Pub Date : 2026-02-01Epub Date: 2025-12-29DOI: 10.1016/j.mam.2025.101443
Asodu Sandeep Sarma, Dror Sharon
Inherited retinal diseases (IRDs) are clinically and genetically complex disorders that cause blindness in about one in 3450 individuals worldwide. More than 350 genes have been implicated in IRDs showing all possible inheritance patterns. Despite the advancement of several genetic therapies, there is currently no cure for the vast majority of IRDs. By converting a sense codon into a nonsense codon, premature termination codon (PTC) variants cause abrupt termination of protein synthesis, leading to loss of protein function in most cases. Nonsense variants account for approximately 18 % of all disease-causing variants in IRDs, and there is currently no effective treatment available to correct them. In recent years, anticodon engineered tRNAs (ACE-tRNAs) or suppressor tRNAs have emerged as potential therapeutic option for treating rare diseases caused by nonsense variants. This review critically summarizes the spectrum of nonsense variants in the genetics of IRDs and examines the promise of ACE-tRNA therapy as a treatment. We focus on the therapy's mechanism of action, current advancements, and its specific advantages and limitations for addressing nonsense variant-induced IRDs.
{"title":"The potential use of anti-codon engineered tRNAs (ACE-tRNAs) to treat nonsense variants causing inherited retinal diseases","authors":"Asodu Sandeep Sarma, Dror Sharon","doi":"10.1016/j.mam.2025.101443","DOIUrl":"10.1016/j.mam.2025.101443","url":null,"abstract":"<div><div>Inherited retinal diseases (IRDs) are clinically and genetically complex disorders that cause blindness in about one in 3450 individuals worldwide. More than 350 genes have been implicated in IRDs showing all possible inheritance patterns. Despite the advancement of several genetic therapies, there is currently no cure for the vast majority of IRDs. By converting a sense codon into a nonsense codon, premature termination codon (PTC) variants cause abrupt termination of protein synthesis, leading to loss of protein function in most cases. Nonsense variants account for approximately 18 % of all disease-causing variants in IRDs, and there is currently no effective treatment available to correct them. In recent years, anticodon engineered tRNAs (ACE-tRNAs) or suppressor tRNAs have emerged as potential therapeutic option for treating rare diseases caused by nonsense variants. This review critically summarizes the spectrum of nonsense variants in the genetics of IRDs and examines the promise of ACE-tRNA therapy as a treatment. We focus on the therapy's mechanism of action, current advancements, and its specific advantages and limitations for addressing nonsense variant-induced IRDs.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"107 ","pages":"Article 101443"},"PeriodicalIF":10.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145866322","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}
Pub Date : 2025-12-01Epub Date: 2025-11-26DOI: 10.1016/j.mam.2025.101426
Gonzalo Ferreira , Luisina Chavarría , Agustín DeMarco , Franco Bernech , Romina Cardozo , Axel Santander , Lucía Domínguez , Nicolás Mujica , Luis Sobrevia , Garth L. Nicolson
The interrelationship between type 2 diabetes mellitus (T2DM) and cancer reflects a convergence of molecular disturbances involving metabolism, inflammation, and cellular stress, often underpinned by genetic alterations. This review examines some key shared mechanisms of progression, with a focus on changes in plasma membrane dynamics, ion channel remodeling, Calcium (Ca2+) signaling, mitochondrial dysfunction, unfolded protein response, and oxidative stress. Changes in membrane composition, fluidity, lipid raft organization, and glycosylation affect receptor function and intracellular signaling in both diseases. These structural changes often occur in conjunction with the remodeling of ion channels. Ca2+ influx, K+, and Na+ are particularly affected, contributing to dysregulated excitability, proliferation, and immune modulation. Disturbed ion transport leads to intracellular Ca2+ overload or oscillatory defects, impairing insulin secretion in diabetes and activating pro-oncogenic pathways in cancer. A sustained Ca2+ imbalance further triggers the maladaptive activation of the UPR, while also affecting mitochondrial function. In T2DM, this response promotes β-cell dysfunction and insulin resistance, whereas in cancer, selective UPR engagement supports cell survival, angiogenesis, and immune evasion. Oxidative stress acts as both a trigger and amplifier in this cascade. Lipid peroxidation and mitochondrial dysfunction reinforce membrane instability and propagate damage, accelerating both metabolic decline and tumor progression. Therapeutically, interventions such as membrane lipid replacement and Ca2+ channel blockers are being explored for their dual potential in addressing some of these molecular dysfunctions. By integrating molecular and epidemiological perspectives, this review highlights the potential of using precision therapies that target some of the overlapping properties of T2DM and cancer, offering a more unified strategy to confront these global health challenges.
{"title":"Membrane remodeling, ion channels, Ca2+ signaling, and stress pathways as molecular links between type 2 diabetes and cancer","authors":"Gonzalo Ferreira , Luisina Chavarría , Agustín DeMarco , Franco Bernech , Romina Cardozo , Axel Santander , Lucía Domínguez , Nicolás Mujica , Luis Sobrevia , Garth L. Nicolson","doi":"10.1016/j.mam.2025.101426","DOIUrl":"10.1016/j.mam.2025.101426","url":null,"abstract":"<div><div>The interrelationship between type 2 diabetes mellitus (T2DM) and cancer reflects a convergence of molecular disturbances involving metabolism, inflammation, and cellular stress, often underpinned by genetic alterations. This review examines some key shared mechanisms of progression, with a focus on changes in plasma membrane dynamics, ion channel remodeling, Calcium (Ca<sup>2+</sup>) signaling, mitochondrial dysfunction, unfolded protein response, and oxidative stress. Changes in membrane composition, fluidity, lipid raft organization, and glycosylation affect receptor function and intracellular signaling in both diseases. These structural changes often occur in conjunction with the remodeling of ion channels. Ca<sup>2+</sup> influx, K<sup>+</sup>, and Na<sup>+</sup> are particularly affected, contributing to dysregulated excitability, proliferation, and immune modulation. Disturbed ion transport leads to intracellular Ca<sup>2+</sup> overload or oscillatory defects, impairing insulin secretion in diabetes and activating pro-oncogenic pathways in cancer. A sustained Ca<sup>2+</sup> imbalance further triggers the maladaptive activation of the UPR, while also affecting mitochondrial function. In T2DM, this response promotes β-cell dysfunction and insulin resistance, whereas in cancer, selective <span>UPR</span> engagement supports cell survival, angiogenesis, and immune evasion. Oxidative stress acts as both a trigger and amplifier in this cascade. Lipid peroxidation and mitochondrial dysfunction reinforce membrane instability and propagate damage, accelerating both metabolic decline and tumor progression. Therapeutically, interventions such as membrane lipid replacement and Ca<sup>2+</sup> channel blockers are being explored for their dual potential in addressing some of these molecular dysfunctions. By integrating molecular and epidemiological perspectives, this review highlights the potential of using precision therapies that target some of the overlapping properties of T2DM and cancer, offering a more unified strategy to confront these global health challenges.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"106 ","pages":"Article 101426"},"PeriodicalIF":10.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617748","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}
Pub Date : 2025-12-01Epub Date: 2025-09-13DOI: 10.1016/j.mam.2025.101410
Nataliya V. Zharova , Filipp D. Mikhailidi , Darya A. Kabanova , Alena Y. Tatarintseva , Olga L. Polyakova , Yury O. Zharikov , Nikolai A. Zharov , Sergey N. Ryagin , André Pontes-Silva , Tatiana S. Zharikova
The development of type 2 diabetes may be influenced by enterotypes and bacterial metabolites. The most important of these are short-chain fatty acids (SCFAs), which play a role in forming the gut-brain axis and in the process of lipogenesis. An increase in lipogenesis can lead to obesity. High levels of adipose tissue in the body trigger chronic inflammation and insulin resistance. This review examines how microbiota composition influences the pathogenesis of type 2 diabetes and the possibility of regulating microbiota through proper nutrition, fecal microbiota transplantation, and prebiotics and probiotics. Additionally, the review notes that an imbalance in the gut microbiota can contribute to diabetes progression and increase cancer risk through inflammatory and immune mechanisms.
{"title":"Influence of microbiota composition on the pathogenesis of type 2 diabetes: Physiological aspects","authors":"Nataliya V. Zharova , Filipp D. Mikhailidi , Darya A. Kabanova , Alena Y. Tatarintseva , Olga L. Polyakova , Yury O. Zharikov , Nikolai A. Zharov , Sergey N. Ryagin , André Pontes-Silva , Tatiana S. Zharikova","doi":"10.1016/j.mam.2025.101410","DOIUrl":"10.1016/j.mam.2025.101410","url":null,"abstract":"<div><div>The development of type 2 diabetes may be influenced by enterotypes and bacterial metabolites. The most important of these are short-chain fatty acids (SCFAs), which play a role in forming the gut-brain axis and in the process of lipogenesis. An increase in lipogenesis can lead to obesity. High levels of adipose tissue in the body trigger chronic inflammation and insulin resistance. This review examines how microbiota composition influences the pathogenesis of type 2 diabetes and the possibility of regulating microbiota through proper nutrition, fecal microbiota transplantation, and prebiotics and probiotics. Additionally, the review notes that an imbalance in the gut microbiota can contribute to diabetes progression and increase cancer risk through inflammatory and immune mechanisms.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"106 ","pages":"Article 101410"},"PeriodicalIF":10.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145050661","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}
Pub Date : 2025-12-01Epub Date: 2025-11-10DOI: 10.1016/j.mam.2025.101421
Subo Cai , Xiao Liang , Hongshuai Wu , Xinyu Li , Qi Pu
While the intricate and precisely specialized structure of the human eye is critical for its appropriate function, it also presents a number of anatomical and physiological barriers, such as tight junctions, enzymatic degradation, and dynamic fluid turnover, which highly restrict the intraocular bioavailability of various therapeutic compounds. This is more significant for those therapeutic compounds that are used for complications affecting the posterior segment. Accordingly, conventional therapeutic strategies for common ocular complications such as diabetic retinopathy (DR), age-related macular degeneration (AMD), glaucoma, and infectious keratitis significantly demand invasive administration approaches and multiple injections, frequently resulting in various side effects and suboptimal therapeutic consequences. To address these major challenges, novel technologies, such as viral- and nanotechnology-based delivery systems, have provided emerging opportunities to bypass ocular barriers and facilitate targeted, maintained, and efficient drug and gene delivery. The present review aims to comprehensively describe the current advancements in both viral- and nanotechnology-based strategies for ocular diseases. It discusses the complex molecular structure and physiological functions of the ocular barriers, focusing on the exact mechanisms that restrict drug permeation. Moreover, this review describes the design principles, physicochemical properties, and therapeutic potential of diverse viral- and nanotechnology-based delivery systems. Their efficacy and safety profiles are thoroughly discussed across various pre-clinical and clinical studies. Furthermore, the review discusses the emergence of hybrid viral-nanotechnology delivery systems that combine the strengths of both approaches, offering enhanced targeting precision and biocompatibility. The major challenges linked to the clinical translation of these novel technologies, such as aspects of biocompatibility and immunogenicity are also addressed. This review highlights the significant transformative potential of viral vectors and nanotechnology in reforming ocular disease management and increasing patient quality of life.
{"title":"Navigating the ocular barrier: Viral- and nanotechnology-based delivery systems as promising therapeutic agents for ocular diseases","authors":"Subo Cai , Xiao Liang , Hongshuai Wu , Xinyu Li , Qi Pu","doi":"10.1016/j.mam.2025.101421","DOIUrl":"10.1016/j.mam.2025.101421","url":null,"abstract":"<div><div>While the intricate and precisely specialized structure of the human eye is critical for its appropriate function, it also presents a number of anatomical and physiological barriers, such as tight junctions, enzymatic degradation, and dynamic fluid turnover, which highly restrict the intraocular bioavailability of various therapeutic compounds. This is more significant for those therapeutic compounds that are used for complications affecting the posterior segment. Accordingly, conventional therapeutic strategies for common ocular complications such as diabetic retinopathy (DR), age-related macular degeneration (AMD), glaucoma, and infectious keratitis significantly demand invasive administration approaches and multiple injections, frequently resulting in various side effects and suboptimal therapeutic consequences. To address these major challenges, novel technologies, such as viral- and nanotechnology-based delivery systems, have provided emerging opportunities to bypass ocular barriers and facilitate targeted, maintained, and efficient drug and gene delivery. The present review aims to comprehensively describe the current advancements in both viral- and nanotechnology-based strategies for ocular diseases. It discusses the complex molecular structure and physiological functions of the ocular barriers, focusing on the exact mechanisms that restrict drug permeation. Moreover, this review describes the design principles, physicochemical properties, and therapeutic potential of diverse viral- and nanotechnology-based delivery systems. Their efficacy and safety profiles are thoroughly discussed across various pre-clinical and clinical studies. Furthermore, the review discusses the emergence of hybrid viral-nanotechnology delivery systems that combine the strengths of both approaches, offering enhanced targeting precision and biocompatibility. The major challenges linked to the clinical translation of these novel technologies, such as aspects of biocompatibility and immunogenicity are also addressed. This review highlights the significant transformative potential of viral vectors and nanotechnology in reforming ocular disease management and increasing patient quality of life.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"106 ","pages":"Article 101421"},"PeriodicalIF":10.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145497249","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}
Pub Date : 2025-12-01Epub Date: 2025-11-08DOI: 10.1016/j.mam.2025.101422
Yan Wu , Shuai Huang , Qian Sha , Jing Yu
The human genome contains a substantial legacy of ancient retroviral infections known as Human Endogenous Retroviruses (HERVs), composing 8 % of our DNA. In healthy young individuals, these elements are kept dormant by robust epigenetic mechanisms, primarily DNA methylation and repressive H3K9me3 histone marks. However, this epigenetic silencing deteriorates with age, leading to the reactivation of HERVs, particularly the youngest HERV-K subfamily. This report posits that this HERV awakening is not a passive byproduct of aging but an active, transmissible driver of pathology. The reactivation of HERVs leads to the production of retrovirus-like particles (RVLPs) that can induce senescence in healthy neighboring cells, propagating a contagious aging phenomenon. Furthermore, the accumulation of HERV-derived dsRNA and reverse-transcribed DNA triggers chronic innate immune responses through pathways including cGAS-STING and IFIH1-MAVS, fueling the systemic, low-grade inflammation characteristic of inflammaging, catalytically accelerated by exogenous viral infections. Pathogens such as SARS-CoV-2, Epstein-Barr Virus (EBV), and Herpes Simplex Virus (HSV-1) can directly transactivate HERVs via their own viral proteins, overwhelming the already compromised epigenetic controls in an aging host. This mechanistic link between viral triggers and endogenous retroviral activity is strongly implicated in a range of age-related diseases, including neurodegenerative disorders such as Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS), where the HERV-K envelope protein is directly neurotoxic. It is also linked to autoimmune diseases like Multiple Sclerosis and various cancers. This report synthesizes these findings and identifies a novel mechanistic link between viral activity, chronic inflammation, and the onset of age-related diseases.
{"title":"Emerging and Re-emerging viruses as triggers of human endogenous retrovirus activation: Implications for aging and age-related pathologies","authors":"Yan Wu , Shuai Huang , Qian Sha , Jing Yu","doi":"10.1016/j.mam.2025.101422","DOIUrl":"10.1016/j.mam.2025.101422","url":null,"abstract":"<div><div>The human genome contains a substantial legacy of ancient retroviral infections known as Human Endogenous Retroviruses (HERVs), composing 8 % of our DNA. In healthy young individuals, these elements are kept dormant by robust epigenetic mechanisms, primarily DNA methylation and repressive H3K9me3 histone marks. However, this epigenetic silencing deteriorates with age, leading to the reactivation of HERVs, particularly the youngest HERV-K subfamily. This report posits that this HERV awakening is not a passive byproduct of aging but an active, transmissible driver of pathology. The reactivation of HERVs leads to the production of retrovirus-like particles (RVLPs) that can induce senescence in healthy neighboring cells, propagating a contagious aging phenomenon. Furthermore, the accumulation of HERV-derived dsRNA and reverse-transcribed DNA triggers chronic innate immune responses through pathways including cGAS-STING and IFIH1-MAVS, fueling the systemic, low-grade inflammation characteristic of inflammaging, catalytically accelerated by exogenous viral infections. Pathogens such as SARS-CoV-2, Epstein-Barr Virus (EBV), and Herpes Simplex Virus (HSV-1) can directly transactivate HERVs via their own viral proteins, overwhelming the already compromised epigenetic controls in an aging host. This mechanistic link between viral triggers and endogenous retroviral activity is strongly implicated in a range of age-related diseases, including neurodegenerative disorders such as Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS), where the HERV-K envelope protein is directly neurotoxic. It is also linked to autoimmune diseases like Multiple Sclerosis and various cancers. This report synthesizes these findings and identifies a novel mechanistic link between viral activity, chronic inflammation, and the onset of age-related diseases.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"106 ","pages":"Article 101422"},"PeriodicalIF":10.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145483552","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}
Diabetes and cancer are among the most prevalent chronic diseases globally, drawing increasing attention due to their shared features of metabolic and signaling dysregulation. Epidemiological evidence indicates that type 2 diabetes significantly elevates the risk of developing multiple types of tumors. This review highlights the key molecular intersections between diabetic pathophysiology and oncogenic processes, with a focus on how hyperinsulinemia and hyperglycemia contribute to tumor initiation and progression. These effects are primarily mediated through profound metabolic reprogramming, including hyperactivation of the hexosamine biosynthetic pathway (HBP) and the accumulation of advanced glycation end-products (AGEs), which promote sustained oxidative stress and chronic inflammation. Consequently, the tumor microenvironment (TME) undergoes substantial remodeling. The metabolism and function of immune cells are disrupted, promoting immune evasion. Meanwhile, cancer cells adapt by engaging mechanisms such as diabetes-induced epigenetic reprogramming, activation of the unfolded protein response (UPR), and alterations in the gut microbiota, thereby enhancing their survival advantage. Emerging evidence suggests that anti-diabetic agents targeting these metabolic intersections exhibit dual roles in cancer therapy, offering both therapeutic potential and potential risks. To address these complexities, future efforts should conduct multi-omics technologies to dissect the metabolic heterogeneity of diabetes-associated tumors, paving the way for precise and personalized therapeutic strategies for patients with this comorbidity.
{"title":"Cross-talk between cancer and diabetes: Exploring shared molecular pathways in cellular metabolism and signaling","authors":"Zhangzhi Tang , Nuo Xu , Pin Lyu , Hui Zhao , Wenjie Zheng","doi":"10.1016/j.mam.2025.101420","DOIUrl":"10.1016/j.mam.2025.101420","url":null,"abstract":"<div><div>Diabetes and cancer are among the most prevalent chronic diseases globally, drawing increasing attention due to their shared features of metabolic and signaling dysregulation. Epidemiological evidence indicates that type 2 diabetes significantly elevates the risk of developing multiple types of tumors. This review highlights the key molecular intersections between diabetic pathophysiology and oncogenic processes, with a focus on how hyperinsulinemia and hyperglycemia contribute to tumor initiation and progression. These effects are primarily mediated through profound metabolic reprogramming, including hyperactivation of the hexosamine biosynthetic pathway (HBP) and the accumulation of advanced glycation end-products (AGEs), which promote sustained oxidative stress and chronic inflammation. Consequently, the tumor microenvironment (TME) undergoes substantial remodeling. The metabolism and function of immune cells are disrupted, promoting immune evasion. Meanwhile, cancer cells adapt by engaging mechanisms such as diabetes-induced epigenetic reprogramming, activation of the unfolded protein response (UPR), and alterations in the gut microbiota, thereby enhancing their survival advantage. Emerging evidence suggests that anti-diabetic agents targeting these metabolic intersections exhibit dual roles in cancer therapy, offering both therapeutic potential and potential risks. To address these complexities, future efforts should conduct multi-omics technologies to dissect the metabolic heterogeneity of diabetes-associated tumors, paving the way for precise and personalized therapeutic strategies for patients with this comorbidity.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"106 ","pages":"Article 101420"},"PeriodicalIF":10.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145394911","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}
Pub Date : 2025-12-01Epub Date: 2025-11-18DOI: 10.1016/j.mam.2025.101424
Fábio Duarte , Yvan Arsenijevic
Inherited retinal dystrophies (IRDs) are a heterogeneous group of rare genetic disorders that affect multiple retinal cell types, including photoreceptors, Müller glia, bipolar cells, retinal ganglion cells (RGCs), and the retinal pigment epithelium (RPE). Recombinant adeno-associated viruses (rAAVs) have emerged as the leading vectors for gene delivery in the retina due to their safety profile and ability to drive long-term expression. However, achieving precise cell targeting and appropriate transgene regulation remains a key challenge. Recent advances in capsid engineering and the discovery of cell-type-specific regulatory elements have opened new avenues for improving the precision of rAAV-mediated therapies. These refined tools can be integrated with various therapeutic strategies, such as gene augmentation, genome editing, RNA modulation, and optogenetics, to expand the range and effectiveness of treatments for IRDs. This review focuses on recent developments in the customization of rAAV vectors to achieve cell-specific gene therapy for IRDs.
{"title":"Precision gene therapy: Tailoring rAAV-mediated gene therapies for inherited retinal dystrophies (IRDs)","authors":"Fábio Duarte , Yvan Arsenijevic","doi":"10.1016/j.mam.2025.101424","DOIUrl":"10.1016/j.mam.2025.101424","url":null,"abstract":"<div><div>Inherited retinal dystrophies (IRDs) are a heterogeneous group of rare genetic disorders that affect multiple retinal cell types, including photoreceptors, Müller glia, bipolar cells, retinal ganglion cells (RGCs), and the retinal pigment epithelium (RPE). Recombinant adeno-associated viruses (rAAVs) have emerged as the leading vectors for gene delivery in the retina due to their safety profile and ability to drive long-term expression. However, achieving precise cell targeting and appropriate transgene regulation remains a key challenge. Recent advances in capsid engineering and the discovery of cell-type-specific regulatory elements have opened new avenues for improving the precision of rAAV-mediated therapies. These refined tools can be integrated with various therapeutic strategies, such as gene augmentation, genome editing, RNA modulation, and optogenetics, to expand the range and effectiveness of treatments for IRDs. This review focuses on recent developments in the customization of rAAV vectors to achieve cell-specific gene therapy for IRDs.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"106 ","pages":"Article 101424"},"PeriodicalIF":10.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145558483","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}
Pub Date : 2025-12-01Epub Date: 2025-09-12DOI: 10.1016/j.mam.2025.101399
Yubin Li , Guanghan Fan , Huadong He
The current century has been associated with the outbreaks of emerging and re-emerging viral infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), monkeypox virus (MPXV), and Zika virus (ZIKV). Although their common clinical manifestations are currently well-known, the urogenital system is gaining attention as a significant, though often underappreciated, anatomical site for emerging and re-emerging viral infections, disease development, and transmission. The present review aims to comprehensively discuss the urogenital complications linked to the infections caused by these viruses, with a primary focus on describing their suggested and established roles in the development of urogenital sequelae. It reviews various molecular and cellular mechanisms, such as direct viral pathogen cytopathic activity, virally-mediated inflammation, and the nephrotoxic side effects of specific medications, by which SARS-CoV-2, MPXV, and ZIKV may affect various parts of the urogenital system. In this context, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for cell entry, which is frequently present in the urogenital tissues, resulting in urogenital injuries. Zika virus exhibits a distinct tropism for the male reproductive tract, demonstrating prolonged viral persistence in semen that facilitates sexual transmission and is linked to testicular damage and adverse congenital outcomes. The present study also addresses diagnostic considerations and therapeutic strategies in the context of urogenital sequelae associated with these viruses. Understanding the intricate molecular basis of these viral-caused sequelae is crucial for improving differential diagnosis and introducing targeted therapeutic strategies.
{"title":"Urogenital manifestations of SARS-CoV-2, MPXV and Zika virus: A comprehensive review","authors":"Yubin Li , Guanghan Fan , Huadong He","doi":"10.1016/j.mam.2025.101399","DOIUrl":"10.1016/j.mam.2025.101399","url":null,"abstract":"<div><div>The current century has been associated with the outbreaks of emerging and re-emerging viral infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), monkeypox virus (MPXV), and Zika virus (ZIKV). Although their common clinical manifestations are currently well-known, the urogenital system is gaining attention as a significant, though often underappreciated, anatomical site for emerging and re-emerging viral infections, disease development, and transmission. The present review aims to comprehensively discuss the urogenital complications linked to the infections caused by these viruses, with a primary focus on describing their suggested and established roles in the development of urogenital sequelae. It reviews various molecular and cellular mechanisms, such as direct viral pathogen cytopathic activity, virally-mediated inflammation, and the nephrotoxic side effects of specific medications, by which SARS-CoV-2, MPXV, and ZIKV may affect various parts of the urogenital system. In this context, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for cell entry, which is frequently present in the urogenital tissues, resulting in urogenital injuries. Zika virus exhibits a distinct tropism for the male reproductive tract, demonstrating prolonged viral persistence in semen that facilitates sexual transmission and is linked to testicular damage and adverse congenital outcomes. The present study also addresses diagnostic considerations and therapeutic strategies in the context of urogenital sequelae associated with these viruses. Understanding the intricate molecular basis of these viral-caused sequelae is crucial for improving differential diagnosis and introducing targeted therapeutic strategies.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"106 ","pages":"Article 101399"},"PeriodicalIF":10.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145050659","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}
Neutrophil extracellular traps (NETs) are a network of fibrous structures composed of DNA, histones, and antimicrobial proteins released by neutrophils, which play a crucial role in the innate immune system's defense against infection. When neutrophils encounter pathogens, they can release NETs to capture and neutralize these invaders, preventing their spread and prompting other immune cells to destroy them. The classical inflammasome is a cytoplasmic polyprotein complex activated by infectious and/or non-infectious stimuli that activates the protease caspase-1 to induce pyroptosis and promotes the maturation and release of interleukin (IL)-1β and IL-18, while the non-classical inflammasome activates cysteinyl aspartate specific proteinase (caspase)-4/11 to induce pyroptosis. Inflammasome activation is also an important component of the innate immune response. This review elaborates on the constituent proteins and molecular regulation of NETs and inflammasomes, summarizes the crosstalk between NETs and inflammasomes and its negative effects in the disease process, and also discusses the therapeutic effects of drugs targeting NETs and/or inflammasomes on related diseases.
{"title":"The crosstalk of neutrophil extracellular trap-inflammasome and their roles in disease progression","authors":"Jieqing Xiong , Jiaojiao Xue , Heqi Zhou , Wenxiu Qi , Haoyu Zhu","doi":"10.1016/j.mam.2025.101419","DOIUrl":"10.1016/j.mam.2025.101419","url":null,"abstract":"<div><div>Neutrophil extracellular traps (NETs) are a network of fibrous structures composed of DNA, histones, and antimicrobial proteins released by neutrophils, which play a crucial role in the innate immune system's defense against infection. When neutrophils encounter pathogens, they can release NETs to capture and neutralize these invaders, preventing their spread and prompting other immune cells to destroy them. The classical inflammasome is a cytoplasmic polyprotein complex activated by infectious and/or non-infectious stimuli that activates the protease caspase-1 to induce pyroptosis and promotes the maturation and release of interleukin (IL)-1β and IL-18, while the non-classical inflammasome activates cysteinyl aspartate specific proteinase (caspase)-4/11 to induce pyroptosis. Inflammasome activation is also an important component of the innate immune response. This review elaborates on the constituent proteins and molecular regulation of NETs and inflammasomes, summarizes the crosstalk between NETs and inflammasomes and its negative effects in the disease process, and also discusses the therapeutic effects of drugs targeting NETs and/or inflammasomes on related diseases.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"106 ","pages":"Article 101419"},"PeriodicalIF":10.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145394878","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}
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