Pub Date : 2024-07-01DOI: 10.1016/j.molmed.2024.06.005
Charalampos D Moschopoulos, Kate Alford, Anastasia Antoniadou, Jaime H Vera
Despite the dramatic decrease in HIV-associated neurocognitive impairment (NCI) in the combined antiretroviral treatment (cART) era, subtler neuropsychological complications remain prevalent. In this review, we discuss the changing pathophysiology of HIV-associated NCI, considering recent evidence of HIV neuropathogenesis, and the pivotal role of cART. Furthermore, we address the multifactorial nature of NCI in people living with HIV, including legacy and ongoing insults to the brain, as well as host-specific factors. We also summarize the ongoing debate about the refinement of diagnostic criteria, exploring the strengths and limitations of these recent approaches. Finally, we present current research in NCI management in people living with HIV and highlight the need for using both pharmacological and nonpharmacological pathways toward a holistic approach.
尽管在联合抗逆转录病毒治疗(cART)时代,HIV 相关神经认知障碍(NCI)急剧下降,但更微妙的神经心理并发症仍然普遍存在。在这篇综述中,我们讨论了 HIV 相关神经认知障碍不断变化的病理生理学,考虑了 HIV 神经发病机制的最新证据,以及 cART 的关键作用。此外,我们还讨论了 HIV 感染者 NCI 的多因素性质,包括对大脑的遗留和持续损伤,以及宿主特异性因素。我们还总结了目前关于完善诊断标准的争论,探讨了这些最新方法的优势和局限性。最后,我们介绍了目前对艾滋病病毒感染者进行 NCI 管理的研究情况,并强调有必要同时使用药物和非药物方法来实现综合治疗。
{"title":"Cognitive impairment in people living with HIV: mechanisms, controversies, and future perspectives.","authors":"Charalampos D Moschopoulos, Kate Alford, Anastasia Antoniadou, Jaime H Vera","doi":"10.1016/j.molmed.2024.06.005","DOIUrl":"https://doi.org/10.1016/j.molmed.2024.06.005","url":null,"abstract":"<p><p>Despite the dramatic decrease in HIV-associated neurocognitive impairment (NCI) in the combined antiretroviral treatment (cART) era, subtler neuropsychological complications remain prevalent. In this review, we discuss the changing pathophysiology of HIV-associated NCI, considering recent evidence of HIV neuropathogenesis, and the pivotal role of cART. Furthermore, we address the multifactorial nature of NCI in people living with HIV, including legacy and ongoing insults to the brain, as well as host-specific factors. We also summarize the ongoing debate about the refinement of diagnostic criteria, exploring the strengths and limitations of these recent approaches. Finally, we present current research in NCI management in people living with HIV and highlight the need for using both pharmacological and nonpharmacological pathways toward a holistic approach.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141493537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-27DOI: 10.1016/j.molmed.2024.06.007
Qian Zhang, Dennis Schwarz, Yumei Cheng, Yahya Sohrabi
The ability of the gut microbiome to adapt to a new environment and utilize a new metabolite or dietary compound by inducing structural variations (SVs) in the genome has an important role in human health. Here, we discuss recent data on host genetic regulation of SV induction and its use as a new therapeutic approach.
{"title":"Unraveling host genetics and microbiome genome crosstalk: a novel therapeutic approach.","authors":"Qian Zhang, Dennis Schwarz, Yumei Cheng, Yahya Sohrabi","doi":"10.1016/j.molmed.2024.06.007","DOIUrl":"https://doi.org/10.1016/j.molmed.2024.06.007","url":null,"abstract":"<p><p>The ability of the gut microbiome to adapt to a new environment and utilize a new metabolite or dietary compound by inducing structural variations (SVs) in the genome has an important role in human health. Here, we discuss recent data on host genetic regulation of SV induction and its use as a new therapeutic approach.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-25DOI: 10.1016/j.molmed.2024.06.003
Runzhi Chen, Xinhua Chen, Jiangtao Gao
Unveiling a metabolic mystery, this article explores how 3-O-acylated bile acids, specifically 3-O-succinylated cholic acid (3-sucCA) and 3-acetylated cholic acid (3-acetyCA), modified by gut microbes Bacteroides uniformis and Christensenella minuta, respectively, may either disrupt or harmonize our metabolic processes, offering novel therapeutic avenues for conditions such as metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes mellitus (T2D).
{"title":"3-O-acylated bile acids: disrupters or harmonizers of metabolism?","authors":"Runzhi Chen, Xinhua Chen, Jiangtao Gao","doi":"10.1016/j.molmed.2024.06.003","DOIUrl":"https://doi.org/10.1016/j.molmed.2024.06.003","url":null,"abstract":"<p><p>Unveiling a metabolic mystery, this article explores how 3-O-acylated bile acids, specifically 3-O-succinylated cholic acid (3-sucCA) and 3-acetylated cholic acid (3-acetyCA), modified by gut microbes Bacteroides uniformis and Christensenella minuta, respectively, may either disrupt or harmonize our metabolic processes, offering novel therapeutic avenues for conditions such as metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes mellitus (T2D).</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141459475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-25DOI: 10.1016/j.molmed.2024.06.002
Erik H Douma, Marten P Smidt, Lars P van der Heide
Innovative therapeutic strategies are urgently needed for Parkinson's disease due to limited efficacy of current treatments and a weak therapeutic pipeline. In this forum article, we propose targeting tyrosine hydroxylase phosphorylation as a novel mechanism of action to address this critical need.
{"title":"Boosting endogenous dopamine production: a novel therapeutic approach for Parkinson's disease.","authors":"Erik H Douma, Marten P Smidt, Lars P van der Heide","doi":"10.1016/j.molmed.2024.06.002","DOIUrl":"https://doi.org/10.1016/j.molmed.2024.06.002","url":null,"abstract":"<p><p>Innovative therapeutic strategies are urgently needed for Parkinson's disease due to limited efficacy of current treatments and a weak therapeutic pipeline. In this forum article, we propose targeting tyrosine hydroxylase phosphorylation as a novel mechanism of action to address this critical need.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141459476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-24DOI: 10.1016/j.molmed.2024.06.006
Abel Plaza-Florido, Inmaculada Pérez-Prieto, Alejandro Lucia
The molecular mechanisms behind the potential 'anti-aging' effects of exercise remain to be elucidated. Janssens et al. studied the lipidome of different mouse tissues and human skeletal muscle. They identified an evolutionary conserved 'lipid aging' signature, characterized by bis(monoacylglycero)phosphate accumulation, which, at the muscle level, can be attenuated by exercise.
{"title":"The aging lipidome: exercise is medicine.","authors":"Abel Plaza-Florido, Inmaculada Pérez-Prieto, Alejandro Lucia","doi":"10.1016/j.molmed.2024.06.006","DOIUrl":"https://doi.org/10.1016/j.molmed.2024.06.006","url":null,"abstract":"<p><p>The molecular mechanisms behind the potential 'anti-aging' effects of exercise remain to be elucidated. Janssens et al. studied the lipidome of different mouse tissues and human skeletal muscle. They identified an evolutionary conserved 'lipid aging' signature, characterized by bis(monoacylglycero)phosphate accumulation, which, at the muscle level, can be attenuated by exercise.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141451599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-18DOI: 10.1016/j.molmed.2024.05.017
Shamim Ahmed, Alon Herschhorn
An effective HIV-1 vaccine is still not available, and most vaccine efficacy trials conducted over the years resulted in no significant overall protection. Here we highlight several insights gained from these trials as well as emerging questions that may be important for further guidance to advance current research directions.
{"title":"Insights from HIV-1 vaccine and passive immunization efficacy trials.","authors":"Shamim Ahmed, Alon Herschhorn","doi":"10.1016/j.molmed.2024.05.017","DOIUrl":"https://doi.org/10.1016/j.molmed.2024.05.017","url":null,"abstract":"<p><p>An effective HIV-1 vaccine is still not available, and most vaccine efficacy trials conducted over the years resulted in no significant overall protection. Here we highlight several insights gained from these trials as well as emerging questions that may be important for further guidance to advance current research directions.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":null,"pages":null},"PeriodicalIF":13.6,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-17DOI: 10.1016/j.molmed.2024.05.012
Steven O'Reilly, Pei-Suen Tsou, John Varga
Cellular senescence is a key hallmark of aging. It has now emerged as a key mediator in normal tissue turnover and is associated with a variety of age-related diseases, including organ-specific fibrosis and systemic sclerosis (SSc). This review discusses the recent evidence of the role of senescence in tissue fibrosis, with an emphasis on SSc, a systemic autoimmune rheumatic disease. We discuss the physiological role of these cells, their role in fibrosis, and that targeting these cells specifically could be a new therapeutic avenue in fibrotic disease. We argue that targeting senescent cells, with senolytics or senomorphs, is a viable therapeutic target in fibrotic diseases which remain largely intractable.
{"title":"Senescence and tissue fibrosis: opportunities for therapeutic targeting.","authors":"Steven O'Reilly, Pei-Suen Tsou, John Varga","doi":"10.1016/j.molmed.2024.05.012","DOIUrl":"https://doi.org/10.1016/j.molmed.2024.05.012","url":null,"abstract":"<p><p>Cellular senescence is a key hallmark of aging. It has now emerged as a key mediator in normal tissue turnover and is associated with a variety of age-related diseases, including organ-specific fibrosis and systemic sclerosis (SSc). This review discusses the recent evidence of the role of senescence in tissue fibrosis, with an emphasis on SSc, a systemic autoimmune rheumatic disease. We discuss the physiological role of these cells, their role in fibrosis, and that targeting these cells specifically could be a new therapeutic avenue in fibrotic disease. We argue that targeting senescent cells, with senolytics or senomorphs, is a viable therapeutic target in fibrotic diseases which remain largely intractable.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":null,"pages":null},"PeriodicalIF":13.6,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Protoporphyrias are caused by pathogenic variants in genes encoding enzymes involved in heme biosynthesis. They induce the accumulation of a hydrophobic phototoxic compound, protoporphyrin (PPIX), in red blood cells (RBCs). PPIX is responsible for painful cutaneous photosensitivity, which severely impairs quality of life. Hepatic elimination of PPIX increases the risk of cholestatic liver disease, requiring lifelong monitoring. Treatment options are scarce and mainly limited to supportive care such as protection from visible light. Here, we review the pathophysiology of protoporphyrias, their diagnosis, and current recommendations for medical care. We discuss new therapeutic strategies, some of which are currently undergoing clinical trials and are likely to radically alter the severity of the disease in the years to come.
{"title":"Erythropoietic protoporphyrias: updates and advances.","authors":"Antoine Poli, Caroline Schmitt, Hervé Puy, Neila Talbi, Thibaud Lefebvre, Laurent Gouya","doi":"10.1016/j.molmed.2024.05.006","DOIUrl":"https://doi.org/10.1016/j.molmed.2024.05.006","url":null,"abstract":"<p><p>Protoporphyrias are caused by pathogenic variants in genes encoding enzymes involved in heme biosynthesis. They induce the accumulation of a hydrophobic phototoxic compound, protoporphyrin (PPIX), in red blood cells (RBCs). PPIX is responsible for painful cutaneous photosensitivity, which severely impairs quality of life. Hepatic elimination of PPIX increases the risk of cholestatic liver disease, requiring lifelong monitoring. Treatment options are scarce and mainly limited to supportive care such as protection from visible light. Here, we review the pathophysiology of protoporphyrias, their diagnosis, and current recommendations for medical care. We discuss new therapeutic strategies, some of which are currently undergoing clinical trials and are likely to radically alter the severity of the disease in the years to come.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":null,"pages":null},"PeriodicalIF":13.6,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-17DOI: 10.1016/j.molmed.2024.05.014
Alberto L Epstein, Samuel D Rabkin
Herpes simplex virus type 1 (HSV-1) is a DNA virus and human pathogen used to construct promising therapeutic vectors. HSV-1 vectors fall into two classes: replication-selective oncolytic vectors for cancer therapy and defective non-replicative vectors for gene therapy. Vectors from each class can accommodate ≥30 kb of inserts, have been approved clinically, and demonstrate a relatively benign safety profile. Despite oncolytic HSV (oHSV) replication in tumors and elicited immune responses, the virus is well tolerated in cancer patients. Current non-replicative vectors elicit only limited immune responses. Seropositivity and immune responses against HSV-1 do not eliminate either the vector or infected cells, and the vectors can therefore be re-administered. In this review we highlight vectors that have been translated to the clinic and host-virus immune interactions that impact on the safety and efficacy of HSVs.
{"title":"Safety of non-replicative and oncolytic replication-selective HSV vectors.","authors":"Alberto L Epstein, Samuel D Rabkin","doi":"10.1016/j.molmed.2024.05.014","DOIUrl":"https://doi.org/10.1016/j.molmed.2024.05.014","url":null,"abstract":"<p><p>Herpes simplex virus type 1 (HSV-1) is a DNA virus and human pathogen used to construct promising therapeutic vectors. HSV-1 vectors fall into two classes: replication-selective oncolytic vectors for cancer therapy and defective non-replicative vectors for gene therapy. Vectors from each class can accommodate ≥30 kb of inserts, have been approved clinically, and demonstrate a relatively benign safety profile. Despite oncolytic HSV (oHSV) replication in tumors and elicited immune responses, the virus is well tolerated in cancer patients. Current non-replicative vectors elicit only limited immune responses. Seropositivity and immune responses against HSV-1 do not eliminate either the vector or infected cells, and the vectors can therefore be re-administered. In this review we highlight vectors that have been translated to the clinic and host-virus immune interactions that impact on the safety and efficacy of HSVs.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":null,"pages":null},"PeriodicalIF":13.6,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-17DOI: 10.1016/j.molmed.2024.05.013
Alessandro Cherubini, Sara Della Torre, Serena Pelusi, Luca Valenti
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver condition. MASLD is a sexually dimorphic condition, with its development and progression influenced by sex chromosomes and hormones. Estrogens typically protect against, whereas androgens promote, MASLD. Therapeutic approaches for a sex-specific personalized medicine include estrogen replacement, androgen blockers, and novel drugs targeting hormonal pathways. However, the interactions between hormonal factors and inherited genetic variation impacts MASLD risk, necessitating more tailored therapies. Understanding sex disparities and the role of estrogens could improve MASLD interventions and management, whereas clinical trials addressing sex differences are crucial for advancing personalized treatment. This review explores the underappreciated impact of sexual dimorphism in MASLD and discusses the potential therapeutic application of sex-related hormones.
{"title":"Sexual dimorphism of metabolic dysfunction-associated steatotic liver disease.","authors":"Alessandro Cherubini, Sara Della Torre, Serena Pelusi, Luca Valenti","doi":"10.1016/j.molmed.2024.05.013","DOIUrl":"https://doi.org/10.1016/j.molmed.2024.05.013","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver condition. MASLD is a sexually dimorphic condition, with its development and progression influenced by sex chromosomes and hormones. Estrogens typically protect against, whereas androgens promote, MASLD. Therapeutic approaches for a sex-specific personalized medicine include estrogen replacement, androgen blockers, and novel drugs targeting hormonal pathways. However, the interactions between hormonal factors and inherited genetic variation impacts MASLD risk, necessitating more tailored therapies. Understanding sex disparities and the role of estrogens could improve MASLD interventions and management, whereas clinical trials addressing sex differences are crucial for advancing personalized treatment. This review explores the underappreciated impact of sexual dimorphism in MASLD and discusses the potential therapeutic application of sex-related hormones.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":null,"pages":null},"PeriodicalIF":13.6,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}