. However, the detailed molecular mechanisms of proline metabolism in HCC remain unclear. In this study, we reported that hydroxyproline, a metabolite of proline, is a key causal factor of HCC progression using Mendelian randomization analysis. An elevated level of hydroxyproline promotes HCC cell growth, migration, and invasion. Using a non-targeted metabolomics approach, we found that USP10 increases the amount of proline and hydroxyproline in HCC cells. We subsequently proved that USP10 stabilizes Yes-associated protein 1 (YAP1), enhancing YAP1/TEA domain transcription factor 4 (TEAD4)-mediated transcription of <em>prolyl 4-hydroxylase subunit alpha 1</em> (<em>P4HA1</em>). This leads to increased expression of <em>P4HA1</em>, which alters the proline catabolic profile. In contrast, knocking down USP10 or suppressing its activity reduced the expression of <em>P4HA1</em>. Given the crucial roles of USP10 in HCC progression, we further validated ginkgolic acid, a hit compound that targets USP10, leading to potential anti-HCC efficacy in xenograft mouse models. Overall, our study provides novel insights into the role and potential molecular mechanisms of USP10 on proline metabolism in HCC for the first time, as well as offers a promising therapeutic strategy of targeting USP10 for HCC treatment.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116904"},"PeriodicalIF":5.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750936","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}

引用次数: 0

An emerging role of SNAREs in ischemic stroke: From pre-to post-diseases

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-28 DOI: 10.1016/j.bcp.2025.116907

Yaxin Liu , Jingyan Hong , Guozuo Wang , Zhigang Mei

{"title":"An emerging role of SNAREs in ischemic stroke: From pre-to post-diseases","authors":"Yaxin Liu , Jingyan Hong , Guozuo Wang , Zhigang Mei","doi":"10.1016/j.bcp.2025.116907","DOIUrl":"10.1016/j.bcp.2025.116907","url":null,"abstract":"<div><div>Ischemic stroke is a debilitating condition characterized by high morbidity, disability, recurrence, and mortality rates on a global scale, posing a significant threat to public health and economic stability. Extensive research has thoroughly explored the molecular mechanisms underlying ischemic stroke, elucidating a strong association between soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor proteins (SNAREs) and the pathogenesis of this condition. SNAREs, a class of highly conserved proteins involved in membrane fusion, play a crucial role in modulating neuronal information transmission and promoting myelin formation in the central nervous system (CNS). Preventing the SNARE complex formation, malfunctions in SNARE-dependent exocytosis, and altered regulation of SNARE-mediated vesicle fusion are linked to excitotoxicity, endoplasmic reticulum (ER) stress, and programmed cell death (PCD) in ischemic stroke. However, its underlying mechanisms remain unclear. This study conducts a comprehensive review of the existing literature on SNARE proteins, encompassing the structure, classification, and expression of the SNARE protein family, as well as the assembly – disassembly cycle of SNARE complexes and their physiological roles in the CNS. We thoroughly examine the mechanisms by which SNAREs contribute to the pathological progression and associated risk factors of ischemic stroke (hypertension, hyperglycemia, dyslipidemia, and atherosclerosis). Furthermore, our findings highlight the promise of SNAREs as a viable target for pharmacological interventions in the treatment of ischemic stroke.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116907"},"PeriodicalIF":5.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750958","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}

引用次数: 0

Increased glucose utilization is a targetable vulnerability to overcome drug resistance associated with neddylation blockade

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-28 DOI: 10.1016/j.bcp.2025.116905

Yueyang Guo , Zhuang Hu , Linyue Bai , Yanjun Tang , Jingyi Hu , Qianqian Zhang , Jiali Liu , Siqi Feng

{"title":"Increased glucose utilization is a targetable vulnerability to overcome drug resistance associated with neddylation blockade","authors":"Yueyang Guo , Zhuang Hu , Linyue Bai , Yanjun Tang , Jingyi Hu , Qianqian Zhang , Jiali Liu , Siqi Feng","doi":"10.1016/j.bcp.2025.116905","DOIUrl":"10.1016/j.bcp.2025.116905","url":null,"abstract":"<div><div>Gastric cancer, a leading cause of cancer-related mortality, has a median survival of just 15 months in advanced stages and currently lacks effective treatment options. Neddylation blockade is a promising therapeutic strategy, yet its clinical application faces challenge with the emergence of drug resistance. Currently, the underlying mechanisms behind the drug resistance are not fully understood. Our study uncovers the link between MLN4924-induced metabolic reprogramming and its antitumor efficacy in gastric cancer cells. We first demonstrated that MLN4924, a neddylation blocker, has multiple effects on gastric cancer cell growth, notably inducing mitochondrial damage. Untargeted metabolomic analysis revealed that MLN4924 enhances glucose utilization in gastric cancer cells in a concentration-dependent manner. Mechanistically, MLN4924 reduces the neddylation of cullin2, thereby inhibiting the degradation of HIF-1α. This leads to the accumulation of HIF-1α, which upregulates GLUT1 levels and facilitates increased glucose uptake. This metabolic adaptation allows gastric cancer cells to maintain their energy supply despite mitochondrial impairment. Based on the increased glucose dependency following neddylation inhibition by MLN4924, we propose a co-targeting strategy with GLUT1 inhibition, which significantly improves therapeutic efficacy <em>in vitro</em> and <em>in vivo</em> models without safety risks. This dual-targeting approach represents a potent new strategy for gastric cancer treatment.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116905"},"PeriodicalIF":5.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735205","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}

引用次数: 0

NONO2P, a nitric oxide donor, induces relaxation in coronary artery, negative inotropism and hypotensive effect in rats

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-28 DOI: 10.1016/j.bcp.2025.116918

Raiana A. Moraes , Daniele S. Brito , Fênix A. Araujo , Rafael L.C. Jesus , Liliane B. Silva , Gabriela B. de C. Lima , Denise S. Sá , Carlos D. Silva da Silva , Laena Pernomian , Camilla F. Wenceslau , Darizy F. Silva

{"title":"NONO2P, a nitric oxide donor, induces relaxation in coronary artery, negative inotropism and hypotensive effect in rats","authors":"Raiana A. Moraes , Daniele S. Brito , Fênix A. Araujo , Rafael L.C. Jesus , Liliane B. Silva , Gabriela B. de C. Lima , Denise S. Sá , Carlos D. Silva da Silva , Laena Pernomian , Camilla F. Wenceslau , Darizy F. Silva","doi":"10.1016/j.bcp.2025.116918","DOIUrl":"10.1016/j.bcp.2025.116918","url":null,"abstract":"<div><div>Reduced NO synthesis and/or bioavailability is related with many cardiovascular diseases, such as coronary artery disease and hypertension. This study aimed to evaluate the effects of cis-[Ru(NO)(NO2)(phen)2](PF6)2-(NONO2P) on blood pressure in normotensive and hypertensive rats. Specifically, we wanted to investigate its action on the atrial contractility, mesenteric and coronary arteries function. Male Wistar and spontaneously hypertensive rats (SHR) (13–18 weeks old) were used to assess the NONO2P effects on blood pressure and heart rate. Superior mesenteric and coronary arteries, and atria were isolated for recording to analyze force changes. Cultured endothelial cells were used to measure intracellular reactive oxygen species (ROS) generation using fluorescent dye (dihydroethidium, DHE). Acute administration of NONO2P induced hypotension in non-anesthetized normotensive and hypertensive rats. Moreover, NONO2P caused a negative inotropic effect without altering cardiac rhythmicity. Further, NONO2P displays a vasorelaxant effect on different blood vessels (mesenteric and coronary arteries). For comparison purposes, we observed that NONO2P and NTG presented with a similar potency and maximum response values in inducing relaxation in coronary arteries. On the other hand, mesenteric arteries were more sensitive to both donors, NONO2P and NTG, than the coronary artery. In addition, exposure to NONO2P induced tolerance and increased ROS levels. This is the first evidence that NONO2P induces hypotension, negative cardiac inotropism and coronary artery relaxation. In addition, pre-exposure to NONO2P induces vascular tolerance. Overall, these results may shed light on the potential therapeutic use of NONO2P, particularly in treating angina and hypertensive crises.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116918"},"PeriodicalIF":5.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750941","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}

引用次数: 0

Advancements in age-related macular degeneration treatment: From traditional anti-VEGF to emerging therapies in gene, stem cell, and nanotechnology

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-28 DOI: 10.1016/j.bcp.2025.116902

Zhanfei Wang , Yaqin Zhang , Chunxiu Xu , Anna Peng , Huan Qin , Kai Yao

{"title":"Advancements in age-related macular degeneration treatment: From traditional anti-VEGF to emerging therapies in gene, stem cell, and nanotechnology","authors":"Zhanfei Wang , Yaqin Zhang , Chunxiu Xu , Anna Peng , Huan Qin , Kai Yao","doi":"10.1016/j.bcp.2025.116902","DOIUrl":"10.1016/j.bcp.2025.116902","url":null,"abstract":"<div><div>Age-related macular degeneration (AMD) is the leading cause of central vision loss in older adults and is projected to affect approximately 400 million individuals worldwide by 2040. Its pathological characteristics include retinal extracellular deposits, such as drusen, which trigger photoreceptor degeneration and damage to the retinal pigment epithelium (RPE), resulting in irreversible vision loss. The pathogenesis of AMD involves genetic, environmental, and aging-related factors. Anti-vascular endothelial growth factor (anti-VEGF) therapy for wet AMD significantly inhibits choroidal neovascularization and delays visual deterioration. However, its high cost, frequent injections, and poor patient compliance limit application, and there remains no effective intervention for dry AMD. In recent years, emerging strategies, such as gene therapy, stem cell therapy, and nanotechnology-based drug delivery systems, offer hope for slowing disease progression by improving targeting, drug stability, and reducing treatment frequency. Nanoparticles, including polymeric and lipid systems, have shown promise for enhancing drug delivery and bioavailability, particularly for dry AMD, where existing therapies are inadequate. These strategies also have the potential to improve patient compliance. This review summarizes AMD epidemiology and examines the limitations of current therapies. It emphasizes the mechanisms and clinical advancements of gene therapy, stem cell therapy, and nanotechnology in AMD treatment. These emerging technologies offer promising opportunities for precision medicine and lay a solid foundation for the future development of multifaceted therapeutic strategies.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116902"},"PeriodicalIF":5.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750956","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}

引用次数: 0