{"title":"Current Perspectives of TLR2 Signalling in the Retina.","authors":"Rachel Dalton, Sarah Doyle","doi":"10.1007/978-3-031-76550-6_21","DOIUrl":"https://doi.org/10.1007/978-3-031-76550-6_21","url":null,"abstract":"<p><p>Toll-like receptor 2 (TLR2) signalling is crucial in initiating the innate immune response. Under normal conditions, TLR2 can recognise and respond to danger signals in the body and protect against damaging pathogens and molecules. However, dysregulation of this tightly controlled cascade has been implicated in various retinal disorders. There are many endogenous sterile ligands present in a degenerating retina that could lead to aberrant TLR2 activation. This culminates in an overaction of the innate immune response, which leads to an excess of pro-inflammatory cytokine production and results in a dangerous cycle of chronic inflammation. Here, we will review the evidence behind TLR2's involvement in retinal diseases such as age-related macular degeneration (AMD) and diabetic retinopathy (DR) and investigate the potential therapeutic benefit of TLR2 inhibition in the retina.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1468 ","pages":"127-131"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Engineering Specific Human iPS Reporter Cell Lines to Generate Optogenetically Modified Photoreceptors.","authors":"Elise Léger-Charnay, Amélie Slembrouck-Brec, Olivier Goureau","doi":"10.1007/978-3-031-76550-6_67","DOIUrl":"https://doi.org/10.1007/978-3-031-76550-6_67","url":null,"abstract":"<p><p>Cell therapy, by transplantation of photoreceptors derived from induced pluripotent stem cells (iPSCs), has been proposed as a promising therapeutic approach for photoreceptor degenerative diseases. A remaining obstacle is that such transplanted cells have to develop into functional light-sensitive photoreceptors, which require outer segment formation and interaction with the underlying retinal pigmented epithelium (RPE). To overcome this limitation, a combination of cell therapy and optogenetics allows to confer light sensitivity to the donor cells thanks to the expression of a microbial opsin and therefore independently of the formation of mature outer segment or RPE contact. To ensure stable and homogenous expression of the microbial opsin in photoreceptors, we inserted the coding sequence of the red-light sensitive chloride pump Jaws under specific photoreceptor promoter into the iPSC genome, using the CRISPR/Cas9 system at the safe AAVS1 locus. We successfully generated a knock-in Jaws-EGFP iPSC line and validated its stemness and pluripotency status. These engineered iPSCs will be used to produce photoreceptors expressing Jaws that will be grafted to assess their ability to restore vision in blind animal models.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1468 ","pages":"409-414"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Connection Between Cellular Metabolism and Retinal Disease.","authors":"Larissa P Govers, Christian Grimm","doi":"10.1007/978-3-031-76550-6_44","DOIUrl":"https://doi.org/10.1007/978-3-031-76550-6_44","url":null,"abstract":"<p><p>The retina is one of the most metabolically active tissues in the human body and has its own complex metabolic environment as the different cell types in this tissue are interconnected to maintain a healthy retinal homeostasis. Any disturbances in the homeostatic balance may have a severe impact on retinal function affecting vision. About 341 genes are listed in the RetNet database as being causative for monogenic inherited retinal diseases. By intersecting this list with the Mammalian Metabolic Enzyme Database, we identified 28 metabolic genes that can result in diseases such as retinitis pigmentosa, Leber congenital amaurosis, or optic atrophy when mutated. Alongside inherited retinal diseases, metabolism also plays a prominent role in acquired retinal diseases. Metabolomics studies have been performed on patients with age-related macular degeneration, diabetic retinopathy, and glaucoma revealing dysregulated metabolic pathways, such as lipid, amino acid, and purine metabolism, in the onset of disease. Although there are distinct pathophysiological differences between inherited and acquired retinal disorders, diving deeper into the role of metabolism and how metabolic dysfunction may overlap with different pathologies, could give us indications on how to design approaches to normalize the homeostatic balance in the retina as treatment options to protect vision.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1468 ","pages":"267-271"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Catharina Rose Grubaugh, Anuradha Dhingra, Aleena Defreitas, M Mahmood Hussain, Kathleen Boesze-Battaglia
{"title":"Role of Microsomal Triglyceride Transfer Protein (MTP) in Lipid Processing Pathways in Retinal Pigment Epithelium.","authors":"Catharina Rose Grubaugh, Anuradha Dhingra, Aleena Defreitas, M Mahmood Hussain, Kathleen Boesze-Battaglia","doi":"10.1007/978-3-031-76550-6_60","DOIUrl":"https://doi.org/10.1007/978-3-031-76550-6_60","url":null,"abstract":"<p><p>Lipid processing in the retinal pigment epithelium (RPE) is important for maintaining the health and function of the neural retina and the RPE itself. One mode of en mass lipid transport from the RPE is apolipoprotein B-containing lipoproteins (Blps), the assembly of which is regulated by microsomal triglyceride transfer protein (MTP). To gain an initial understanding of how the loss of MTP and, thereby, Blp secretion alters other lipid processing pathways in the RPE, we measured the expression of proteins associated with β-oxidation and lipid droplets in mice lacking MTP expression in the RPE (RPEΔMttp) and age-matched controls. Expression of perilipin 2, a lipid droplet-associated protein, nearly doubled in the RPE of RPEΔMttp, and its localization with neutral lipids also increased. Meanwhile, expression of CPT1A, which mediates the transport of fatty acids into the mitochondria for β-oxidation, was unaffected. These results suggest that the loss of Blp assembly alters intracellular lipid storage patterns. Future studies will examine the effects of the loss of RPE-specific MTP expression and Blp secretion on additional lipid processing pathways.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1468 ","pages":"363-367"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bruna Lopes da Costa, Jorge Pincay, Scott E Brodie, Stephen H Tsang, Peter M J Quinn
{"title":"Prime Editing Strategy to Install the Mfrp Retinal Degeneration 6 Mutation.","authors":"Bruna Lopes da Costa, Jorge Pincay, Scott E Brodie, Stephen H Tsang, Peter M J Quinn","doi":"10.1007/978-3-031-76550-6_19","DOIUrl":"https://doi.org/10.1007/978-3-031-76550-6_19","url":null,"abstract":"<p><p>Mutations in the MFRP (membrane-type frizzled-related protein) gene are associated with a spectrum of ocular diseases. Here, we report on a patient with MFRP-linked autosomal recessive retinitis pigmentosa (arRP) with nanophthalmos who exhibited yellow deposits circumferentially along with far temporal intraretinal pigment migration. In future studies, we plan to explore the amelioration of MFRP-associated phenotypes in patient-specific induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium and in vivo using the classical Mfrp<sup>rd6</sup> mouse model of RP. To effectively screen gene editing correction approaches for the Mfrp<sup>rd6</sup> mouse model, we require a strategy to install the desired mutation in the Neuro-2a (N2a) mouse neuroblastoma cell line. In this study, we developed a prime editing strategy for the installation of the Mfrp<sup>rd6</sup> c.445+3_6AAGTdel mutation.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1468 ","pages":"113-118"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rimaz Toto, Carl P Soltau, Cassie L Rayner, Steven E Bottle, Nigel L Barnett
{"title":"Steroid-Nitroxide Hybrid Compound Protects the Retina in a Model of CNV.","authors":"Rimaz Toto, Carl P Soltau, Cassie L Rayner, Steven E Bottle, Nigel L Barnett","doi":"10.1007/978-3-031-76550-6_81","DOIUrl":"https://doi.org/10.1007/978-3-031-76550-6_81","url":null,"abstract":"<p><p>Nitroxide-based drugs have proven effective in modulating radical-induced oxidative stress by modulating antioxidant enzymes and genes that control distinct immune and anti-inflammatory responses. Due to their reasonable chemical stability and ability to shuttle between oxidized and reduced forms at physiologically relevant redox potentials, nitroxide-based radicals have also proven effective as biological probes of redox status. Herein, we investigated the potential of a unique nitroxide-based antioxidant and anti-inflammatory agent to protect the retina from experimentally induced degeneration. An established rat model of retinal degeneration was used viz. laser-induced choroidal neovascularization (CNV) to study the effects of the hybrid steroidal anti-inflammatory-antioxidant prednisolone 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) nitroxide compound. Vascular endothelial cell distribution at the CNV lesion site was investigated using isolectin B4 fluorescence histology, and the inflammatory response of microglia was investigated using IBA-1 immunohistochemistry. The prednisolone-TEMPO (Pred-TEMPO) hybrid reduced the laser-induced CNV lesion area compared to untreated control rats. These findings demonstrate that nitroxide-based compounds are potential therapeutics for retinal degenerative diseases involving inflammatory and oxidative stress-mediated components, including age-related macular degeneration.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1468 ","pages":"497-501"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alexandra Bernardo-Colón, Lijin Dong, Mones Abu-Asab, S Patricia Becerra
{"title":"Deletion of Pnpla2 Causes Malformation and Malperformance of Mouse Photoreceptors.","authors":"Alexandra Bernardo-Colón, Lijin Dong, Mones Abu-Asab, S Patricia Becerra","doi":"10.1007/978-3-031-76550-6_40","DOIUrl":"https://doi.org/10.1007/978-3-031-76550-6_40","url":null,"abstract":"<p><p>Photoreceptor cells express the patatin-like phospholipase domain-containing 2 (PNPLA2) gene that codes for pigment epithelium-derived factor receptor (PEDF-R). PEDF-R exhibits phospholipase activity that mediates the neurotrophic action of its ligand PEDF. Because phospholipids are the most abundant lipid class in the retina, we investigated the role of PNPLA2 in photoreceptors by generating CRISPR Pnpla2 knockout mouse lines. We aim to characterize one of the two lines of mice generated with global Pnpla2 gene deletion. The retinas of Pnpla2<sup>-/-</sup> mice had undetectable Pnpla2 gene expression, shorter retina and ONL heights, and photoreceptor deformities with loss of rhodopsin and opsin relative to controls. Furthermore, Pnpla2 deletion compromised photoreceptor function in vivo. In conclusion, ablation of the Pnpla2 gene in mice caused malformation and malperformance of photoreceptors, identifying PEDF-R as an important component for photoreceptor structure and function.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1468 ","pages":"241-246"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Débora Heller, Giulia Beletato Nery, Andre Luis Lacerda Bachi, Ibitsam Al-Hashimi
{"title":"Positive Role of Saliva in the Oral Microbiome.","authors":"Débora Heller, Giulia Beletato Nery, Andre Luis Lacerda Bachi, Ibitsam Al-Hashimi","doi":"10.1007/978-3-031-79146-8_7","DOIUrl":"https://doi.org/10.1007/978-3-031-79146-8_7","url":null,"abstract":"<p><p>Saliva plays a pivotal role in shaping the oral microbiome and maintaining oral homeostasis and health. This chapter explores the importance of saliva in promoting eubiosis of the oral microbiome and its implications for oral and systemic health. Saliva is a dynamic fluid rich in antimicrobial components and buffering agents that contribute to the microbial balance and homeostasis within the oral cavity. It provides a cleansing mechanism that facilitates the removal of bacteria and debris and limits the growth and colonization of microorganisms. The salivary antimicrobial proteins and peptides, in combination with antibodies, predominantly secretory immunoglobulin A (sIgA), are crucial for combating microbial pathogens and preventing oral infections. Saliva also possesses a buffering mechanism that regulates the pH levels within the oral cavity, which creates an environment that is inimical for the growth of acid-producing pathogens and promotes remineralization of the teeth. Furthermore, salivary proteins and glycoproteins form an inter-face (tissue coat) over the oral mucosa and teeth to protect the oral tissue from external environmental insults, maintain tissue integrity, and promote wound healing. Understanding the positive role of saliva in the oral microbiome provides an insight into potential novel strategies for promoting oral health and combating microbial dysbiosis. Recognizing the multifaceted roles of saliva as a guardian (gatekeeper) of oral microbial balance, we can unlock the therapeutic potential of saliva in enhancing the well-being of the body and averting oral and systemic diseases.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1472 ","pages":"103-118"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Heitor Sales de Barros Santos, Maria Eduarda Lisbôa Pagnussatti, Rodrigo Alex Arthur
{"title":"Symbiosis Between the Oral Microbiome and the Human Host: Microbial Homeostasis and Stability of the Host.","authors":"Heitor Sales de Barros Santos, Maria Eduarda Lisbôa Pagnussatti, Rodrigo Alex Arthur","doi":"10.1007/978-3-031-79146-8_3","DOIUrl":"https://doi.org/10.1007/978-3-031-79146-8_3","url":null,"abstract":"<p><p>The oral cavity presents a highly diverse microbial composition. All the three domains of life, Bacteria, Eukarya, and Archaea, as well as viruses constitute the oral microbiome. Bacteria are among the most abundant microorganisms in the oral cavity, followed by viruses, fungi, and Archaea. These microorganisms tend to live in harmony with each other and with the host by preventing the colonization of oral sites by exogenous microorganisms. Interactions between the host and its microbiota are crucial for keeping ecological stability in the oral cavity and a condition compatible with oral health. This chapter focuses on describing the oral microbiota in healthy individuals based on both targeted and nontargeted genome sequencing methods and the functional activity played by those microorganisms based on metagenomic, metatranscriptomic, metaproteomic, and metabolomic analyses. Additionally, this chapter explores mutualistic and antagonistic microbe-microbe relationships. These interactions are mediated by complex mechanisms like cross-feeding networks, production of bacteriocins and secondary metabolites, synthesis of pH-buffering compounds, and the use of universal signaling molecules. At last, the role played by host-microbe interactions on colonization resistance and immune tolerance will help provide a better understanding about the harmonious and peaceful coexistence among host and microbial cells under oral health-related conditions.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1472 ","pages":"31-51"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
McKenna M Somerville, Mary Anne Garner, Christopher A Girkin, Alecia K Gross
{"title":"Role of Microglia in Glaucomatous Pathology.","authors":"McKenna M Somerville, Mary Anne Garner, Christopher A Girkin, Alecia K Gross","doi":"10.1007/978-3-031-76550-6_25","DOIUrl":"https://doi.org/10.1007/978-3-031-76550-6_25","url":null,"abstract":"<p><p>Glaucoma is a leading cause of irreversible blindness worldwide and is characterized by progressive loss of retinal ganglion cells. Much research has gone into further understanding the pathology of this disease, including the extent to which microglia modulate its pathogenesis. This has revealed a role of the innate immune system in glaucomatous pathology that begins before the onset of retinal ganglion cell dysfunction and degeneration. Stimulation of the innate immune response triggers downstream cascades implicated in chronic disease, making immune pathways invaluable in our understanding of glaucomatous pathology. This review will focus on evidence that supports the role of the microglial immunologic response in the pathogenesis of glaucoma.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1468 ","pages":"149-153"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}