Molecular Aspects of Medicine最新文献

{"title":"Gene therapies and gene product-based drug candidates for normalizing and preserving tissue functions in animal models of ocular hypertension and glaucoma","authors":"Najam A. Sharif PhD, DSc","doi":"10.1016/j.mam.2023.101218","DOIUrl":"https://doi.org/10.1016/j.mam.2023.101218","url":null,"abstract":"<div><p>More than 76 million people worldwide are afflicted with the neurodegenerative eye diseases described and grouped together as glaucoma. A common feature amongst the many forms of glaucoma is chronically elevated intraocular pressure (IOP) within the anterior chamber of the eye that physically damages the retina, optic nerve and parts of the brain connected with visual perception. The mediators of the contusing raised IOP responsible for such damage and loss of vision include locally released inflammatory agents, tissue remodeling enzymes and infiltrating immune cells which damage the retinal ganglion cell (RGC) axons and eventually kill a significant number of the RGCs. Additional culprits include genetic defects of the patient that involve aberrations in receptors, enzymes and/or endogenous ligands and possible over- or under-production of the latter. Other genetic abnormalities may include issues with signal transduction machinery within key cells of critical tissues in the front (e.g. trabecular meshwork [TM] and Schlemm's canal [SC]) and back of the eye (e.g. retinal ganglion cells and their axons). Genome-wide associated studies (GWAS) coupled with next generation sequencing have provided powerful linkage of certain gene defects and polymorphic variants to the onset and progression of diseases of the tissues involved in fluid dynamics in the TM and SC, and many retinal elements (lamina cribosa, optic nerve head) at the back of the eye which cause ocular hypertension (OHT) and glaucomatous optic neuropathy (GON), respectively. Despite the availability of some drugs, fluid drainage microshunts and full surgical techniques to lower and control intraocular pressure, the major modifiable biomarker of open-angle and other forms of glaucoma, their side-effect profiles, less than optimum effectiveness and short duration of action present opportunities to clinically manage the glaucomas with next generation of treatments with high therapeutic indices, including gene therapies. Thus, identification, characterization and deployment of genetic data coupled with traditional drug discovery and novel gene replacement, gene editing and genetic engineering technologies may provide some solutions to the aforementioned problems. These aspects will be discussed in this article.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"94 ","pages":"Article 101218"},"PeriodicalIF":10.6,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134653721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ubiquitin proteasome system and glaucoma: A survey of genetics and molecular biology studies supporting a link with pathogenic and therapeutic relevance","authors":"Irene Pandino ,&nbsp;Sara Giammaria ,&nbsp;Gabriele Antonio Zingale ,&nbsp;Gloria Roberti ,&nbsp;Manuele Michelessi ,&nbsp;Massimo Coletta ,&nbsp;Gianluca Manni ,&nbsp;Luca Agnifili ,&nbsp;Alice Verticchio Vercellin ,&nbsp;Alon Harris ,&nbsp;Francesco Oddone ,&nbsp;Diego Sbardella","doi":"10.1016/j.mam.2023.101226","DOIUrl":"10.1016/j.mam.2023.101226","url":null,"abstract":"<div><p>Glaucoma represents a group of progressive neurodegenerative diseases characterized by the loss of retinal ganglion cells (RGCs) and their axons with subsequent visual field impairment. The disease develops through largely uncharacterized molecular mechanisms, that are likely to occur in different localized cell types, either in the anterior (e.g., trabecular meshwork cells) or posterior (e.g., Muller glia, retinal ganglion cells) segments of the eye. Genomic and preclinical studies suggest that glaucoma pathogenesis may develop through altered ubiquitin (Ub) signaling. Ubiquitin conjugation, referred to as ubiquitylation, is a major post-synthetic modification catalyzed by E1-E2-E3 enzymes, that profoundly regulates the turnover, trafficking and biological activity of the targeted protein. The development of new technologies, including proteomics workflows, allows the biology of ubiquitin signaling to be described in health and disease. This post-translational modification is emerging as a key role player in neurodegeneration, gaining relevance for novel therapeutic options, such as in the case of Proteolysis Targeting Chimeras technology. Although scientific evidence supports a link between Ub and glaucoma, their relationship is still not well-understood. Therefore, this review provides a detailed research-oriented discussion on current evidence of Ub signaling in glaucoma. A review of genomic and genetic data is provided followed by an in-depth discussion of experimental data on ASB10, parkin and optineurin, which are proteins that play a key role in Ub signaling and have been associated with glaucoma.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"94 ","pages":"Article 101226"},"PeriodicalIF":10.6,"publicationDate":"2023-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89720265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vaccines for HPV-associated diseases","authors":"Jeffrey M. Skolnik,&nbsp;Matthew P. Morrow","doi":"10.1016/j.mam.2023.101224","DOIUrl":"10.1016/j.mam.2023.101224","url":null,"abstract":"<div><p>Human papillomavirus (HPV) infection represents a significant global health concern owing to its role in the etiology of conditions ranging from benign low-grade lesions to cancers of the cervix, head and neck, anus, vagina, vulva, and penis. Prophylactic vaccination programs, primarily targeting adolescent girls, have achieved dramatic reductions in rates of HPV infection and cervical cancer in recent years. However, there is a clear demand for a strategy to manage the needs of the many people who are already living with persistent HPV infection and/or HPV-associated conditions. Unlike prophylactic vaccines, which act to prevent HPV infection, therapeutic vaccination presents an opportunity to induce cellular immunity against established HPV infections and lesions and prevent progression to cancer. Several HPV vaccines are undergoing clinical development, using a range of platforms. Peptide- or protein-based vaccines, vector-based vaccines, whole-cell vaccines, and nucleic acid vaccines each offer relative merits and limitations for the delivery of HPV antigens and the subsequent generation of targeted immune responses. There has been particular interest in DNA-based vaccines, which elicit both cellular and humoral immune responses to provide long-lasting immunity. DNA vaccines offer several practical advantages over other vaccine platforms, including the potential for rapid and scalable manufacturing, targeting of many different antigens, and potential for repeat boosting. Furthermore, unlike vectored approaches, DNA vaccines are thermostable over extended time periods, which may enable shipping and storage. Several delivery strategies are available to address the main challenge of DNA vaccines, namely their relatively low transfection efficiency. We review the latest clinical data supporting the development of DNA vaccines and reflect on this exciting prospect in the management of HPV-related disease.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"94 ","pages":"Article 101224"},"PeriodicalIF":10.6,"publicationDate":"2023-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71488123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational methods in glaucoma research: Current status and future outlook","authors":"Minjae J. Kim ,&nbsp;Cole A. Martin ,&nbsp;Jinhwa Kim ,&nbsp;Monica M. Jablonski","doi":"10.1016/j.mam.2023.101222","DOIUrl":"10.1016/j.mam.2023.101222","url":null,"abstract":"<div><p>Advancements in computational techniques have transformed glaucoma research, providing a deeper understanding of genetics, disease mechanisms, and potential therapeutic targets. Systems genetics integrates genomic and clinical data, aiding in identifying drug targets, comprehending disease mechanisms, and personalizing treatment strategies for glaucoma. Molecular dynamics simulations offer valuable molecular-level insights into glaucoma-related biomolecule behavior and drug interactions, guiding experimental studies and drug discovery efforts. Artificial intelligence (AI) technologies hold promise in revolutionizing glaucoma research, enhancing disease diagnosis, target identification, and drug candidate selection. The generalized protocols for systems genetics, MD simulations, and AI model development are included as a guide for glaucoma researchers. These computational methods, however, are not separate and work harmoniously together to discover novel ways to combat glaucoma. Ongoing research and progresses in genomics technologies, MD simulations, and AI methodologies project computational methods to become an integral part of glaucoma research in the future.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"94 ","pages":"Article 101222"},"PeriodicalIF":10.6,"publicationDate":"2023-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71488122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in understanding glaucoma pathogenesis: A multifaceted molecular approach for clinician scientists","authors":"Eren Ekici ,&nbsp;Sasan Moghimi","doi":"10.1016/j.mam.2023.101223","DOIUrl":"https://doi.org/10.1016/j.mam.2023.101223","url":null,"abstract":"<div><p><span><span>Glaucoma, a leading cause of irreversible blindness worldwide, is a spectrum of neurodegenerative diseases characterized by the gradual deterioration of retinal ganglion cells (RGCs) and optic neuropathy. With complex etiology, glaucoma's major risk factors include elevated intraocular pressure (IOP), advanced age, ethnicity, systemic vascular factors, and </span>genetic predisposition<span>. By 2040, glaucoma is expected to affect over 110 million individuals aged 40 to 80, posing a significant economic burden. Glaucoma can be classified into open-angle, angle-closure, and developmental subtypes, with primary and secondary forms. The disease often progresses silently, gradually impairing the visual field (VF) until it reaches an advanced stage. Understanding the abnormal functional changes associated with glaucoma at the tissue, cellular, molecular, and genetic levels is crucial for comprehending its pathogenesis. This review examines the published data from the past two decades to shed light on the biological mechanisms underlying glaucoma development. The most evident factors in the development of glaucomatous optic neuropathy include elevated IOP, aging, genetic influences, followed by impaired ocular blood flow regulation. These factors are interconnected processes that lead to optic nerve damage, compromised circulation, and structural changes in glial and connective tissues. Contributing factors involve extracellular matrix remodeling, </span></span>excitotoxicity<span><span>, nitric oxide, </span>oxidative stress, and neuroinflammation. Ultimately, all types of glaucoma result in RGC dysfunction and loss, causing irreversible visual impairment. While our understanding of glaucoma pathogenesis is evolving, further research is crucial for a comprehensive understanding of glaucoma pathogenesis and the development of effective treatments.</span></p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"94 ","pages":"Article 101223"},"PeriodicalIF":10.6,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91985488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of the microbiota in glaucoma","authors":"Ling Huang ,&nbsp;Yiwen Hong ,&nbsp;Xiangyu Fu ,&nbsp;Haishan Tan ,&nbsp;Yongjiang Chen ,&nbsp;Yujiao Wang ,&nbsp;Danian Chen","doi":"10.1016/j.mam.2023.101221","DOIUrl":"10.1016/j.mam.2023.101221","url":null,"abstract":"<div><p>Glaucoma is a common irreversible vision loss disorder because of the gradual loss of retinal ganglion cells (RGCs) and the optic nerve axons. Major risk factors include elder age and high intraocular pressure (IOP). However, high IOP is neither necessary nor sufficient to cause glaucoma. Some non-IOP signaling cascades can mediate RGC degeneration. In addition, gender, diet, obesity, depression, or anxiety also contribute to the development of glaucoma. Understanding the mechanism of glaucoma development is crucial for timely diagnosis and establishing new strategies to improve current IOP-reducing therapies. The microbiota exerts a marked influence on the human body during homeostasis and disease. Many glaucoma patients have abnormal compositions of the microbiota (dysbiosis) in multiple locations, including the ocular surface, intraocular cavity, oral cavity, stomach, and gut. Here, we discuss findings in the last ten years or more about the microbiota and metabolite changes in animal models, patients with three risk factors (aging, obesity, and depression), and glaucoma patients. Antigenic mimicry and heat stress protein (HSP)-specific T-cell infiltration in the retina may be responsible for commensal microbes contributing to glaucomatous RGC damage. LPS-TLR4 pathway may be the primary mechanism of oral and ocular surface dysbiosis affecting glaucoma. Microbe-derived metabolites may also affect glaucoma pathogenesis. Homocysteine accumulation, inflammatory factor release, and direct dissemination may link gastric <em>H. pylori</em> infection and anterior chamber viral infection (such as cytomegalovirus) to glaucoma. Potential therapeutic protocols targeting microbiota include antibiotics, modified diet, and stool transplant. Later investigations will uncover the underlying molecular mechanism connecting dysbiosis to glaucoma and its clinical applications in glaucoma management.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"94 ","pages":"Article 101221"},"PeriodicalIF":10.6,"publicationDate":"2023-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49693438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding the complex genetics and molecular mechanisms underlying glaucoma","authors":"Weiwei Wang ,&nbsp;Huaizhou Wang","doi":"10.1016/j.mam.2023.101220","DOIUrl":"10.1016/j.mam.2023.101220","url":null,"abstract":"<div><p>Glaucoma is the leading cause of irreversible blindness worldwide. Currently the only effective treatment for glaucoma is to reduce the intraocular pressure, which can halt the progression of the disease. Highlighting the importance of identifying individuals at risk of developing glaucoma and those with early-stage glaucoma will help patients receive treatment before sight loss. However, some cases of glaucoma do not have raised intraocular pressure. In fact, glaucoma is caused by a variety of different mechanisms and has a wide range of different subtypes. Understanding other risk factors, the underlying mechanisms, and the pathology of glaucoma might lead to novel treatments and treatment of underlying diseases. In this review we present the latest research into glaucoma including the genetics and molecular basis of the disease.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"94 ","pages":"Article 101220"},"PeriodicalIF":10.6,"publicationDate":"2023-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49684186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Signalling pathways and cell death mechanisms in glaucoma: Insights into the molecular pathophysiology","authors":"Devaraj Basavarajappa ,&nbsp;Caridad Galindo-Romero ,&nbsp;Vivek Gupta ,&nbsp;Marta Agudo-Barriuso ,&nbsp;Veer B. Gupta ,&nbsp;Stuart L. Graham ,&nbsp;Nitin Chitranshi","doi":"10.1016/j.mam.2023.101216","DOIUrl":"10.1016/j.mam.2023.101216","url":null,"abstract":"<div><p>Glaucoma is a complex multifactorial eye disease manifesting in retinal ganglion cell (RGC) death and optic nerve degeneration, ultimately causing irreversible vision loss. Research in recent years has significantly enhanced our understanding of RGC degenerative mechanisms in glaucoma. It is evident that high intraocular pressure (IOP) is not the only contributing factor to glaucoma pathogenesis. The equilibrium of pro-survival and pro-death signalling pathways in the retina strongly influences the function and survival of RGCs and optic nerve axons in glaucoma. Molecular evidence from human retinal tissue analysis and a range of experimental models of glaucoma have significantly contributed to unravelling these mechanisms. Accumulating evidence reveals a wide range of molecular signalling pathways that can operate -either alone or via intricate networks - to induce neurodegeneration. The roles of several molecules, including neurotrophins, interplay of intracellular kinases and phosphates, caveolae and adapter proteins, serine proteases and their inhibitors, nuclear receptors, amyloid beta and tau, and how their dysfunction affects retinal neurons are discussed in this review. We further underscore how anatomical alterations in various animal models exhibiting RGC degeneration and susceptibility to glaucoma-related neuronal damage have helped to characterise molecular mechanisms in glaucoma. In addition, we also present different regulated cell death pathways that play a critical role in RGC degeneration in glaucoma.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"94 ","pages":"Article 101216"},"PeriodicalIF":10.6,"publicationDate":"2023-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49684185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular aspects of optic nerve autophagy in glaucoma","authors":"Yasushi Kitaoka ,&nbsp;Kana Sase","doi":"10.1016/j.mam.2023.101217","DOIUrl":"10.1016/j.mam.2023.101217","url":null,"abstract":"<div><p>The optic nerve consists of the glia, vessels, and axons including myelin and axoplasm. Since axonal degeneration precedes retinal ganglion cell death in glaucoma, the preceding axonal degeneration model may be helpful for understanding the molecular mechanisms of optic nerve degeneration. Optic nerve samples from these models can provide information on several aspects of autophagy. Autophagosomes, the most typical organelles expressing autophagy, are found much more frequently inside axons than around the glia. Thus, immunoblot findings from the optic nerve can reflect the autophagy state in axons. Autophagic flux impairment may occur in degenerating optic nerve axons, as in other central nervous system neurodegenerative diseases. Several molecular candidates are involved in autophagy enhancement, leading to axonal protection. This concept is an attractive approach to the prevention of further retinal ganglion cell death. In this review, we describe the factors affecting autophagy, including nicotinamide riboside, p38, ULK, AMPK, ROCK, and SIRT1, in the optic nerve and propose potential methods of axonal protection via enhancement of autophagy.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"94 ","pages":"Article 101217"},"PeriodicalIF":10.6,"publicationDate":"2023-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41240336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic strategies for glaucoma and optic neuropathies","authors":"Jung Lo ,&nbsp;Kamakshi Mehta ,&nbsp;Armaan Dhillon ,&nbsp;Yu-Kai Huang ,&nbsp;Ziming Luo ,&nbsp;Mi-Hyun Nam ,&nbsp;Issam Al Diri ,&nbsp;Kun-Che Chang","doi":"10.1016/j.mam.2023.101219","DOIUrl":"10.1016/j.mam.2023.101219","url":null,"abstract":"<div><p>Glaucoma is a neurodegenerative eye disease that causes permanent vision impairment. The main pathological characteristics of glaucoma are retinal ganglion cell (RGC) loss and optic nerve degeneration. Glaucoma can be caused by elevated intraocular pressure (IOP), although some cases are congenital or occur in patients with normal IOP. Current glaucoma treatments rely on medicine and surgery to lower IOP, which only delays disease progression. First-line glaucoma medicines are supported by pharmacotherapy advancements such as Rho kinase inhibitors and innovative drug delivery systems. Glaucoma surgery has shifted to safer minimally invasive (or microinvasive) glaucoma surgery, but further trials are needed to validate long-term efficacy. Further, growing evidence shows that adeno-associated virus gene transduction and stem cell-based RGC replacement therapy hold potential to treat optic nerve fiber degeneration and glaucoma. However, better understanding of the regulatory mechanisms of RGC development is needed to provide insight into RGC differentiation from stem cells and help choose target genes for viral therapy. In this review, we overview current progress in RGC development research, optic nerve fiber regeneration, and human stem cell-derived RGC differentiation and transplantation. We also provide an outlook on perspectives and challenges in the field.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"94 ","pages":"Article 101219"},"PeriodicalIF":10.6,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41240337","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}