Diabetic patients suffer from a host of physiological abnormalities beyond just those of glucose metabolism. These abnormalities often lead to systemic inflammation via modulation of several inflammation-related genes, their respective gene products, homocysteine metabolism, and pyroptosis. The very nature of this homeostatic disruption re-sets the overall physiology of diabetics via upregulation of immune responses, enhanced retinal neovascularization, upregulation of epigenetic events, and disturbances in cells’ redox regulatory system. This altered pathophysiological milieu can lead to the development of diabetic retinopathy (DR), a debilitating vision-threatening eye condition with microvascular complications. DR is the most prevalent cause of irreversible blindness in the working-age adults throughout the world as it can lead to severe structural and functional remodeling of the retina, decreasing vision and thus diminishing the quality of life. In this manuscript, we attempt to summarize recent developments and new insights to explore the very nature of this intertwined crosstalk between components of the immune system and their metabolic orchestrations to elucidate the pathophysiology of DR. Understanding the multifaceted nature of the cellular and molecular factors that are involved in DR could reveal new targets for effective diagnostics, therapeutics, prognostics, preventive tools, and finally strategies to combat the development and progression of DR in susceptible subjects.

No abstract

Traumatic brain injury (TBI) is a damage to the brain from an external force that results in temporary or permanent impairment in brain functions. Unfortunately, not many treatment options are available to TBI patients. Therefore, knowledge of the complex interplay between gut microbiome (GM) and brain health may shed novel insights as it is a rapidly expanding field of research around the world. Recent studies show that GM plays important roles in shaping neurogenerative processes such as blood-brain-barrier (BBB), myelination, neurogenesis, and microglial maturation. In addition, GM is also known to modulate many aspects of neurological behavior and cognition; however, not much is known about the role of GM in brain injuries. Since GM has been shown to improve cellular and molecular functions via mitigating TBI-induced pathologies such as BBB permeability, neuroinflammation, astroglia activation, and mitochondrial dysfunction, herein we discuss how a dysbiotic gut environment, which in fact, contributes to central nervous system (CNS) disorders during brain injury and how to potentially ward off these harmful effects. We further opine that a better understanding of GM-brain (GMB) axis could help assist in designing better treatment and management strategies in future for the patients who are faced with limited options.

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 (Cortés-López 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).

Age-related macular degeneration (AMD) is a leading cause of blindness and is becoming a global crisis since affected people will increase to 288 million by 2040. Genetics, age, diabetes, gender, obesity, hypertension, race, hyperopia, iris-color, smoking, sun-light and pyroptosis have varying roles in AMD, but oxidative stress-induced inflammation remains a significant driver of pathobiology. Eye is a unique organ as it contains a remarkable oxygen-gradient that generates reactive oxygen species (ROS) which upregulates inflammatory pathways. ROS becomes a source of functional and morphological impairments in retinal pigment epithelium (RPE), endothelial cells and retinal ganglion cells. Reports demonstrated that hydrogen sulfide (HS) acts as a signaling molecule and that it may treat ailments. Therefore, we propose a novel hypothesis that HS may restore homeostasis in the eyes thereby reducing damage caused by oxidative injury and inflammation. Since HS has been shown to be a powerful antioxidant because of its free-radicals' inhibition properties in addition to its beneficial effects in age-related conditions, therefore, patients may benefit from HS salubrious effects not only by minimizing their oxidant and inflammatory injuries to retina but also by lowering retinal glutamate excitotoxicity.

Higher levels of nonprotein amino acid homocysteine (Hcy), that is, hyperhomocysteinemia (HHcy) (~5% of general population) has been associated with severe vasculopathies in different organs; however, precise molecular mechanism(s) as to how HHcy plays havoc with body’s vascular networks are largely unknown. Interventional modalities have not proven beneficial to counter multifactorial HHcy’s effects on the vascular system. An ancient Indian form of exercise called ‘yoga’ causes transient ischemia as a result of various body postures however the cellular mechanisms are not clear. We discuss a novel perspective wherein we argue that application of remote ischemic conditioning (RIC) could, in fact, deliver anticipated results to patients who are suffering from chronic vascular dysfunction due to HHcy. RIC is the mechanistic phenomenon whereby brief episodes of ischemia‐reperfusion events are applied to distant tissues/organs; that could potentially offer a powerful tool in mitigating chronic lethal ischemia in target organs during HHcy condition via simultaneous reduction of inflammation, oxidative and endoplasmic reticulum stress, extracellular matrix remodeling, fibrosis, and angiogenesis. We opine that during ischemic conditioning our organs cross talk by releasing cellular messengers in the form of exosomes containing messenger RNAs, circular RNAs, anti‐pyroptotic factors, protective cytokines like musclin, transcription factors, small molecules, anti‐inflammatory, antiapoptotic factors, antioxidants, and vasoactive gases. All these could help mobilize the bone marrow–derived stem cells (having tissue healing properties) to target organs. In that context, we argue that RIC could certainly play a savior’s role in an unfortunate ischemic or adverse event in people who have higher levels of the circulating Hcy in their systems.

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin condition characterized by painful nodules which suppurate and later develop into scar tissues followed by the development of hypodermal tracts. Although the mechanisms behind HS are not fully understood, it is known that dietary factors play important roles in flare frequency and severity. We hypothesize that the high fat diet (HFD) causes dysbiosis, systemic inflammation, and hyperhomocysteinemia (HHcy) in susceptible individuals, which subsequently elevate inflammatory cytokines such as IL-1β, IL-6, IL-17, and tumor necrosis factor alpha (TNF-α). This increase in dysbiosis-led inflammation coupled with a dysregulation of the 1-carbon metabolism results in an increase in matrix metalloproteinases MMP-2, MMP-8, and MMP-9 along with tissue matrix remodeling in the development and maintenance of the lesions and tracts. This manuscript weaves together the potential roles played by the gut microbiome, HHcy, MMPs, and the 1-carbon metabolism toward HS disease causation in susceptible individuals.

No abstract