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AIM: To investigate the applications of hydrogen sulfide (H2S) in eye-specific ailments in mice. METHODS: Heterozygous cystathionine-β-synthase (CBS+/-) and wild-type C57BL/6J (WT) mice fed with or without high methionine diet (HMD) were administered either phosphate buffered saline (PBS) or the slow-release H2S donor: GYY4137. Several analyses were performed to study GYY4137 effects by examining retinal lysates for key protein expressions along with plasma glutamate and glutathione estimations. Intraocular pressure (IOP) was monitored during GYY4137 treatment; barium sulfate and bovine serum albumin conjugated fluorescein isothiocyanate (BSA-FITC) angiographies were performed for examining vasculature and its permeability post-treatment. Vision-guided behavior was also tested employing novel object recognition test (NORT) and light-dark box test (LDBT) recordings. RESULTS: CBS deficiency (CBS+/-) coupled with HMD led disruption of methionine/homocysteine (Hcy) metabolism leading to hyperhomocysteinemia (HHcy) in CBS+/- mice as reflected by increased Hcy, and s-adenosylhomocysteine hydrolase (SAHH) levels. Unlike CBS, cystathionine-γ lyase (CSE), methylenetetrahydrofolate reductase (MTHFR) levels which were reduced but compensated by GYY4137 intervention. Heightened oxidative and endoplasmic reticulum (ER) stress responses were mitigated by GYY4137 effects along with enhanced glutathione (GSH) levels. Increased glutamate levels in CBS+/- strain were prominent than WT mice and these mice also exhibited higher IOP that was lowered by GYY4137 treatment. CBS deficiency also resulted in vision-guided behavioral impairment as revealed by NORT and LDBT findings. Interestingly, GYY4137 was able to improve CBS+/- mice behavior together with lowering their glutamate levels. Blood-retinal barrier (BRB) appeared compromised in CBS+/- with vessels leakage that was mitigated in GYY4137 treated group. This corroborated the results for occludin (an integral plasma membrane protein of the cellular tight junctions) stabilization. CONCLUSION: Findings reveal that HHcy-induced glutamate excitotoxicity, oxidative damage, ER-stress and vascular permeability alone or together can compromise ocular health and that GYY4137 could serve as a potential therapeutic agent for treating HHcy induced ocular disorders.

Homocysteine, a non-proteinogenic amino acid but an important metabolic intermediate is generated as an integral component for the '1-carbon metabolism' during normal physiology. It is catabolized to cysteine via the transulfuration pathway resulting in the generation of hydrogen sulfide, a naturally endogenous byproduct. Genetics or metabolic derangement can alter homocysteine concentration leading to hyperhomocysteinemia (HHcy), a physiologically unfavorable condition that causes serious medical conditions including muscle wasting. HHcy environment can derail physiological processes by targeting biomolecules such as Akt; however, not much is known regarding the effects of HHcy on regulation of transcription factors such as forkhead box O (FOXO) proteins. Recently, hydrogen sulfide has been shown to be highly effective in alleviating the effects of HHcy by serving as an antiapoptotic factor, but role of FOXO and its interaction with hydrogen sulfide are yet to be established. In this review, we discuss role(s) of HHcy in skeletal muscle atrophy and how HHcy interact with FOXO and peroxisome proliferator-activated receptor gamma coactivator 1-alpha expressions that are relevant in musculoskeletal atrophy. Further, therapeutic intervention with hydrogen sulfide for harnessing its beneficial effects might help mitigate the dysregulated 1-carbon metabolism that happens to be the hallmark of HHcy-induced pathologies such as muscle atrophy. Key words: homocysteine, hydrogen sulfide, metabolism, transcription factors. L'homocysteine, un acide amine non proteinogenique, mais un important intermediaire metabolique, est produite comme composant integral pour le 'metabolisme du carbone 1' en presence d'une physiologie normale. Elle est catabolisee en cysteine par l'intermediaire de la voie de transulfuration, ce qui entraine la production de sulfure d'hydrogene, un produit derive endogene naturel. Des perturbations genetiques et metaboliques peuvent modifier les concentrations d'homocysteine, ce qui mene a l'hyperhomocysteinemie (HHcy), un etat physiologique defavorable qui entraine des etats morbides graves, y compris la fonte musculaire. Un environnement d'HHcy peut entrainer des perturbations des processus physiologiques en ciblant des molecules biologiques comme l'Akt, mais on ne connait que peu de choses des effets de l'HHcy sur la regulation de facteurs de transcription comme les proteines FOXO (pour << forkhead box O >>). On a recemment montre que le sulfure d'hydrogene est tres efficace pour attenuer les effets de l'HHcy en agissant comme facteur anti-apoptotique, mais le role des proteines FOXO et son interaction avec le sulfure d'hydrogene restent a etablir. Dans cet article de synthese, nous discutons du ou des roles de l'HHcy dans l'atrophie du muscle squelettique, et de comment l'HHcy interagit avec l'expression des proteines FOXO et du coactivateur 1-alpha du recepteur gamma active par proliferateur du peroxisome, lesquels jouent un role dans l'atrophie musculosquelettique. En outre, une intervention therapeutique mettant a profit ses bienfaits a l'aide de sulfure d'hydrogene pourrait contribuer a attenuer le dereglement du metabolisme du carbone 1, qui caracterise dans les faits des pathologies engendrees par l'HHcy comme l'atrophie musculaire. [Traduit par la Redaction] Mots-cles : homocysteine, sulfure d'hydrogene, metabolisme, facteurs de transcription., Introduction Hyperhomocysteinemia (HHcy)-induced atrophy of skeletal muscle has been identified as one of the reasons for reduced muscular density especially in the calf muscles (McDermott et al. 2007). As discovered [...]

Circular RNAs (circRNAs) are being hailed as a newly rediscovered class of covalently closed transcripts that are produced via alternative, noncanonical pre-mRNA back-splicing events. These single-stranded RNA molecules have been identified in organisms ranging from the worm (Cortes-Lopez et al. 2018. BMC Genomics, 19:8; Ivanov et al. 2015. Cell Rep. 10:170- 177) to higher eukaryotes (Yang et al. 2017. Cell Res. 27: 626-641) to plants (Li et al. 2017. Biochem. Biophys. Res. Commun. 488: 382-386). At present, research on circRNAs is an active area because of their diverse roles in development, health, and diseases. Partly because their circularity makes them resistant to degradation, they hold great promise as unique biomarkers for ocular and central nervous system (CNS) disorders. We believe that further work on their applications could help in developing them as 'first-in-class' diagnostics, therapeutics, and prognostic targets for numerous eye conditions. Interestingly, many circRNAs play key roles in transcriptional regulation by acting as miRNAs sponges, meaning that they serve as master regulators of RNA and protein expression. Since the retina is an extension of the brain and is part of the CNS, we highlight the current state of circRNA biogenesis, properties, and function and we review the crucial roles that they play in the eye and the brain. We also discuss their regulatory roles as miRNA sponges, regulation of their parental genes or linear mRNAs, translation into micropeptides or proteins, and responses to cellular stress. We posit that future advances will provide newer insights into the fields of RNA metabolism in general and diseases of the aging eye and brain in particular. Furthermore, in keeping pace with the rapidly evolving discipline of RNA'omics'-centered metabolism and to achieve uniformity among researchers, we recently introduced the term 'cromics' (circular ribonucleic acids based omics) (Singh et al. 2018. Exp. Eye Res. 174: 80-92). Key words: circular RNA, gene regulation, microRNA sponge, epigenomics, diagnostics. Les ARN circulaire (circARN) constituent une nouvelle classe de transcrits lies de maniere covalente, produits par epissage inverse. Ces molecules ont ete relevees dans des organismes vivants couvrant le spectre des vers (Cortes-Lopez et al. 2018. BMC Genomics, 19 : 8; Ivanov et al. 2015. Cell Rep. 10 : 170-177) aux eucaryotes superieurs (Yang et al. 2017. Cell Res. 27: 626-641) aux plantes (Li et al. 2017. Biochem. Biophys. Res. Commun. 488 : 382-386). La recherche sur les circARN represente un domaine actif en raison de leurs divers roles dans les etats sains et pathologiques. Leur circularite les rend resistants a la degradation; ils ont donc un avenir tres prometteur en tant que biomarqueurs unitaires. Nous croyons que plus de travaux sur leurs applications pourraient contribuer a les developper en tete d'une nouvelle classe de cibles diagnostiques, therapeutiques et pronostiques pour les maladies de l'reil. Beaucoup de circaARN jouent un role dans la regulation de la transcription par leur action en tant qu'eponges a miARN. Puisque la retine est un prolongement du cerveau et fait partie du systeme nerveux central, nous mettons a l'avant-plan l'etat actuel de la biogenese, des proprietes et du fonctionnement des circARN, et nous proposons une synthese des roles essentiels qu'ils jouent dans l'reil et le cerveau. Nous discutons aussi de leurs roles en tant qu'eponges a miARN dans la regulation des genes ou des ARNm lineaires, dans la translation en micropeptides et en proteines, ainsi que dans les reactions au stress cellulaire. Nous posons que des percees a venir fourniront de nouvelles perspectives dans le domaine du metabolisme de l'ARN en general, ainsi que dans les maladies de l'reil et du cerveau vieillissants. En outre, pour suivre Revolution rapide du domaine du metabolisme centre sur << l'ARN-omique >>, ainsi que par souci d'uniformite entre les chercheurs, nous avons recemment introduit le terme anglais<>(pour<>) (Singh et al. 2018. Exp. Eye Res. 174 : 80-92). [Traduit par la Redaction] Mots-cles: circARN, regulation des genes, eponges a microARN, epigenomique, diagnostic., Introduction With the advent of high-throughput sequencing technology and concurrent emergence of bioinformatics tools, it is now possible to discover and interpret many biological components simultaneously. The rediscovery of circular [...]

Although homocysteine (Hcy), a part of the epigenome, contributes to cell death by pyroptosis and decreases peroxisome proliferator-activated receptor [gamma] (PPAR[gamma]) levels, the mechanisms are unclear. Hcy is found in high concentrations in the sera of obese individuals, which can elicit an immune response as well by hypermethylating CpG islands of specific gene promoters, a marker of epigenetics. Hcy has also been established to chelate divalent metal ions like [Cu.sup.2+] and [Zn.sup.2+], but this role of Hcy has not been established in relationship with obesity. It has been known for a while that PPAR[gamma] dysregulation results in various metabolic disorders including glucose and lipid metabolism. Recently, zinc finger protein 407 (Zfp407) is reported to regulate PPAR[gamma] target gene expression without affecting PPAR[gamma] transcript and protein levels by synergistically working with PPAR[gamma]. However, the mechanism(s) of this synergy, as well as other factors contributing to or inhibiting this synergism, have not been proven. This review suggests that Hcy contributes to pyroptosis, changes gut microbiome, and alters PPAR[gamma]- dependent mechanism(s) via Zfp407-mediated upregulated adipogenesis and misbalanced fatty acid metabolism, which can predispose to obesity and, consequently, obesity-related metabolic disorders. Key words: PGC-1[alpha], zinc finger protein, DNA methylation, lipopolysaccharide, fatty acid metabolism, type 2 diabetes, insulin. Bien que l'on sache que l'homocysteine (Hcy), une partie de l'epigenome, contribue a la mort cellulaire par la pyroptose et qu'elle entraine une diminution des taux de recepteurs 7 actives par les proliferateurs de peroxysomes (ou PPAR[gamma] pour << peroxisome proliferator-activated receptor [gamma] >>), les modes d'action demeurent a eclaircir. On trouve de l'Hcy a concentration elevee dans le serum de personnes obeses, ce qui peut aussi provoquer une reaction immunitairepar l'hypermethylation des ilots CpG de promoteurs de genes specifiques, un marqueur de l'epigenetique. On a aussi etabli que l'Hcy entre en chelation avec des ions metalliques divalents comme [Cu.sup.2+] et [Zn.sup.2+], mais ce role de l'Hcy n'a pas ete etabli en relation avec l'obesite. On sait depuis un certain temps que la deregulation des PPAR[gamma] entraine diverses maladies d'ordre metabolique mettant en jeu le metabolisme du glucose et des lipides. On a rapporte recemment que la proteine a doigt de zinc 407 (Zfp407) participe a la regulation de l'expression de genes cibles des PPAR[gamma] sans modifier les taux de transcrits et de proteines des PPAR[gamma] en agissant en synergie avec les PPAR[gamma]. Cependant, le ou les modes d'action de cette synergie, ainsi que d'autres facteurs contribuant a cette synergie ou a son inhibition ne sont pas appuyes par des donnees probantes. Cet article de synthese laisse entrevoir que l'Hcy participe a la pyroptose et entraine des modifications du microbiome enterique et d'eventuellement plusieurs modes d'action dependants des PPAR[gamma] par l'intermediaire de la regulation a la hausse de l'adipogenese et d'un desequilibre de la regulation du metabolisme des acides gras, tous deux medies par la Zfp407, ce qui peut predisposer a l'obesite et consecutivement aux maladies d'ordre metabolique liees a l'obesite. [Traduit par la Redaction] Mots-cles : PGC-1[alpha], proteine a doigt de zinc, methylation de l'ADN, lipopolysaccharide, metabolisme des acides gras, diabete de type 2, insuline., Homocysteine (Hcy) and obesity Obesity is one of the leading causes of health complications like type 2 diabetes, stroke, hypertension, cardiovascular diseases, and even some cancers. As of 2014, the [...]

Purpose: To characterize the global profile of circular RNAs (circRNAs) and their differential expression levels in homocysteine (Hcy)-treated ARPE-19 cells, a line of human retinal pigment epithelial (RPE) cells. Materials and Methods: We treated ARPE-19 cells with and without Hcy to investigate the influence of Hcy on circRNA expression levels using dedicated human circRNA microarrays. Results: A total of 12,233 circRNAs were identified out of them 54 were differentially expressed (17 were down-regulated, and 37 were up-regulated) with a fold change >2.0 (p < 0.05) in Hcy-treated versus untreated cells. Conclusions: To our knowledge, this is the first report profiling circRNAs in human RPE cells post-Hcy treatment mimicking hyperhomocysteinemic (HHcy) conditions that negatively affect retinal biology and vision. These findings are of potential clinical significance as they will help understand Hcy metabolism and HHcy-mediated diseases and identify potential diagnostic and therapeutic targets for eye diseases that are caused by elevated Hcy concentrations. [ABSTRACT FROM AUTHOR]

Systematic understanding of immune aging on a whole-body scale is currently lacking. We characterized age-associated alterations in immune cells across multiple mouse organs using single-cell RNA and antigen receptor sequencing and flow cytometry-based validation. We defined organ-specific and common immune alterations and identified a subpopulation of age-associated granzyme K (GZMK)-expressing CD8 + T (Taa) cells that are distinct from T effector memory (Tem) cells. Taa cells were highly clonal, had specific epigenetic and transcriptional signatures, developed in response to an aged host environment, and expressed markers of exhaustion and tissue homing. Activated Taa cells were the primary source of GZMK, which enhanced inflammatory functions of non-immune cells. In humans, proportions of the circulating GZMK + CD8 + T cell population that shares transcriptional and epigenetic signatures with mouse Taa cells increased during healthy aging. These results identify GZMK + Taa cells as a potential target to address age-associated dysfunctions of the immune system., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)