Biochemical pharmacology最新文献

{"title":"Functional significance of CYP2B6 gene rare allelic variants identified in Japanese individuals","authors":"Shuki Yamazaki ,&nbsp;Eiji Hishinuma ,&nbsp;Yuma Suzuki ,&nbsp;Akiko Ueda ,&nbsp;Caroline Kijogi ,&nbsp;Tomoki Nakayoshi ,&nbsp;Akifumi Oda ,&nbsp;Sakae Saito ,&nbsp;Shu Tadaka ,&nbsp;Kengo Kinoshita ,&nbsp;Masamitsu Maekawa ,&nbsp;Yu Sato ,&nbsp;Masaki Kumondai ,&nbsp;Nariyasu Mano ,&nbsp;Noriyasu Hirasawa ,&nbsp;Masahiro Hiratsuka","doi":"10.1016/j.bcp.2024.116515","DOIUrl":"10.1016/j.bcp.2024.116515","url":null,"abstract":"<div><p>Cytochrome P450 2B6 (CYP2B6) catalyzes the metabolism of many drugs, including efavirenz and propofol. Genetic polymorphisms in CYP2B6 alter its enzymatic activity and substantially affect its pharmacokinetics. High-frequency variants, such as <em>CYP2B6*6</em>, are associated with the risk of developing side effects due to reduced CYP2B6 activity. However, the impact of rare alterations on enzyme function remains unknown, and some of these variants may significantly decrease the CYP2B6 activity. Therefore, in this study, we evaluated <em>in vitro</em> the functional alterations in 29 missense variants of the <em>CYP2B6</em> gene identified in 8,380 Japanese individuals. Wild-type CYP2B6 and 29 rare CYP2B6 variants were transiently expressed in mammalian cells. The expression levels of variant CYP2B6 proteins in the microsomal fractions extracted from 293FT cells were assessed using western blotting and reduced-carbon monoxide difference spectroscopy, and a specific peak at 450 nm was detected in the wild-type and 19 variants. Furthermore, kinetic parameters were determined by assaying the reactions with efavirenz and propofol and quantifying the metabolite concentrations. We found that 12 variants had significantly lower or abolished enzymatic activity with both the substrates. <em>In silico</em> three-dimensional docking and molecular-dynamics simulations suggested that these functional changes were due to conformational changes in essential regions, such as the heme-binding site and ligand channels involved in transporting substrates to the active site. These findings have implications for predicting the plasma concentrations of CYP2B6 substrates and controlling their side effects.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116515"},"PeriodicalIF":5.3,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0006295224004982/pdfft?md5=698d466834d5b9d437cd921fd7deed03&pid=1-s2.0-S0006295224004982-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103949","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":"Regulatory function of glycolysis-related lncRNAs in tumor progression: Mechanism, facts, and perspectives","authors":"Xinyi Peng ,&nbsp;Shuhao Li ,&nbsp;Anqi Zeng ,&nbsp;Linjiang Song","doi":"10.1016/j.bcp.2024.116511","DOIUrl":"10.1016/j.bcp.2024.116511","url":null,"abstract":"<div><p>Altered metabolism is a hallmark of cancer, and reprogramming of energy metabolism, known as the “Warburg effect”, has long been associated with cancer. Cancer cells use the process of glycolysis to quickly manufacture energy from glucose, pyruvic acid, and lactate, which in turn accelerates the growth of cancer and glycolysis becomes a key target for anti-cancer therapies. Recent groundbreaking discoveries regarding long noncoding RNAs (lncRNAs) have opened a new chapter in the mechanism of cancer occurrence. It is widely recognized that lncRNAs regulate energy metabolism through glycolysis in cancer cells. LncRNAs have been demonstrated to engage in several cancer processes such as proliferation, apoptosis, migration, invasion, and chemoresistance, whereas glycolysis is enhanced or inhibited by the dysregulation of lncRNAs. As a result, cancer survival and development are influenced by different signaling pathways. In this review, we summarize the roles of lncRNAs in a variety of cancers and describe the mechanisms underlying their role in glycolysis. Additionally, the predictive potential of glycolysis and lncRNAs in cancer therapy is discussed.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116511"},"PeriodicalIF":5.3,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118906","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 the glycation association with dyslipidaemia: Novel approach for diabetic nephropathy","authors":"Ashwini D. Jagdale ,&nbsp;Mukul M. Angal ,&nbsp;Rahul S. Patil ,&nbsp;Rashmi S. Tupe","doi":"10.1016/j.bcp.2024.116513","DOIUrl":"10.1016/j.bcp.2024.116513","url":null,"abstract":"<div><p>The transcription factor known as sterol regulatory element-binding protein (SREBP) and the glycation pathways, specifically the formation of Advanced Glycation End Products (AGEs), have a significant and deleterious impact on the kidney. They alter renal lipid metabolism and promote glomerulosclerosis, mesangial cell expansion, tubulointerstitial fibrosis, and inflammation, leading to diabetic nephropathy (DN) progression. Although several pieces of scientific evidence are reported for potential causes of glycation and lipotoxicity in DN, the underlying mechanism of renal lipid accumulation still needs to be fully understood. We provide a rationalized view on how AGEs exert multiple effects that cause SREBP activation and inflammation, contributing to DN through Receptor for AGEs (RAGE) signaling, AGE-R1-dependent downregulation of Sirtuin 1 (SIRT-1), and increased SREBP Cleavage Activating Protein (SCAP) glycosylation. This review emphasizes the association between glycation and the SREBP pathway and how it affects the onset of DN associated with obesity. Finally, we discuss the correlation of glycation and the SREBP pathway with insulin resistance (IR), oxidative stress, endoplasmic reticulum stress, inflammation, and existing and emerging therapeutic approaches toward better controlling obesity-related DN.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116513"},"PeriodicalIF":5.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103948","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":"Ketamine – An Imperfect Wonder Drug?","authors":"Tanner Magruder ,&nbsp;Marielle Isenhart ,&nbsp;Maximillian V. Striepe ,&nbsp;Andrew Mannisto ,&nbsp;Karry M. Jannie ,&nbsp;Jolene Smith ,&nbsp;Kenneth E. McCarson ,&nbsp;Daniel T. Christian ,&nbsp;Vanja Duric","doi":"10.1016/j.bcp.2024.116516","DOIUrl":"10.1016/j.bcp.2024.116516","url":null,"abstract":"<div><p>Ketamine is a potent sedative and dissociative anesthetic agent that has been used clinically for over 50 years since it was first developed in the 1960 s as an alternative to phencyclidine (PCP). When compared to PCP, ketamine exhibited a much lower incidence of severe side effects, including hallucinations, leading to its increased popularity in clinical practice. Ketamine was initially used as an anesthetic agent, especially in emergency medicine and in surgical procedures where rapid induction and recovery was necessary. However, over the last few decades, ketamine was found to have additional clinically useful properties making it effective in the treatment of a variety of other conditions. Presently, ketamine has a wide range of clinical uses beyond anesthesia including management of acute and chronic pain, as well as treatment of psychiatric disorders such as major depression. In addition to various clinical uses, ketamine is also recognized as a common drug of abuse sought for its hallucinogenic and sedative effects. This review focuses on exploring the different clinical and non-clinical uses of ketamine and its overall impact on patient care.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116516"},"PeriodicalIF":5.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103950","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":"An introduction to the special issue “Sam Enna legacy of excellence”","authors":"Jacques Piette,&nbsp;Lynn LeCount","doi":"10.1016/j.bcp.2024.116510","DOIUrl":"10.1016/j.bcp.2024.116510","url":null,"abstract":"","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"228 ","pages":"Article 116510"},"PeriodicalIF":5.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103947","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 LAMB3-EGFR signaling pathway mediates synergistic Anti-Cancer effects of berberine and emodin in Pancreatic cancer","authors":"Caiming Xu ,&nbsp;Silvia Pascual-Sabater ,&nbsp;Cristina Fillat ,&nbsp;Ajay Goel","doi":"10.1016/j.bcp.2024.116509","DOIUrl":"10.1016/j.bcp.2024.116509","url":null,"abstract":"<div><p>Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, primarily due to the intrinsic development of chemoresistance. The most apparent histopathological feature associated with chemoresistance is the alterations in extracellular matrix (ECM) proteins. Natural dietary botanicals such as berberine (BBR) and emodin (EMO) have been shown to possess chemo-preventive potential by regulating ECM in various cancers. Herein, we further investigated the potential synergistic effects of BBR and EMO in enhancing anticancer efficacy by targeting ECM proteins in pancreatic cancer. Genomewide transcriptomic profiling identified that LAMB3 was significantly upregulated in PDAC tissue and highly associated with poor overall survival (OS, hazard ratio [HR], 2.99, 95 % confidence interval [CI], 1.46–6.15; p = 0.003) and progress-free survival (PFS, HR, 2.59; 95 % CI, 1.30–5.18; p = 0.007) in PDAC. A systematic series of functional experiments in BxPC-3 and MIA-PaCa-2 cells revealed that the combination of BBR and EMO exhibited synergistic anti-tumor potential, as demonstrated by cell proliferation, clonogenicity, migration, and invasion assays (p &lt; 0.05–0.001). The combination also altered the expression of key proteins involved in apoptosis, EMT, and EGFR/ERK1,2/AKT signaling. These findings were further supported by patient-derived organoids (PDOs), where the combined treatment resulted in fewer and smaller organoids compared to each compound individually (<em>p</em> &lt; 0.05–0.001). Our results suggest that BBR combined with EMO exerts synergistic anti-cancer effects by modulating the EGFR-signaling pathway through interference with LAMB3 in PDAC.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"228 ","pages":"Article 116509"},"PeriodicalIF":5.3,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103951","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":"Functional characterisation and modification of a novel Kunitzin peptide for use as an anti-trypsin antimicrobial peptide against drug-resistant Escherichia coli","authors":"Zhizhong Wang ,&nbsp;Wenjing Ding ,&nbsp;Daning Shi ,&nbsp;Xiaoling Chen ,&nbsp;Chengbang Ma ,&nbsp;Yangyang Jiang ,&nbsp;Tao Wang ,&nbsp;Tianbao Chen ,&nbsp;Chris Shaw ,&nbsp;Lei Wang ,&nbsp;Mei Zhou","doi":"10.1016/j.bcp.2024.116508","DOIUrl":"10.1016/j.bcp.2024.116508","url":null,"abstract":"<div><p>In recent decades, antimicrobial peptides (AMPs) have emerged as highly promising candidates for the next generation of antibiotic agents, garnering significant attention. Although their potent antimicrobial activities and ability to combat drug resistance make them stand out among alternative agents, their poor stability has presented a great challenge for further development. In this work, we report a novel Kunitzin AMP, Kunitzin-OL, from the frog <em>Odorrana lividia</em>, exhibiting dual antimicrobial and anti-trypsin activities. Through functional screening and comparison with previously reported Kunitzin peptides, we serendipitously discovered a unique motif (−KVKF-) and unveiled its crucial role in the antibacterial functions of Kunitzin-OL by modifying it through motif removal and duplication. Among the designed derivatives, peptides 4 and 8 demonstrated remarkable antimicrobial activities and low cytotoxicity, with high therapeutic index (TI) values (TI₄ = 20.8, TI₈ = 20.8). Furthermore, they showed potent antibacterial efficacy against drug-resistant <em>Escherichia coli</em> strains and exhibited lipopolysaccharide (LPS)-neutralising activity, effectively alleviating LPS-induced inflammatory responses. Overall, our findings provide a new short motif for designing effective AMP drugs and highlight the potential of the Kunitztin trypsin inhibitory loop as a valuable motif for the design of AMPs with enhancing proteolytic stability.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116508"},"PeriodicalIF":5.3,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S000629522400491X/pdfft?md5=b8bf587ee39b655f5fe553aa8f0ca7bf&pid=1-s2.0-S000629522400491X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071918","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":"Therapeutic potential of relaxin or relaxin mimetics in managing cardiovascular complications of diabetes","authors":"Arun George Devasia ,&nbsp;Meyammai Shanmugham ,&nbsp;Adaikalavan Ramasamy ,&nbsp;Sophie Bellanger ,&nbsp;Laura J. Parry ,&nbsp;Chen Huei Leo","doi":"10.1016/j.bcp.2024.116507","DOIUrl":"10.1016/j.bcp.2024.116507","url":null,"abstract":"<div><p>Diabetes mellitus is a metabolic disease with an escalating global prevalence. Despite the abundance and relative efficacies of current therapeutic approaches, they primarily focus on attaining the intended glycaemic targets, but patients ultimately still suffer from various diabetes-associated complications such as retinopathy, nephropathy, cardiomyopathy, and atherosclerosis. There is a need to explore innovative and effective diabetic treatment strategies that not only address the condition itself but also combat its complications. One promising option is the reproductive hormone relaxin, an endogenous ligand of the RXFP1 receptor. Relaxin is known to exert beneficial actions on the cardiovascular system through its vasoprotective, anti-inflammatory and anti-fibrotic effects. Nevertheless, the native relaxin peptide exhibits a short biological half-life, limiting its therapeutic potential. Recently, several relaxin mimetics and innovative delivery technologies have been developed to extend its biological half-life and efficacy. The current review provides a comprehensive landscape of the cardiovascular effects of relaxin, focusing on its potential therapeutic applications in managing complications associated with diabetes. The latest advancements in the development of relaxin mimetics and delivery methods for the treatment of cardiometabolic disorders are also discussed.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116507"},"PeriodicalIF":5.3,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054814","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":"Dietary sodium modulates mTORC1-dependent trained immunity in macrophages to accelerate CKD development","authors":"Huihui Chen ,&nbsp;Jie Song ,&nbsp;Li Zeng ,&nbsp;Jie Zha ,&nbsp;Jiefu Zhu ,&nbsp;Anqun Chen ,&nbsp;Yu Liu ,&nbsp;Zheng Dong ,&nbsp;Guochun Chen","doi":"10.1016/j.bcp.2024.116505","DOIUrl":"10.1016/j.bcp.2024.116505","url":null,"abstract":"<div><p>Chronic Kidney Disease (CKD) is a significant global health issue linked to dietary habits, especially high salt intake. However, the precise mechanisms driving this progression remain incompletely understood. This study reveals that a high-salt diet intensifies macrophage trained immunity, leading to a marked pro-inflammatory response upon repeated pathogenic exposures, as evidenced by increased renal damage and fibrosis. Under high-salt conditions, there was an induction of CD45⁺F4/80⁺ macrophage infiltration into the renal tissue, accompanied by heightened production of inflammatory cytokines. Distinct responses were observed between circulating and resident renal macrophages to a high-salt diet, with a notable upsurge in the migration of pro-inflammatory macrophages, driven by CCL2-CCR2 signaling and aberrant mTORC1 pathway activation. Treatment with rapamycin-liposome effectively reduced this inflammatory cascade by mitigating mTORC1 signaling. Transplantation of monocytes from CKD mice with a high-salt diet significantly exacerbates renal inflammatory damage in the host mice, showing increased migratory tendency and inflammatory activity. The cell co-culture experiment further confirmed that macrophages derived from CKD mice, particularly those under conditions of high salt exposure, significantly induced apoptosis and inflammatory responses in renal tubular cells. Taken together, recurrent exposure to LPS elicits the activation of trained immunity, consequently augmenting inflammatory response of monocytes/macrophages in the involved kidneys. The high-salt diet exacerbates this phenomenon, attributable at least in part to the overactivation of the mTORC1 pathway. This research emphasizes the importance of dietary modulation and targeted immunological interventions in slowing CKD progression, providing new insights into mTORC1-mediated pathophysiological mechanisms and potential management strategies for CKD.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116505"},"PeriodicalIF":5.3,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142048029","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":"Chronic post-ischemic pain (CPIP) a model of complex regional pain syndrome (CRPS-I): Role of oxidative stress and inflammation","authors":"Julia Maria Frare ,&nbsp;Patrícia Rodrigues ,&nbsp;Náthaly Andrighetto Ruviaro ,&nbsp;Gabriela Trevisan","doi":"10.1016/j.bcp.2024.116506","DOIUrl":"10.1016/j.bcp.2024.116506","url":null,"abstract":"<div><p>Complex regional pain syndrome (CRPS) presents as a persistent and distressing pain condition often stemming from limb trauma or ischemia, manifesting as either CRPS-I (without initial nerve injury) or CRPS-II (accompanied by nerve injury). Despite its prevalence and significant impact on functionality and emotional well-being, standard treatments for CRPS remain elusive. The multifaceted nature of CRPS complicates the identification of its underlying mechanisms. In efforts to elucidate these mechanisms, researchers have turned to animal models such as chronic post-ischemic pain (CPIP), which mirrors the symptoms of CRPS-I. Various mechanisms have been proposed to underlie the acute and chronic pain experienced in CRPS-I, including oxidative stress and inflammation. Traditional treatment approaches often involve antidepressants, non-steroidal anti-inflammatory drugs (NSAIDs), and opioids. However, these methods frequently fall short of providing adequate relief. Accordingly, there is a growing interest in exploring alternative treatments, such as antioxidant supplementation, anti-inflammatory agents, and non-pharmacological interventions. Future research directions should focus on optimizing treatment strategies and addressing remaining gaps in knowledge to improve patient outcomes. This review aims to delve into the pathophysiological mechanisms implicated in the CPIP model, specifically focusing on oxidative stress and inflammation, with the ultimate goal of proposing innovative therapeutic strategies for alleviating the symptoms of CRPS-I.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116506"},"PeriodicalIF":5.3,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054813","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}