Metabolomics Unraveling the Biochemical Insight of High Altitude Diseases and Sepsis A Narrative Review

High altitude diseases and sepsis may seem distinct at first glance, but there are underlying physiological similarities that lie in their responses to hypoxia, tissue dysfunction, inflammation, and multi-organ failure conditions. Understanding these commonalities can help medical professionals draw parallels between them and apply relevant knowledge to improve patient care and treatment.In this direction,a literature review of metabolomics-based studies has been done for high-altitude diseases and sepsis, and the panel of common disease-related metabolic markers and associated pathways areunraveled. Themetabolic pathways found dysregulated in both conditions are amino acid metabolism, lipid metabolism, energy metabolism, inflammatory response-related metabolism, bile acid metabolism, and purine and pyrimidine metabolism

Altered Mitochondrial DNA Methylation Patterns in Thrombosis

DNA methylation being one of the chief controllers of gene expression has not only been the reason behind the initiation of a plethora of diseases like Cancer, Alzheimer’s disease, Parkinson’s disease, etc. Still, it is an active contributor to the pathophysiology of several cardiovascular diseases like coronary artery disease (CAD), Atherosclerosis, Stroke, Cardiomyopathy, etc. The role of nuclear DNA methylation in VTE has been studied earlier, but the comparison of methylation in both nuclear genes and mitochondrial genes in high altitude VTE (HA-VTE) and sea level VTE (SL-VTE) patients has not been studied in depth. Through this present study, DNA methylation patterns of mitochondrial encoded as well as nuclear-encoded mitochondrial genes of five high-altitude VTE patients and five sea-level VTE patients have been obtained. On comparing HA-VTE vs. SL-VTE methylation, one hundred and twenty hypermethylated genes and one hundred and thirty-eight hypomethylated genes were observed. Post gene enrichment and ontology study, the TCA cycle and NADH dehydrogenase were found to be the highly enriched pathways in both the study groups. Protein-protein interaction network using STRING pointed out the enriched pathway of L-2-hydroxyglutaric acid when both the gene sets were enriched. These results show the crucial role of mitochondrial DNA methylation in the pathophysiology of thrombosis and show great potential to study the role of mitochondria in thrombosis

Potential Candidate Molecules of Past and Present for Combating High Altitude Hypoxia Induced Maladies

Hypobaric hypoxia occurs at high altitudes where barometric pressure is low causing insufficient supply of oxygen leading to many high-altitude illnesses like acute mountain sickness (AMS), high altitude pulmonary edema (HAPE), high altitude cerebral edema (HACE) etc.Medications have been applied to treat and prevent injuries caused by HBH, showing anti-inflammatory, anti-edemagenic, and antioxidant properties. AMS symptoms, such as headache, nausea, weariness, usually go away in 1-2 days. HACE causes brain swelling, elevated intracranial pressure, resulting in confusion, stupor, ataxia, and death.Acetazolamide, dexamethasone, nifedipine are the drugs used for treatment acting oncarbonic anhydrase enzyme, calcium channels.Acetazolamide increases arterial partial pressure of oxygen.Nifedipine relaxes vascular smooth muscles and increases blood flow. Some drugscause side effects also like dizziness, diuresis, nausea, malaise, etc. Hence, a new drug search is needed to find more targeted and fewer side effects for faster relief and better health at high altitudes

A Pilot Study Investigating the Impact of High Altitude on Myostatin and Irisin Levels

Many people visit and stay at high altitude due to adventure or occupation. The high-altitude environment comprises many factors alien to sea residents and detrimental to physical and mental health. Myokines are peptides and cytokines secreted from muscles and have a prime role in regulating skeletal muscle growth and myo-degradation. Therefore, the present study investigated the function of myokines in regulating muscle mass during acute and chronic high-altitude exposure. The study was conducted on Indian healthy subjects (n=29) who were distributed into three groups: Control (sea level (SL; n=15), acute high altitude stayed subjects (stayed at high altitude for less than ten days (AHA; n=7); chronic high altitude stayed subjects (stayed at high altitude for 15 days to 3 months (CHA; n=7). Acute exposure to high altitude leads to an increase in myostatin levels, indicating enhanced myo-degradation. Irisin levels were also increased in AHA group compared to SL group, depicting inclined myogenesis. However, CHA group showed an increase in myostatin levels but a non-significant change in irisin content in relation to SL group, suggesting enhanced myo-degradation. These findings generated a unique role of myokines, including myostatin and irisin, in managing skeletal muscle health with reference to high altitude.&nbsp

Comparative Analysis of Low Lander Transcriptomes at Himalayas and Andes Reveals Differential Regulation of Erythropoiesis at Extreme Altitude

Systematic human expeditions to very high (≥ 3500 meters) and extreme altitudes (≥ 5500 meters) have documented marked changes in human physiology. However, only a handful of studies have reported lowlander transcriptome alterations at extreme altitudes. In this study, we compared the lowlander transcriptomes available in the literature for Chinese mountaineers (n=4, 3 males and 1 female)inthe Himalayas (Mount Xixabangma base camp, 5600 meters) and French mountaineers (n=8, all males) at Andes (La Rinconada, Peru, 5100 meters). We sought to find out significantly alteredpathways, gene networks, andtranscription factors (TFs) for each data set. We observed profound upregulation of GATA1 in the Himalaya transcriptome data set (+ 1.38-fold) in comparison tothe Andes data set (-1.36-fold). Core transcriptome analysis revealed that GATA1 upregulated erythropoiesis genes like KLF1, HBD, HBG, EPB42, ALAS2, and AHSP in the Himalayan dataset in contrast to the Andean data set.We also observed contrasting expression profiles ofKLF1 in the Himalayas (+1.22-fold) and Andes (-1.15-fold)for lowlander populations and differential expression regulation of its downstream target genes like AHSP, ALAS2, SLC4A1, EPB42,HBG2, andHBB.We also observed upregulation of SP1 (+ 2.46-fold) in the Himalayan transcriptome as compared to the Andean transcriptome which also regulates erythropoiesis genes along with GATA1. Our results indicate profound upregulation of erythropoiesis-promotingTFs and genes in Chinese mountaineers at extreme altitudes in contrast to French mountaineers at similar altitudes. Though our present analysis does not provide possible reasons for the observed differences inhypoxia-responsive erythropoiesis gene signatures, it certainly highlights ethnicity-dependenttranscriptome level variations in lowlanders at extreme altitudes

Computational Investigation of Regulatory Region SNPs of Autophagy Gene BECN1

The autophagy process plays a cytoprotective role and ensures the healthy survival of a cell. The role of autophagy has been implicated in various diseases, making it an essential candidate for therapeutic interventions. Beclin 1, a candidate autophagy protein, plays a critical role during autophagy initiation and maturation by interacting with various other autophagy proteins. Beclin1 has been reported to be involved in various human diseases. This study uses a computational approach to study the effect of non-coding region single nucleotide polymorphisms (SNPs) of gene encoding beclin1. RegulomeDB, SNP2TFBS, and PROMO ALLGEN were used to predict the effect of promoter region variants on transcription factor binding sites. SNPs located within 3'UTR were analyzed by miRdSNP, PolymiRTS Database 3.0, miRNASNP-V3, MicroSNIPER, and miRmap. Nine promoter region variants that alter the transcription factor binding sites and 4 variants in 3'UTR were identified that either create a new target site for miRNA or disrupt an existing one. The functional analysis of these identified SNPs could be done experimentally to unravel their relation with a particular disease and the genetic predisposition of human subjects for a disease

Cold Injury Prevention and Management in High Altitude Extreme Environments Pharmacological and Therapeutical Interventions

Cold injury refers to local or systemic body response that occurs due to massive loss of body heat when the body is exposed to extremely cold temperatures. The current modalities for the prevention and management of cold injury(ies) are very limited due to the paucity of availability of targeted therapeutics. Pathophysiological cascades in cold injury include: (a) desensitization of sensory neurons can be manifest as a result of altered pathophysiological functions viz., Ca2+ imaging, calcitonin gene-related peptide release, expressions of inflammatory mediators (PGE2: prostaglandin E2, NGF: nerve growth factors), (b) inflammatory markers viz.; interleukins (IL-1β, IL-6, and IL-10), tumor necrosis factor-alpha (TNF-α), and CD62E/endothelial-leukocyte adhesion molecule 1 (E-selectin); (c) oxidative stress markers associated with cold injury measured through serum level of protein carbonyl, 4-hydroxy-2-nonenal (4-HNE), superoxide dismutase (SODs), advanced oxidative protein products (AOPP) and nitrotyrosine; (d) endothelial damage: nitric oxide (NO), prostacyclin (PGI2), reactive oxygen species (ROS), Von-Willebrand factor (VWF), CD31/PECAM-1 (platelet/endothelial cell adhesion molecule 1), CD36/SR-B3 (scavenger receptor class B member 3) and tissue-type plasminogen activator (TTPA). In this review paper, we elaborate on the current state-of-the-art pharmacological interventions for cold injury that may be beneficial in developing novel and targeted therapeutics for the prevention, management, and treatment of cold injury

Multi Targeted Non Invasive Photoceutical Therapeutic Approach for Combat and Traumatic Soft Tissue Injuries

Combat and soft tissue traumatic injuries pose unique challenges in terms of their severity, complexity, and thus need for the exploration of rapid, novel therapeutic interventions. Traditionally, combat injuries have been managed through invasive surgical procedures associated with potential complications and prolonged recovery times. However, advancements in non-invasive treatment modalities have opened up new possibilities for managing combat injuries more effectively and efficiently. The present article aims to provide a comprehensive overview of non-invasive, drug-free, biophysical therapeutic approaches for combat and external traumatic injuries, focusing on their benefits, efficacy, and potential applications. The non-invasive nature and favourable safety profile of photobiomodulation therapy (PBMT) make it an attractive option for combat injury management. The evidence on underlying mechanistic insights supports the efficacy of PBMT in promoting tissue repair, reducing pain, inflammation, oxidative stress, and facilitating functional recovery. In conclusion, the present review highlights the significant potential of non-invasive PBMT using dual/multi-wavelength light energy as a valuable therapeutic approach for traumatic soft tissue and combat injuries and extensively explores associated mechanistic insights. Further research on combination therapies using potential pharmacological agents in conjunction with PBMT, with optimal irradiation protocols and other energy-based healing modalities will favour the translation of potential non-invasive healing intervention for combat and traumatic injuries in clinical applications

SUMO Sites Prediction in Human Transcription Factors Involved in Hypoxia induced Cardiac Illnesses

Protein SUMOylation is a reversible and well knownpost-translational modificationprocess of the cells. It may change a protein's cellular location, interactions, and possible structural shape before it develops to carry out its basic functions.Also, it decides the binding of transcription factors and DNA binding proteins tochromatin in addition to various cis and trans regulatory factors. Alterations in protein SUMOylation have been linked with a variety of disorders and developmental anomalies.Tentative approaches to identify SUMO binding sites are challenging due todynamic nature of the SUMOylation processand various critical lab experimentswhich are involved very high cost.Therefore, the computational methodologies may guide the experimental identification of SUMOylation sites and provide insights for improving comprehensionofSUMOylation mechanism in the cells.In this study, we identify the SUMO binding sites in transcription factors that are actively involved and have crucial roles in cardiac development andpathophysiology of the heart.A list of important transcription factors was preparedfrom thehuman transcription factor database.The GPS-SUMO, SUMO plot, and JASSA web serverswere used for the prediction of SUMO binding sites in cardiac transcription factors.We identified the SUMOylation of several novel, previously uncharacterized SUMO targetsthat are actively involved in thecardiovascular system.Thus, the present study may help to uncoverthe significance ofSUMO modificationin cardiac development and illnesses which creates a fresh avenue for future studies ontarget-specific SUMOylation for identification of novel therapeutic targets andmanagement strategies forhypoxia-induced cardiovascular disorders

Emerging Evidence for Association of Transsulfuration Pathway with Hypoxia Responses

When people ascend to a high altitude (HA), the body’s oxygen (O2) sensing mechanisms can sense perturbation in partial pressure and trigger adaptive responses. Rapid ascending to HA without ample time for acclimatization culminates in high-altitude illnesses, which can derail the body functioning of lowlanders moving to HA. High-altitude native populations have undergone positive natural selection to efficiently overcome the challenges of chronic hypobaric hypoxia (HH) and thus offer a unique model to understand physiological and genetic adaptations at high altitudes. In addition, evolutionary shreds of evidence propose that sulfur belonging to the same periodic table family can mimic oxygen to bypass its metabolic oxygen demand and modulate energy production.Intriguingly, our group has identified a strong association between diminished hydrogen sulfide (H2S)levels and HH-induced pathological responses. We have recently presented experimental evidence of cysteine deficit, which functionally regulates both lowered levels of endogenous H2S and HH-induced neuropathological responses. In this review, we sought to understand the role of H2S and the transsulfuration pathway at HA