Pub Date : 2025-01-18DOI: 10.1016/j.phrs.2025.107604
Yuanshan Yao , Bin Li , Chunji Chen , Jing Wang , Feng Yao , Zhigang Li
Herpes virus entry mediator (HVEM) is a novel costimulatory molecule which mediates stimulatory or inhibitory signals in immune responses which makes it an attractive target in cancer therapeutics. However, the role of tumor cell intrinsic HVEM on tumor biology remains largely unknown. In this study, We demonstrated that CK+HVEM+ tumor correlates with better survival using Multiplex immuno histochemistry (mIHC) in Human Lung Adenocarcinoma Tissue microarray. Next, we showed that HVEM knockdown promoted NSCLC cell invasion and metastasis in vitro whereas exhibited no effect on proliferation. Conversely, HVEM overexpression results in the opposite phenotype. Meanwhile, the conclusion were further confirmed in vivo experiment that overexpression of HVEM reduced the invasion and metastasis of NSCLC whereas no effect on tumor mass. Besides, vivo experiment showed that M1 TAMs in the HVEM overxrpression group was increased and the proportion of M2 macrophages was decreased compared to the vector group. Mechanistically, The C-terminal 228–283 amino acid segment of HVEM protein interacts with the N-terminal 1–383 amino acid segment of MPRIP protein, inhibiting its downstream glycolysis signaling pathway and suppressing NSCLC cells progression. In addition, macrophage coculture assay suggested that HVEM overexpression inhibited M2 macrophage polarization through GM-CSF/GM-CSFRα axis. In summary, our study has demonstrated that tumor cell intrinsic HVEM is a potential tumour metastasis suppressor, which may serve as a potential target for immunotherapy.
{"title":"HVEM as a tumor-intrinsic regulator in non-small cell lung cancer: Suppression of metastasis via glycolysis inhibition and modulation of macrophage polarization","authors":"Yuanshan Yao , Bin Li , Chunji Chen , Jing Wang , Feng Yao , Zhigang Li","doi":"10.1016/j.phrs.2025.107604","DOIUrl":"10.1016/j.phrs.2025.107604","url":null,"abstract":"<div><div>Herpes virus entry mediator (HVEM) is a novel costimulatory molecule which mediates stimulatory or inhibitory signals in immune responses which makes it an attractive target in cancer therapeutics. However, the role of tumor cell intrinsic HVEM on tumor biology remains largely unknown. In this study, We demonstrated that CK+HVEM+ tumor correlates with better survival using Multiplex immuno histochemistry (mIHC) in Human Lung Adenocarcinoma Tissue microarray. Next, we showed that HVEM knockdown promoted NSCLC cell invasion and metastasis in vitro whereas exhibited no effect on proliferation. Conversely, HVEM overexpression results in the opposite phenotype. Meanwhile, the conclusion were further confirmed in vivo experiment that overexpression of HVEM reduced the invasion and metastasis of NSCLC whereas no effect on tumor mass. Besides, vivo experiment showed that M1 TAMs in the HVEM overxrpression group was increased and the proportion of M2 macrophages was decreased compared to the vector group. Mechanistically, The <em><u>C</u></em>-terminal 228–283 amino acid segment of HVEM protein interacts with the <em><u>N</u></em>-terminal 1–383 amino acid segment of MPRIP protein, inhibiting its downstream glycolysis signaling pathway and suppressing NSCLC cells progression. In addition, macrophage coculture assay suggested that HVEM overexpression inhibited M2 macrophage polarization through GM-CSF/GM-CSFRα axis. In summary, our study has demonstrated that tumor cell intrinsic HVEM is a potential tumour metastasis suppressor, which may serve as a potential target for immunotherapy.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107604"},"PeriodicalIF":9.1,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-15DOI: 10.1016/j.phrs.2025.107607
Sara E.L. Tolouei , Rodrigo Marcon , Fabiana Cardoso Vilela, Cristina Setim Freitas, Melina Heller, Edineia Lemos de Andrade, Sergio José Macedo Júnior, Adara Áurea dos Santos, Ruth Fernandes Rocha, Guilherme Pasetto Fadanni, Naiani Ferreira Marques, Jarbas Mota Siqueira Júnior, João B. Calixto
Obesity is a global epidemic often associated with serious medical complications such as diabetes, hypertension and metabolic dysfunction-associated steatohepatitis. Considering the multifactorial nature of these diseases, medicinal plants could be a valuable therapeutic strategy as their phytoconstituents interact with multiple and relevant biological targets. In this context, Ilex paraguariensis emerges as a potential alternative to treat obesity and associated metabolic diseases since several studies have demonstrated its anti-inflammatory, anti-obesity and anti-diabetic effects. We present a comprehensive and complete non-clinical investigation of the efficacy, safety and putative mechanisms of action of a standardized aqueous extract of I. paraguariensis (TI-076). We also describe a scalable preparation of TI-076 and demonstrate its long-term stability. TI-076 exhibits long-term stability and its major constituents are well absorbed orally in mice and rats. The five in vivo proofs of concept studies revealed that TI-076 reduced obesity, hyperglycaemia, blood pressure, liver fat accumulation, levels of serum insulin, leptin and cholesterol, food intake, inflammation and increased GLP-1 levels. The mechanisms through which TI-076 acts seem to involve the modulation of several genes associated with inflammation (Il1b, Nlrp3, Pparα and Pparγ), white adipose and liver metabolism (Cartpt, Mgll, Ramp3, Faah, Cck, Clps, Pparα and Pparγ), liver damage and fibrosis (Creb1, Col1a1 and Col3a1). Finally, TI-076 did not interact with CYP3A4 in vivo and proved to be safe. These findings strongly suggest that TI-076 holds great potential for clinical trials aimed at developing a safe phytomedicine for treating obesity and related metabolic diseases.
{"title":"Preclinical development of a standardized extract of Ilex paraguariensis A.St.-Hil for the treatment of obesity and metabolic syndrome","authors":"Sara E.L. Tolouei , Rodrigo Marcon , Fabiana Cardoso Vilela, Cristina Setim Freitas, Melina Heller, Edineia Lemos de Andrade, Sergio José Macedo Júnior, Adara Áurea dos Santos, Ruth Fernandes Rocha, Guilherme Pasetto Fadanni, Naiani Ferreira Marques, Jarbas Mota Siqueira Júnior, João B. Calixto","doi":"10.1016/j.phrs.2025.107607","DOIUrl":"10.1016/j.phrs.2025.107607","url":null,"abstract":"<div><div>Obesity is a global epidemic often associated with serious medical complications such as diabetes, hypertension and metabolic dysfunction-associated steatohepatitis. Considering the multifactorial nature of these diseases, medicinal plants could be a valuable therapeutic strategy as their phytoconstituents interact with multiple and relevant biological targets. In this context, <em>Ilex paraguariensis</em> emerges as a potential alternative to treat obesity and associated metabolic diseases since several studies have demonstrated its anti-inflammatory, anti-obesity and anti-diabetic effects. We present a comprehensive and complete non-clinical investigation of the efficacy, safety and putative mechanisms of action of a standardized aqueous extract of <em>I. paraguariensis</em> (TI-076). We also describe a scalable preparation of TI-076 and demonstrate its long-term stability. TI-076 exhibits long-term stability and its major constituents are well absorbed orally in mice and rats. The five <em>in vivo</em> proofs of concept studies revealed that TI-076 reduced obesity, hyperglycaemia, blood pressure, liver fat accumulation, levels of serum insulin, leptin and cholesterol, food intake, inflammation and increased GLP-1 levels. The mechanisms through which TI-076 acts seem to involve the modulation of several genes associated with inflammation (<em>Il1b, Nlrp3, Pparα</em> and <em>Pparγ</em>), white adipose and liver metabolism (<em>Cartpt, Mgll, Ramp3</em>, <em>Faah, Cck, Clps, Pparα</em> and <em>Pparγ</em>), liver damage and fibrosis (<em>Creb1, Col1a1</em> and <em>Col3a1</em>). Finally, TI-076 did not interact with CYP3A4 <em>in vivo</em> and proved to be safe. These findings strongly suggest that TI-076 holds great potential for clinical trials aimed at developing a safe phytomedicine for treating obesity and related metabolic diseases.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107607"},"PeriodicalIF":9.1,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.phrs.2024.107558
Theresa Brand , Bettina Tanitha Baumgarten , Sabrina Denzinger , Yvonne Reinders , Miriam Kleindl , Constanze Schanbacher , Florian Funk , Nilgün Gedik , Mahmood Jabbasseh , Petra Kleinbongard , Jan Dudek , Julia Szendroedi , Elen Tolstik , Kai Schuh , Martina Krüger , Dobromir Dobrev , Friederike Cuello , Albert Sickmann , Joachim P. Schmitt , Kristina Lorenz
Impaired cardiomyocyte Ca2+ handling is a central hallmark of heart failure (HF), which causes contractile dysfunction and arrhythmias. However, the underlying molecular mechanisms and the precise contribution of defects in Ca2+-cycling regulation in the development of HF are still not completely resolved. Here, we used transgenic mice that express a human mutation in the cardiomyocyte Ca2+-regulator phospholamban (PLNR9C-tg) causing severe HF due to a reduction in Ca2+ reuptake into the sarco(endo)plasmic reticulum (SR). PLNR9C-induced HF is a rapidly progressing condition characterized by prominent Ca2+ cycling and relaxation defects and premature death of mutation carriers. We found that endoplasmic reticulum (ER) and mitochondrial function are affected even before transition to overt HF. Early correction of aberrant Ca2+ cycling by cardiac expression of the Raf kinase inhibitor protein (RKIP), an endogenous activator of β-adrenoceptors (βAR), delayed the cellular alterations, functional failure and prolonged lifespan. Our study highlights the importance of early and persistent correction of Ca2 + dynamics, not only for excitation/contraction coupling, but also for the prevention of rather irreparable events on cardiac energetics and ER stress adaptations. The latter may even impede with later onset of Ca2+-related therapeutic interventions and should gain more focus for HF treatment.
{"title":"From Ca2+ dysregulation to heart failure: β-adrenoceptor activation by RKIP postpones molecular damages and subsequent cardiac dysfunction in mice carrying mutant PLNR9C by correction of aberrant Ca2+-handling","authors":"Theresa Brand , Bettina Tanitha Baumgarten , Sabrina Denzinger , Yvonne Reinders , Miriam Kleindl , Constanze Schanbacher , Florian Funk , Nilgün Gedik , Mahmood Jabbasseh , Petra Kleinbongard , Jan Dudek , Julia Szendroedi , Elen Tolstik , Kai Schuh , Martina Krüger , Dobromir Dobrev , Friederike Cuello , Albert Sickmann , Joachim P. Schmitt , Kristina Lorenz","doi":"10.1016/j.phrs.2024.107558","DOIUrl":"10.1016/j.phrs.2024.107558","url":null,"abstract":"<div><div>Impaired cardiomyocyte Ca<sup>2+</sup> handling is a central hallmark of heart failure (HF), which causes contractile dysfunction and arrhythmias. However, the underlying molecular mechanisms and the precise contribution of defects in Ca<sup>2+</sup>-cycling regulation in the development of HF are still not completely resolved. Here, we used transgenic mice that express a human mutation in the cardiomyocyte Ca<sup>2+</sup>-regulator phospholamban (PLN<sup>R9C</sup>-tg) causing severe HF due to a reduction in Ca<sup>2+</sup> reuptake into the sarco(endo)plasmic reticulum (SR). PLN<sup>R9C</sup>-induced HF is a rapidly progressing condition characterized by prominent Ca<sup>2+</sup> cycling and relaxation defects and premature death of mutation carriers. We found that endoplasmic reticulum (ER) and mitochondrial function are affected even before transition to overt HF. Early correction of aberrant Ca<sup>2+</sup> cycling by cardiac expression of the Raf kinase inhibitor protein (RKIP), an endogenous activator of β-adrenoceptors (βAR), delayed the cellular alterations, functional failure and prolonged lifespan. Our study highlights the importance of early and persistent correction of Ca<sup>2 +</sup> dynamics, not only for excitation/contraction coupling, but also for the prevention of rather irreparable events on cardiac energetics and ER stress adaptations. The latter may even impede with later onset of Ca<sup>2+</sup>-related therapeutic interventions and should gain more focus for HF treatment.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"211 ","pages":"Article 107558"},"PeriodicalIF":9.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.phrs.2024.107561
Srinivas Kamath , Elysia Sokolenko , Kate Collins , Nicole S.L. Chan , Natalie Mills , Scott R. Clark , Francine Z. Marques , Paul Joyce
Gut microbial dysbiosis or altered gut microbial consortium, in schizophrenia suggests a pathogenic role through the gut-brain axis, influencing neuroinflammatory and neurotransmitter pathways critical to psychotic, affective, and cognitive symptoms. Paradoxically, conventional psychotropic interventions may exacerbate this dysbiosis, with antipsychotics, particularly olanzapine, demonstrating profound effects on microbial architecture through disruption of bacterial phyla ratios, diminished taxonomic diversity, and attenuated short-chain fatty acid synthesis. To address these challenges, novel therapeutic strategies targeting the gut microbiome, encompassing probiotic supplementation, prebiotic compounds, faecal microbiota transplantation, and rationalised co-pharmacotherapy, show promise in attenuating antipsychotic-induced metabolic disruptions while enhancing therapeutic efficacy. Harnessing such insights, precision medicine approaches promise to transform antipsychotic prescribing practices by identifying patients at risk of metabolic side effects based on their microbial profiles. This IUPHAR review collates the current literature landscape of the gut-brain axis and its intricate relationship with schizophrenia while advocating for integrating microbiome assessments and therapeutic management. Such a fundamental shift in proposing microbiome-informed psychotropic prescriptions to optimise therapeutic efficacy and reduce adverse metabolic impacts would align antipsychotic treatments with microbiome safety, prioritising 'gut-neutral' or gut-favourable drugs to safeguard long-term patient outcomes in schizophrenia therapy.
{"title":"IUPHAR themed review: The gut microbiome in schizophrenia","authors":"Srinivas Kamath , Elysia Sokolenko , Kate Collins , Nicole S.L. Chan , Natalie Mills , Scott R. Clark , Francine Z. Marques , Paul Joyce","doi":"10.1016/j.phrs.2024.107561","DOIUrl":"10.1016/j.phrs.2024.107561","url":null,"abstract":"<div><div>Gut microbial dysbiosis or altered gut microbial consortium, in schizophrenia suggests a pathogenic role through the gut-brain axis, influencing neuroinflammatory and neurotransmitter pathways critical to psychotic, affective, and cognitive symptoms. Paradoxically, conventional psychotropic interventions may exacerbate this dysbiosis, with antipsychotics, particularly olanzapine, demonstrating profound effects on microbial architecture through disruption of bacterial phyla ratios, diminished taxonomic diversity, and attenuated short-chain fatty acid synthesis. To address these challenges, novel therapeutic strategies targeting the gut microbiome, encompassing probiotic supplementation, prebiotic compounds, faecal microbiota transplantation, and rationalised co-pharmacotherapy, show promise in attenuating antipsychotic-induced metabolic disruptions while enhancing therapeutic efficacy. Harnessing such insights, precision medicine approaches promise to transform antipsychotic prescribing practices by identifying patients at risk of metabolic side effects based on their microbial profiles. This IUPHAR review collates the current literature landscape of the gut-brain axis and its intricate relationship with schizophrenia while advocating for integrating microbiome assessments and therapeutic management. Such a fundamental shift in proposing microbiome-informed psychotropic prescriptions to optimise therapeutic efficacy and reduce adverse metabolic impacts would align antipsychotic treatments with microbiome safety, prioritising 'gut-neutral' or gut-favourable drugs to safeguard long-term patient outcomes in schizophrenia therapy.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"211 ","pages":"Article 107561"},"PeriodicalIF":9.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.phrs.2024.107545
Nicole R. Silva , Shokouh Arjmand , Luana B. Domingos , Adriano M. Chaves-Filho , Melina Mottin , Caroline C. Real , Anna L. Waszkiewicz , Pedro H. Gobira , Alessio Nicola Ferraro , Anne M. Landau , Carolina H. Andrade , Heidi K. Müller , Gregers Wegener , Sâmia R.L. Joca
Ketamine (KET) is recognized as rapid-acting antidepressant, but its mechanisms of action remain elusive. Considering the role of endocannabinoids (eCB) in stress and depression, we investigated if S-KET antidepressant effects involve the regulation of the eCB system using an established rat model of depression based on selective breeding: the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL). S-KET (15 mg/kg) effects were assessed in rats exposed to the open field and forced swimming test (FST), followed by analysis of the eCB signaling in the rat prefrontal cortex (PFC), a brain region involved in depression neurobiology. Changes in eCB receptors and enzymes were assessed at mRNA and protein levels (qPCR and western blot), CB1 binding ([3H]SR141716A autoradiography) and endocannabinoid content (lipidomics). The results demonstrated that the depressive behavior in FSL was negatively correlated with 2-AG levels, which were restored upon acute S-KET treatment. Although S-KET decreased CB1 and FAAH gene expression in FSL, there were no significant changes at protein levels. [3H]SR141716A binding to CB1 receptors was increased by S-KET and in silico analysis suggested that it binds to CB1, CB2, GPR55 and FAAH. Overall, S-KET effects correlated with an increased endocannabinoid signaling in the PFC, but systemic treatment with rimonabant failed to block its behavioral effects. Altogether, our results indicate that S-KET facilitates eCB signaling in the PFC of FSL. The inability of rimonabant to block the antidepressant effect of S-KET highlights the complexity of its interaction with the ECS, warranting further investigation into the molecular pathways.
{"title":"Modulation of the endocannabinoid system by (S)-ketamine in an animal model of depression","authors":"Nicole R. Silva , Shokouh Arjmand , Luana B. Domingos , Adriano M. Chaves-Filho , Melina Mottin , Caroline C. Real , Anna L. Waszkiewicz , Pedro H. Gobira , Alessio Nicola Ferraro , Anne M. Landau , Carolina H. Andrade , Heidi K. Müller , Gregers Wegener , Sâmia R.L. Joca","doi":"10.1016/j.phrs.2024.107545","DOIUrl":"10.1016/j.phrs.2024.107545","url":null,"abstract":"<div><div>Ketamine (KET) is recognized as rapid-acting antidepressant, but its mechanisms of action remain elusive. Considering the role of endocannabinoids (eCB) in stress and depression, we investigated if S-KET antidepressant effects involve the regulation of the eCB system using an established rat model of depression based on selective breeding: the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL). S-KET (15 mg/kg) effects were assessed in rats exposed to the open field and forced swimming test (FST), followed by analysis of the eCB signaling in the rat prefrontal cortex (PFC), a brain region involved in depression neurobiology. Changes in eCB receptors and enzymes were assessed at mRNA and protein levels (qPCR and western blot), CB1 binding ([<sup>3</sup>H]SR141716A autoradiography) and endocannabinoid content (lipidomics). The results demonstrated that the depressive behavior in FSL was negatively correlated with 2-AG levels, which were restored upon acute S-KET treatment. Although S-KET decreased CB1 and FAAH gene expression in FSL, there were no significant changes at protein levels. [<sup>3</sup>H]SR141716A binding to CB1 receptors was increased by S-KET and <em>in silico</em> analysis suggested that it binds to CB1, CB2, GPR55 and FAAH. Overall, S-KET effects correlated with an increased endocannabinoid signaling in the PFC, but systemic treatment with rimonabant failed to block its behavioral effects. Altogether, our results indicate that <strong>S</strong>-KET facilitates eCB signaling in the PFC of FSL. The inability of rimonabant to block the antidepressant effect of S-KET highlights the complexity of its interaction with the ECS, warranting further investigation into the molecular pathways.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"211 ","pages":"Article 107545"},"PeriodicalIF":9.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.phrs.2024.107555
Huan He , Weiwei Huang , Zigang Pan , Lingjun Wang , Zhongqi Yang , Zixin Chen
Heart failure (HF) remains one of the leading causes of high morbidity and mortality globally. Impaired cardiac energy metabolism plays a critical role in the pathological progression of HF. Various forms of HF exhibit marked differences in energy metabolism, particularly in mitochondrial function and substrate utilization. Recent studies have increasingly highlighted that improving energy metabolism in HF patients as a crucial treatment strategy. Mitochondrial transfer is emerging as a promising and precisely regulated therapeutic strategy for treating metabolic disorders. This paper specifically reviews the characteristics of mitochondrial energy metabolism across different types of HF and explores the modes and mechanisms of mitochondrial transfer between different cell types in the heart, such as cardiomyocytes, fibroblasts, and immune cells. We focused on the therapeutic potential of intercellular mitochondrial transfer in improving energy metabolism disorders in HF. We also discuss the role of signal transduction in mitochondrial transfer, highlighting that mitochondria not only function as energy factories but also play crucial roles in intercellular communication, metabolic regulation, and tissue repair. This study provides new insights into improving energy metabolism in heart failure patients and proposes promising new therapeutic strategies.
{"title":"Intercellular Mitochondrial transfer: Therapeutic implications for energy metabolism in heart failure","authors":"Huan He , Weiwei Huang , Zigang Pan , Lingjun Wang , Zhongqi Yang , Zixin Chen","doi":"10.1016/j.phrs.2024.107555","DOIUrl":"10.1016/j.phrs.2024.107555","url":null,"abstract":"<div><div>Heart failure (HF) remains one of the leading causes of high morbidity and mortality globally. Impaired cardiac energy metabolism plays a critical role in the pathological progression of HF. Various forms of HF exhibit marked differences in energy metabolism, particularly in mitochondrial function and substrate utilization. Recent studies have increasingly highlighted that improving energy metabolism in HF patients as a crucial treatment strategy. Mitochondrial transfer is emerging as a promising and precisely regulated therapeutic strategy for treating metabolic disorders. This paper specifically reviews the characteristics of mitochondrial energy metabolism across different types of HF and explores the modes and mechanisms of mitochondrial transfer between different cell types in the heart, such as cardiomyocytes, fibroblasts, and immune cells. We focused on the therapeutic potential of intercellular mitochondrial transfer in improving energy metabolism disorders in HF. We also discuss the role of signal transduction in mitochondrial transfer, highlighting that mitochondria not only function as energy factories but also play crucial roles in intercellular communication, metabolic regulation, and tissue repair. This study provides new insights into improving energy metabolism in heart failure patients and proposes promising new therapeutic strategies.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"211 ","pages":"Article 107555"},"PeriodicalIF":9.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.phrs.2024.107557
Jingyun Wu , Irene Santos-Garcia , Ivan Eiriz , Thomas Brüning , Aleš Kvasnička , David Friedecký , Tuula A. Nyman , Jens Pahnke
Huntington's disease (HD) is a debilitating neurodegenerative disorder characterized by severe motor deficits, cognitive decline and psychiatric disturbances. An early and significant morphological hallmark of HD is the activation of astrocytes triggered by mutant huntingtin, leading to the release of inflammatory mediators.
Fingolimod (FTY), an FDA-approved sphingosine-1-phosphate (S1P) receptor agonist is used to treat multiple sclerosis (MS), a neuroinflammatory disease, and has shown therapeutic promise in other neurological conditions.
Our study aimed to investigate the therapeutic potential of FTY for treating HD by utilizing a well-characterized mouse model of HD (zQ175dn) and wild-type littermates.
The study design included a crossover, long-term oral treatment with 1 mg/kg to 2 mg/kg FTY from the age of 15–46 weeks (n = 128). Different motor behavior and physiological parameters were assessed throughout the study.
The findings revealed that FTY rescued disease-related body weight loss in a sex-dependent manner, indicating its potential to regulate metabolic disturbances and to counteract neurodegenerative processes in HD. FTY intervention also rescued testicular atrophy, restored testis tissue structure in male mice suggesting a broader impact on peripheral tissues affected by huntingtin pathology. Histological analyses of the brain revealed delayed accumulation of activated astrocytes contributing to the preservation of the neural microenvironment by reducing neuroinflammation.
The extent of FTY-related disease improvement was sex-dependent. Motor functions and body weight improved mostly in female mice with sustained estrogen levels, whereas males had to compensate for the ongoing, disease-related testis atrophy and the loss of androgen production.
Our study underscores the beneficial therapeutic effects of FTY on HD involving endogenous steroid hormones and their important anabolic effects. It positions FTY as a promising candidate for therapeutic interventions targeting various aspects of HD pathology. Further studies are needed to fully evaluate its therapeutic potential in patients.
{"title":"Sex-dependent efficacy of sphingosine-1-phosphate receptor agonist FTY720 in mitigating Huntington’s disease","authors":"Jingyun Wu , Irene Santos-Garcia , Ivan Eiriz , Thomas Brüning , Aleš Kvasnička , David Friedecký , Tuula A. Nyman , Jens Pahnke","doi":"10.1016/j.phrs.2024.107557","DOIUrl":"10.1016/j.phrs.2024.107557","url":null,"abstract":"<div><div>Huntington's disease (HD) is a debilitating neurodegenerative disorder characterized by severe motor deficits, cognitive decline and psychiatric disturbances. An early and significant morphological hallmark of HD is the activation of astrocytes triggered by mutant huntingtin, leading to the release of inflammatory mediators.</div><div>Fingolimod (FTY), an FDA-approved sphingosine-1-phosphate (S1P) receptor agonist is used to treat multiple sclerosis (MS), a neuroinflammatory disease, and has shown therapeutic promise in other neurological conditions.</div><div>Our study aimed to investigate the therapeutic potential of FTY for treating HD by utilizing a well-characterized mouse model of HD (zQ175dn) and wild-type littermates.</div><div>The study design included a crossover, long-term oral treatment with 1 mg/kg to 2 mg/kg FTY from the age of 15–46 weeks (n = 128). Different motor behavior and physiological parameters were assessed throughout the study.</div><div>The findings revealed that FTY rescued disease-related body weight loss in a sex-dependent manner, indicating its potential to regulate metabolic disturbances and to counteract neurodegenerative processes in HD. FTY intervention also rescued testicular atrophy, restored testis tissue structure in male mice suggesting a broader impact on peripheral tissues affected by huntingtin pathology. Histological analyses of the brain revealed delayed accumulation of activated astrocytes contributing to the preservation of the neural microenvironment by reducing neuroinflammation.</div><div>The extent of FTY-related disease improvement was sex-dependent. Motor functions and body weight improved mostly in female mice with sustained estrogen levels, whereas males had to compensate for the ongoing, disease-related testis atrophy and the loss of androgen production.</div><div><em>Our study underscores the beneficial therapeutic effects of FTY on HD involving endogenous steroid hormones and their important anabolic effects</em>. It positions FTY as a promising candidate for therapeutic interventions targeting various aspects of HD pathology. Further studies are needed to fully evaluate its therapeutic potential in patients.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"211 ","pages":"Article 107557"},"PeriodicalIF":9.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.phrs.2024.107564
Arief Gunawan Darmanto , Ting-Lin Yen , Jing-Shiun Jan , Tran Thanh Duy Linh , Rajeev Taliyan , Chih-Hao Yang , Joen-Rong Sheu
Psychiatric disorders pose a significant global health challenge, exacerbated by the COVID-19 pandemic and insufficiently addressed by the current treatments. This review explores the emerging role of bile acids and the TGR5 receptor in the pathophysiology of psychiatric conditions, emphasizing their signaling within the gut-brain axis. We detail the synthesis and systemic functions of bile acids, their transformation by gut microbiota, and their impact across various neuropsychiatric disorders, including major depressive disorder, general anxiety disorder, schizophrenia, autism spectrum disorder, and bipolar disorder. The review highlights how dysbiosis and altered bile acid metabolism contribute to the development and exacerbation of these neuropsychiatric disorders through mechanisms involving inflammation, oxidative stress, and neurotransmitter dysregulation. Importantly, we detail both pharmacological and non-pharmacological interventions that modulate TGR5 signaling, offering potential breakthroughs in treatment strategies. These include dietary adjustments to enhance beneficial bile acids production and the use of specific TGR5 agonists that have shown promise in preclinical and clinical settings for their regulatory effects on critical pathways such as cAMP-PKA, NRF2-mediated antioxidant responses, and neuroinflammation. By integrating findings from the dynamics of gut microbiota, bile acids metabolism, and TGR5 receptor related signaling events, this review underscores cutting-edge therapeutic approaches poised to revolutionize the management and treatment of psychiatric disorders.
{"title":"Beyond metabolic messengers: Bile acids and TGR5 as pharmacotherapeutic intervention for psychiatric disorders","authors":"Arief Gunawan Darmanto , Ting-Lin Yen , Jing-Shiun Jan , Tran Thanh Duy Linh , Rajeev Taliyan , Chih-Hao Yang , Joen-Rong Sheu","doi":"10.1016/j.phrs.2024.107564","DOIUrl":"10.1016/j.phrs.2024.107564","url":null,"abstract":"<div><div>Psychiatric disorders pose a significant global health challenge, exacerbated by the COVID-19 pandemic and insufficiently addressed by the current treatments. This review explores the emerging role of bile acids and the TGR5 receptor in the pathophysiology of psychiatric conditions, emphasizing their signaling within the gut-brain axis. We detail the synthesis and systemic functions of bile acids, their transformation by gut microbiota, and their impact across various neuropsychiatric disorders, including major depressive disorder, general anxiety disorder, schizophrenia, autism spectrum disorder, and bipolar disorder. The review highlights how dysbiosis and altered bile acid metabolism contribute to the development and exacerbation of these neuropsychiatric disorders through mechanisms involving inflammation, oxidative stress, and neurotransmitter dysregulation. Importantly, we detail both pharmacological and non-pharmacological interventions that modulate TGR5 signaling, offering potential breakthroughs in treatment strategies. These include dietary adjustments to enhance beneficial bile acids production and the use of specific TGR5 agonists that have shown promise in preclinical and clinical settings for their regulatory effects on critical pathways such as cAMP-PKA, NRF2-mediated antioxidant responses, and neuroinflammation. By integrating findings from the dynamics of gut microbiota, bile acids metabolism, and TGR5 receptor related signaling events, this review underscores cutting-edge therapeutic approaches poised to revolutionize the management and treatment of psychiatric disorders.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"211 ","pages":"Article 107564"},"PeriodicalIF":9.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.phrs.2024.107563
Luisa Diomede , Andrea Conz , Michele Mosconi , Tatiana Stoilova , Matteo Paloni , Matteo Salvalaglio , Alfredo Cagnotto , Laura Colombo , Marcella Catania , Giuseppe Di Fede , Fabrizio Tagliavini , Mario Salmona
Alzheimer’s disease, the leading cause of dementia globally, represents an unresolved clinical challenge due to its complex pathogenesis and the absence of effective treatments. Considering the multifactorial etiology of the disease, mainly characterized by the accumulation of amyloid β plaques and neurofibrillary tangles of tau protein, we discuss the A673V mutation in the gene coding for the amyloid precursor protein, which is associated with the familial form of Alzheimer’s disease in a homozygous state. The mutation offers new insights into the molecular mechanisms of the disease, particularly regarding the contrasting roles of the A2V and A2T mutations in amyloid β peptide aggregation and toxicity. This review aims to describe relevant studies on A2V-mutated variants of the amyloid β peptide, revealing a protective effect against amyloid-β and tau pathology. Notably, special attention is given to the development of the peptide Aβ1–6A2V(D), which shows significant neuroprotective activity through inhibition of the assembly of amyloid β into amyloid fibrils. The therapeutic potential of this peptide emerges from its ability to reduce amyloid β-induced toxicity, with promising results from studies in human neuroblastoma cells and transgenic animal models.
{"title":"The AβA2V paradigm: From molecular insights to therapeutic strategies in Alzheimer’s disease and primary tauopathies","authors":"Luisa Diomede , Andrea Conz , Michele Mosconi , Tatiana Stoilova , Matteo Paloni , Matteo Salvalaglio , Alfredo Cagnotto , Laura Colombo , Marcella Catania , Giuseppe Di Fede , Fabrizio Tagliavini , Mario Salmona","doi":"10.1016/j.phrs.2024.107563","DOIUrl":"10.1016/j.phrs.2024.107563","url":null,"abstract":"<div><div>Alzheimer’s disease, the leading cause of dementia globally, represents an unresolved clinical challenge due to its complex pathogenesis and the absence of effective treatments. Considering the multifactorial etiology of the disease, mainly characterized by the accumulation of amyloid β plaques and neurofibrillary tangles of tau protein, we discuss the A673V mutation in the gene coding for the amyloid precursor protein, which is associated with the familial form of Alzheimer’s disease in a homozygous state. The mutation offers new insights into the molecular mechanisms of the disease, particularly regarding the contrasting roles of the A2V and A2T mutations in amyloid β peptide aggregation and toxicity. This review aims to describe relevant studies on A2V-mutated variants of the amyloid β peptide, revealing a protective effect against amyloid-β and tau pathology. Notably, special attention is given to the development of the peptide Aβ1–6<sub>A2V</sub>(D), which shows significant neuroprotective activity through inhibition of the assembly of amyloid β into amyloid fibrils. The therapeutic potential of this peptide emerges from its ability to reduce amyloid β-induced toxicity, with promising results from studies in human neuroblastoma cells and transgenic animal models.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"211 ","pages":"Article 107563"},"PeriodicalIF":9.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.phrs.2024.107546
Yurou Qiu , Qing Xu , Peichen Xie , Chenshuang He , Qiuchan Li , Xin Yao , Yang Mao , Xiaoqian Wu , Tiejun Zhang
The complex mechanisms underlying the development of cardiovascular diseases remain not fully elucidated. Epigenetics, which modulates gene expression without DNA sequence changes, is shedding light on these mechanisms and their heritable effects. This review focus on epigenetic regulation in cardiovascular aging and diseases, detailing specific epigenetic enzymes such as DNA methyltransferases (DNMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs), which serve as writers or erasers that modify the epigenetic landscape. We also discuss the readers of these modifications, such as the 5-methylcytosine binding domain proteins, and the erasers ten-eleven translocation (TET) proteins. The emerging role of RNA methylation, particularly N6-methyladenosine (m6A), in cardiovascular pathogenesis is also discussed. We summarize potential therapeutic targets, such as key enzymes and their inhibitors, including DNMT inhibitors like 5-azacytidine and decitabine, HDAC inhibitors like belinostat and givinotide, some of which have been approved by the FDA for various malignancies, suggesting their potential in treating cardiovascular diseases. Furthermore, we highlight the role of novel histone modifications and their associated enzymes, which are emerging as potential therapeutic targets in cardiovascular diseases. Thus, by incorporating the recent studies involving patients with cardiovascular aging and diseases, we aim to provide a more detailed and updated review that reflects the advancements in the field of epigenetic modification in cardiovascular diseases.
心血管疾病发病的复杂机制仍未完全阐明。表观遗传学在不改变 DNA 序列的情况下调节基因表达，它正在揭示这些机制及其遗传效应。这篇综述重点探讨了心血管衰老和疾病中的表观遗传调控，详细介绍了特定的表观遗传酶，如 DNA 甲基转移酶（DNMTs）、组蛋白乙酰转移酶（HATs）和组蛋白去乙酰化酶（HDACs），它们是改变表观遗传结构的写手。我们还讨论了这些修饰的读者，如 5-甲基胞嘧啶结合域蛋白和十-十一易位（TET）蛋白。我们还讨论了 RNA 甲基化，尤其是 N6-甲基腺苷（m6A）在心血管发病机制中新出现的作用。我们总结了潜在的治疗靶点，如关键酶及其抑制剂，包括 DNMT 抑制剂（如 5-azacytidine 和 decitabine）、HDAC 抑制剂（如 belinostat 和 givinotide），其中一些已被 FDA 批准用于治疗各种恶性肿瘤，这表明它们在治疗心血管疾病方面具有潜力。此外，我们还强调了新型组蛋白修饰及其相关酶的作用，它们正在成为心血管疾病的潜在治疗靶点。因此，通过纳入涉及心血管衰老和疾病患者的最新研究，我们旨在提供更详细、更新的综述，以反映表观遗传修饰在心血管疾病领域的进展。
{"title":"Epigenetic modifications and emerging therapeutic targets in cardiovascular aging and diseases","authors":"Yurou Qiu , Qing Xu , Peichen Xie , Chenshuang He , Qiuchan Li , Xin Yao , Yang Mao , Xiaoqian Wu , Tiejun Zhang","doi":"10.1016/j.phrs.2024.107546","DOIUrl":"10.1016/j.phrs.2024.107546","url":null,"abstract":"<div><div>The complex mechanisms underlying the development of cardiovascular diseases remain not fully elucidated. Epigenetics, which modulates gene expression without DNA sequence changes, is shedding light on these mechanisms and their heritable effects. This review focus on epigenetic regulation in cardiovascular aging and diseases, detailing specific epigenetic enzymes such as DNA methyltransferases (DNMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs), which serve as writers or erasers that modify the epigenetic landscape. We also discuss the readers of these modifications, such as the 5-methylcytosine binding domain proteins, and the erasers ten-eleven translocation (TET) proteins. The emerging role of RNA methylation, particularly N6-methyladenosine (m<sup>6</sup>A), in cardiovascular pathogenesis is also discussed. We summarize potential therapeutic targets, such as key enzymes and their inhibitors, including DNMT inhibitors like 5-azacytidine and decitabine, HDAC inhibitors like belinostat and givinotide, some of which have been approved by the FDA for various malignancies, suggesting their potential in treating cardiovascular diseases. Furthermore, we highlight the role of novel histone modifications and their associated enzymes, which are emerging as potential therapeutic targets in cardiovascular diseases. Thus, by incorporating the recent studies involving patients with cardiovascular aging and diseases, we aim to provide a more detailed and updated review that reflects the advancements in the field of epigenetic modification in cardiovascular diseases.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"211 ","pages":"Article 107546"},"PeriodicalIF":9.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824407","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}
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