Biochemical pharmacology最新文献_第4页

The progression of metabolic dysfunction-associated steatotic liver disease toward hepatocellular carcinoma in an efficient rat model 高效大鼠模型中代谢功能障碍相关脂肪变性肝病向肝细胞癌的进展

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-25 DOI: 10.1016/j.bcp.2025.117369

Linda Vanessa Márquez-Quiroga , Irina Cardoso-Lezama , Brisa Rodope Alarcón-Sánchez , Pamela Gaitán-González , Osiris Germán Idelfonso-García , Eduardo E. Vargas-Pozada , Carolina Piña-Vázquez , Erika Ramos-Tovar , Saúl Villa-Treviño , Jaime Arellanes-Robledo , Pablo Muriel

{"title":"The progression of metabolic dysfunction-associated steatotic liver disease toward hepatocellular carcinoma in an efficient rat model","authors":"Linda Vanessa Márquez-Quiroga , Irina Cardoso-Lezama , Brisa Rodope Alarcón-Sánchez , Pamela Gaitán-González , Osiris Germán Idelfonso-García , Eduardo E. Vargas-Pozada , Carolina Piña-Vázquez , Erika Ramos-Tovar , Saúl Villa-Treviño , Jaime Arellanes-Robledo , Pablo Muriel","doi":"10.1016/j.bcp.2025.117369","DOIUrl":"10.1016/j.bcp.2025.117369","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a critical worldwide public health issue and is among the main risk factors for hepatocellular carcinoma (HCC) development; however, although some experimental models have been proposed, the recapitulation of the chronological progression from MASLD to HCC remains an unmet need. We aimed to establish an efficient MASLD model leading to HCC, named the MACER (MASLD-CANCER) model. Six-week-old male Fischer 344 rats, weighing 100–120 g, were fed a hepatopathogenic (HPG) diet containing high levels of fat, sucrose, and cholesterol in combination with low doses of CCl<sub>4</sub> and diethylnitrosamine (DEN). Hepatosteatosis, inflammation, fibrosis, and HCC markers were assessed. The evidence revealed that the MACER model induced an altered lipid metabolism profile, promoted hepatosteatosis, and increased liver injury, inflammation, and cellular senescence beginning the third week after exposure to hepatotoxins. In addition, this model showed expression of the proliferation marker Ki-67 at seven weeks and induction of collagen deposition and expression of HCC markers, such as GGT and GSTP1, from 13 weeks onward. Moreover, our model progressed to advanced HCC stages even after removing hepatotoxins. The MACER model is a novel and useful tool for investigating chronological MASLD toward HCC progression and for assessing the efficacy of chemopreventive agents.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117369"},"PeriodicalIF":5.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181745","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

From orphan receptor to inflammation regulation: The role of GPR35 in the pathogenesis of depression 从孤儿受体到炎症调节：GPR35在抑郁症发病机制中的作用。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-25 DOI: 10.1016/j.bcp.2025.117370

Yang Yang , Wei Guan

{"title":"From orphan receptor to inflammation regulation: The role of GPR35 in the pathogenesis of depression","authors":"Yang Yang , Wei Guan","doi":"10.1016/j.bcp.2025.117370","DOIUrl":"10.1016/j.bcp.2025.117370","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors and have attracted significant attention as pharmacological targets, and they represent the largest target class for many drugs used in the treatment of various diseases. One of the intriguing members of this family is G protein-coupled receptor 35 (GPR35), which belongs to the class A GPCR superfamily and is an orphan receptor. GPR35 has been shown to be expressed in many organ-tissue systems, including the gastrointestinal tract, immune system, and central nervous system (CNS). Therefore, its association with the progression of pathophysiological diseases in these organ-tissue systems is not surprising. Accumulating evidence has implicated GPR35 in the regulation of inflammatory responses. Additionally, GPR35 has been demonstrated to be involved in depression-like behaviours induced by inflammation in mice. Despite these findings, the precise mechanisms by which GPR35 contributes to the pathogenesis of depression remain unclear. In this article, we highlight the structure, widespread expression, and endogenous ligands of GPR35, as well as its role in the pathophysiology of mental disorders, particularly in depression. In addition, we explored the role of GPR35 agonists and antagonists in the antidepressant mechanism, expanding the potential therapeutic value of GPR35 in depression. In summary, GPR35 has shown clear preclinical potential in the treatment of depression, which will provide a theoretical basis for accelerating its translation from the laboratory to the clinic, holding promise as a new breakthrough in the treatment of mental disorders.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117370"},"PeriodicalIF":5.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181752","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

Advances in understanding the mechanism of noncoding RNA (ncRNA)-mediated regulation of macrophage polarization in NAFLD 非编码RNA （ncRNA）介导的NAFLD巨噬细胞极化调控机制研究进展。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-25 DOI: 10.1016/j.bcp.2025.117372

Chang Ge , Yi Yuan , Xiaoning Li , Jianmin Zhang , Jitao Ling , Xuehong Zheng , Yuting Wu , Xin Huang , Pingping Yang , Xiao Liu , Deju Zhang , Jianping Liu , Jing Zhang , Peng Yu

{"title":"Advances in understanding the mechanism of noncoding RNA (ncRNA)-mediated regulation of macrophage polarization in NAFLD","authors":"Chang Ge , Yi Yuan , Xiaoning Li , Jianmin Zhang , Jitao Ling , Xuehong Zheng , Yuting Wu , Xin Huang , Pingping Yang , Xiao Liu , Deju Zhang , Jianping Liu , Jing Zhang , Peng Yu","doi":"10.1016/j.bcp.2025.117372","DOIUrl":"10.1016/j.bcp.2025.117372","url":null,"abstract":"<div><div>Nonalcoholic fatty liver disease (NAFLD), recently reclassified as metabolic dysfunction-associated steatotic liver disease (MASLD), has emerged as the most prevalent chronic liver disorder worldwide, progressing from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Increasing evidence highlights the pivotal role of immune-inflammatory responses in NAFLD pathogenesis, with macrophage polarization serving as a key regulatory mechanism that influences disease initiation, progression, and potential resolution. Noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as essential modulators of macrophage phenotype and function by influencing transcriptional checkpoints, inflammatory signaling pathways, and intercellular communication. Recent findings further underscore the role of lipotoxicity-associated ncRNAs in transmitting stress signals from hepatocytes to macrophages, thereby amplifying immune dysregulation and fibrogenesis. This review summarizes current knowledge on ncRNA expression and function in NAFLD, with a focus on their regulatory roles in macrophage polarization across disease stages, from steatosis to HCC. We categorize ncRNA-targeted therapies into specific approaches (e.g., miRNA mimics or inhibitors) and nonspecific interventions (e.g., exosome- or compound-mediated modulation), and further discuss their therapeutic potential and challenges, as well as emerging macrophage-targeted delivery systems. By linking molecular mechanisms to therapeutic strategies, we propose ncRNA-based modulation of macrophage polarization as a promising avenue for the diagnosis and treatment of NAFLD.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117372"},"PeriodicalIF":5.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181915","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

The MLL4: Roles in cell differentiation, adipogenesis and cancer. MLL4：在细胞分化、脂肪形成和癌症中的作用。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-25 DOI: 10.1016/j.bcp.2025.117371

Yu Zhang, Kaili Lv, Xubin Ma, Liang Wang, Yichao Xu

{"title":"The MLL4: Roles in cell differentiation, adipogenesis and cancer.","authors":"Yu Zhang, Kaili Lv, Xubin Ma, Liang Wang, Yichao Xu","doi":"10.1016/j.bcp.2025.117371","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117371","url":null,"abstract":"<p><p>Epigenetic regulation of gene expression plays an important role in cellular biological processes. MLL4 (KMT2D), as a histone lysine methyltransferase, is responsible for the mono-, di- and tri- methylation of histone 3 lysine 4 (H3K4), and H3K4me1 at the super enhancer/enhancer or promoter regions usually couples with H3K27ac to promote the expression of many genes. The biology function of MLL4 in cell proliferation and adipogenesis has been widely reported. And silencing MLL4 prevent the development of obesity and fatty liver, making it a potential target. Furthermore, MLL4 is frequently mutated and loses the methyltransferase activity in multiple cancers. Dual functions of MLL4 in cancer have been reported due to the broad widely distribution of H3K4 in chromatin. The paradoxical function of MLL4 complicate it as the potential target of cancer therapy. Notably, MLL4 may be a biomarker for drug sensitivity or serves as a synthetic lethal gene for specific anti-cancer agents. In this review, we examine the protein structural features of MLL4, discuss the MLL4 action in cell differentiation, adipogenesis, and cancer, and identify current challenges for future investigations.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117371"},"PeriodicalIF":5.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181693","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

Chronic inhibition of cGMP-specific phosphodiesterase 5 attenuates myocardial hypertrophy by promoting mitophagy in cardiomyocytes 慢性抑制cgmp特异性磷酸二酯酶5通过促进心肌细胞的线粒体自噬来减轻心肌肥大。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-24 DOI: 10.1016/j.bcp.2025.117366

Xuedi Zhang , Yeding Song , Haitao Mai , Wenbin Feng , Jinlin Sun , Zhenggang Zhao , Sujin Zhou , Allan Zijian Zhao , Yunping Mu , Fanghong Li

{"title":"Chronic inhibition of cGMP-specific phosphodiesterase 5 attenuates myocardial hypertrophy by promoting mitophagy in cardiomyocytes","authors":"Xuedi Zhang , Yeding Song , Haitao Mai , Wenbin Feng , Jinlin Sun , Zhenggang Zhao , Sujin Zhou , Allan Zijian Zhao , Yunping Mu , Fanghong Li","doi":"10.1016/j.bcp.2025.117366","DOIUrl":"10.1016/j.bcp.2025.117366","url":null,"abstract":"<div><div>Cardiac hypertrophy is a pathological adaptive response to chronic hemodynamic stress or injury, which may progress irreversibly to heart failure if left untreated. The objective of the study was to investigate whether inhibition of phosphodiesterase 5 can induce mitophagy to alleviate pathological cardiac hypertrophy. Sildenafil (Sif) effectively alleviates isoproterenol-induced cardiac hypertrophy <em>in vivo</em> by decreasing left ventricular wall thickness, reducing cardiac interstitial fibrosis, and improving cardiac functional parameters. Additionally, Sif protects against cardiomyocyte hypertrophy <em>in vitro</em> by lowering atrial natriuretic peptide levels and cardiomyocyte cross-sectional area. It also enhances mitochondrial function through the activation of PTEN-induced putative kinase-1 (PINK1)/Parkin-mediated mitophagy. Importantly, the autophagy inhibitor chloroquine abolished Sif-induced mitophagy and cardioprotection, thereby confirming the essential role of autophagic flux. Furthermore, the protective effects of Sif were reversed by the protein kinase G (PKG) inhibitor KT5823, indicating a dependence on the cyclic GMP (cGMP)-PKG signaling pathway. Altogether, Sif enhances mitophagy and maintain mitochondrial integrity by activating the PINK1/Parkin pathway through the cGMP-PKG signaling cascade, highlighting its potential to protect the myocardium perioperatively.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117366"},"PeriodicalIF":5.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172811","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

Metal-dependent protein phosphatase 1A: A potential therapeutic target in fibrotic disorders 金属依赖性蛋白磷酸酶1A：纤维化疾病的潜在治疗靶点

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-24 DOI: 10.1016/j.bcp.2025.117368

Yu Zhang , Hanghang Wang , Zecheng Jin, Lihong Hu, Qian Chai, Yinan Zhang

{"title":"Metal-dependent protein phosphatase 1A: A potential therapeutic target in fibrotic disorders","authors":"Yu Zhang , Hanghang Wang , Zecheng Jin, Lihong Hu, Qian Chai, Yinan Zhang","doi":"10.1016/j.bcp.2025.117368","DOIUrl":"10.1016/j.bcp.2025.117368","url":null,"abstract":"<div><div>Metal-dependent protein phosphatase 1A (PPM1A), a ubiquitously distributed member of the phosphatase superfamily, serves as a crucial signaling modulator through its capacity to dephosphorylate multiple nodal proteins in cellular transduction pathways. Localized to both cytoplasmic and nuclear compartments, PPM1A has emerged as a central negative regulator of key fibrotic and inflammatory cascades, such as transforming growth factor-β (TGF-β), nuclear factor-kappa-B (NF-κB), and mitogen-activated protein kinase (MAPK) pathways. Substantial evidence demonstrates that PPM1A modulates injury responses by attenuating TGF-β-mediated extracellular matrix (ECM) production, inhibiting fibroblast-to- myofibroblast transformation, and restoring tissue homeostasis across multiple organ systems. Research on its activity and status has positioned it as a promising therapeutic target for fibrotic implications. This review provides a comprehensive overview of structural determinants of PPM1A function, its multifaceted roles in cellular physiology, the pathological consequences of PPM1A dysregulation, and current progress in developing PPM1A-targeted therapies.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117368"},"PeriodicalIF":5.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145154285","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

Pursuing healthy aging and longevity through natural product and stem cell-driven rejuvenation 通过天然产品和干细胞驱动的返老还童，追求健康的衰老和长寿。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-23 DOI: 10.1016/j.bcp.2025.117359

Di Wu , Qinzheng Xu , Shuang Wu , Jiachen Tan , Faheem Ahmed Khan , Nuruliarizki Shinta Pandupuspitasari , Chunjie Huang

{"title":"Pursuing healthy aging and longevity through natural product and stem cell-driven rejuvenation","authors":"Di Wu , Qinzheng Xu , Shuang Wu , Jiachen Tan , Faheem Ahmed Khan , Nuruliarizki Shinta Pandupuspitasari , Chunjie Huang","doi":"10.1016/j.bcp.2025.117359","DOIUrl":"10.1016/j.bcp.2025.117359","url":null,"abstract":"<div><div>Aging is an inevitable biological process associated with progressive physiological decline and increased disease susceptibility. Cellular senescence stands as a key mechanism among the hallmarks of aging, which is characterized by irreversible cell-cycle arrest, chromatin remodeling, and a pro-inflammatory senescence-associated secretory phenotype (SASP). Importantly, SASP drives inflammaging and propagates senescence via a bystander effect, exacerbating tissue dysfunction. Recent advances in senolytic therapies and senostatics offer promising strategies to eliminate or rejuvenate senescent cells, improving physiological function in aged and disease models. Notably, panobinostat has emerged as an effective post-chemotherapy senolytic, mitigating chemoresistance. However, current senolytics face challenges, including off-target effects and limited clinical applicability. Growing evidence highlights natural products (e.g., polyphenols, flavonoids) and stem cell therapies as potential anti-aging interventions, with demonstrated efficacy in age-related disease models and ovarian rejuvenation. Despite progress, key hurdles remain in developing personalized, multi-target therapies that safely modulate aging trajectories. This review explores the mechanisms of cellular senescence, anti-aging mechanisms of phytochemicals, and phytochemicals and stem cell-therapy in ovary rejuvenation. We further discuss the challenges in developing “tailor-made” anti-aging interventions that rewire the aging trajectory, which will be critical for achieving healthy aging.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117359"},"PeriodicalIF":5.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147604","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 synergic GLP-1/Acylethanolamide-based combined therapy for MAFLD: Studies in rat models GLP-1/酰基乙醇酰胺联合治疗mald：大鼠模型研究

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-23 DOI: 10.1016/j.bcp.2025.117364

Marialuisa de Ceglia , Rubén Tovar , Miguel Rodríguez-Pozo , Antonio Vargas , Ana Gavito , Juan Suárez , Elena Baixeras , Fernando Rodríguez de Fonseca , Juan Decara

{"title":"A synergic GLP-1/Acylethanolamide-based combined therapy for MAFLD: Studies in rat models","authors":"Marialuisa de Ceglia , Rubén Tovar , Miguel Rodríguez-Pozo , Antonio Vargas , Ana Gavito , Juan Suárez , Elena Baixeras , Fernando Rodríguez de Fonseca , Juan Decara","doi":"10.1016/j.bcp.2025.117364","DOIUrl":"10.1016/j.bcp.2025.117364","url":null,"abstract":"<div><div>Obesity remains a major epidemic in developed countries, with metabolic-associated fatty liver disease (MAFLD) as one of its main hepatic consequences. Pharmacological treatments for MAFLD are limited, but modulation of glucagon-like peptide-1 (GLP-1) or acylethanolamide signalling offers promising therapeutic potential, while exerting anti-obesity effects. This study evaluated the effects of a combined therapy using a dual ligand targeting peroxisome proliferator-activated receptor alpha (PPARα) and peripheral cannabinoid receptor 1 (CB1) (OLHHA, acting as a PPARα agonist and CB1 antagonist) in combination with the GLP-1 receptor agonist liraglutide. Our aim was to assess their potential as a multitarget therapy to ameliorate liver dysfunction in an obesity animal model. In Wistar rats, we evaluated the effects of administering 3 mg/kg OLHHA and 25 µg/kg liraglutide, both acutely and chronically (daily for 42 days), in the context of exposure to a high-fat/high-fructose diet. Although both OLHHA and liraglutide individually ameliorated certain hepatic alterations induced by MAFLD, our findings demonstrate that their combined administration was significantly more effective in promoting body weight loss, improving lipid profiles and transaminase levels, and exerting robust antisteatotic effects in obese rats. This enhanced efficacy was evidenced by a marked reduction in hepatic fat content, downregulation of lipogenesis-related enzymes, and upregulation of proteins involved in lipid oxidation. Moreover, OLHHA, either alone or in combination with liraglutide, efficiently restored redox balance disrupted by MAFLD in obese rats. Collectively, these results highlight the potential of this multitarget therapeutic strategy for the treatment of obesity, MAFLD, and their associated comorbidities.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117364"},"PeriodicalIF":5.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147599","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

The oral microbiome–redox–inflammation axis in neurodegeneration: mechanistic insights and therapeutic perspectives 口腔微生物-氧化还原-炎症轴在神经退行性变：机制的见解和治疗的观点。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-22 DOI: 10.1016/j.bcp.2025.117362

Thi Thuy Tien Vo , Ming-Horng Tsai , Chueh-Yi Cheng , Yung-Li Wang , Wei-Ju Lee , I-Ta Lee

{"title":"The oral microbiome–redox–inflammation axis in neurodegeneration: mechanistic insights and therapeutic perspectives","authors":"Thi Thuy Tien Vo , Ming-Horng Tsai , Chueh-Yi Cheng , Yung-Li Wang , Wei-Ju Lee , I-Ta Lee","doi":"10.1016/j.bcp.2025.117362","DOIUrl":"10.1016/j.bcp.2025.117362","url":null,"abstract":"<div><div>The oral microbiome is a highly diverse and metabolically active ecosystem that plays a pivotal role in maintaining oral and systemic homeostasis. Disruption of this balance, referred to as oral dysbiosis, has been increasingly implicated in the pathogenesis of neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Although the precise molecular mechanisms remain incompletely defined, accumulating evidence indicates that oxidative stress and redox signaling act as central mediators linking microbial imbalance to neuroinflammatory responses and progressive neuronal dysfunction. In this review, we critically synthesize interdisciplinary findings on the oral microbiome–brain axis, emphasizing redox-sensitive pathways that mediate communication between oral pathogens and the central nervous system. We discuss how reactive oxygen species (ROS), generated by microbial metabolites and pathogen-associated molecular patterns, activate various signaling cascades, thereby exacerbating neuroinflammation and glial activation. We further evaluate evidence that oral dysbiosis contributes to blood–brain barrier (BBB) disruption, peripheral immune priming, and chronic neuroimmune dysregulation. By integrating mechanistic, cellular, and clinical perspectives, we identify oxidative stress and redox signaling as critical biological bridges between oral dysbiosis and neurodegeneration. This framework highlights not only the translational potential of targeting redox pathways and the oral microbiome for preventive and therapeutic strategies but also the need for future research to clarify causal relationships and validate clinical applications.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117362"},"PeriodicalIF":5.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136380","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

Exploring the potential of soluble guanylyl cyclase stimulators and activators in heart failure 探索可溶性胍基环化酶刺激剂和激活剂在心力衰竭中的潜力。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-21 DOI: 10.1016/j.bcp.2025.117363

Olga Gawrys , Petr Kala , Michal Šnorek , Vojtěch Melenovský , Stefano Corda , Peter Sandner

{"title":"Exploring the potential of soluble guanylyl cyclase stimulators and activators in heart failure","authors":"Olga Gawrys , Petr Kala , Michal Šnorek , Vojtěch Melenovský , Stefano Corda , Peter Sandner","doi":"10.1016/j.bcp.2025.117363","DOIUrl":"10.1016/j.bcp.2025.117363","url":null,"abstract":"<div><div>Heart failure (HF) is a life-threatening disease characterized by substantial morbidity and mortality. Yet despite recent advances, prognosis remains poor. Cyclic guanosine 3′,5′-monophosphate (cGMP) mediates a wide range of physiological processes in various cell types. Its deficiency has been implicated in numerous pathological cardiovascular diseases, including HF, pulmonary hypertension (PH), and kidney disease. Therefore, restoring and enhancing the nitric oxide (NO)–soluble guanylyl cyclase (sGC)–cGMP signalling pathway appears to have far-reaching therapeutic potential.</div><div>The discovery of sGC stimulators and activators marked a milestone in the field of NO–sGC–cGMP pharmacology, enabling NO-independent and long-acting enhancement of cGMP signalling without the formation of NO-derived radicals. Over a decade ago, the sGC stimulator riociguat was approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH). More recently, the sGC stimulator vericiguat was approved for symptomatic chronic HF. A number of sGC activators are currently being investigated for the treatment of chronic kidney diseases.</div><div>This review summarizes the evidence for NO–sGC–cGMP signalling in the regulation of cardiovascular and cardiac function, focusing on preclinical and clinical evidence for sGC stimulators and sGC activators in HF subtypes. Promising results have been observed in clinical trials of HF with reduced ejection fraction (HFrEF), but not in clinical trials of HF with preserved ejection fraction (HFpEF). Further studies are needed to determine the precise mechanisms of action of sGC agonists in HF and associated cardiorenal diseases to fully leverage their therapeutic potential and address the challenges of implementing these agents in routine clinical practice.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117363"},"PeriodicalIF":5.6,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130007","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