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

Polyphenols as Therapeutic Approach to High Altitude Mediated Skeletal Muscle Impairments

Skeletal muscle impairments at high altitudes resulted into various consequences in un-acclimatised individuals thus hampering their physical activities by imposing severe oxidative stress, skeletal muscle atrophy, mitochondrial dysfunction/autophagy, and regeneration disability. Researchers have described many natural and synthetic supplements to alleviate oxidative stress-induced muscle impairments. In this review article we are focusing on the skeletal muscle impairments and their alleviation by using natural polyphenols. Polyphenols are plant-based compounds showing anti-oxidative and anti-inflammatory properties like Curcumin, Catechins, Resveratrol, Quercetin and Salidrosides appear to mainly act by reversing oxidative stress and mitochondrial dysfunction eventually ameliorate skeletal muscle impairments under various imposed pathological conditions. This review also drew attention on the molecular targets of polyphenols and their possible therapeutic effects in preventing HA induced muscle impairments. Unavailability of suitable intervention, there is a need to find a probable solution having highly protective anti-atrophic, anti-oxidative, anti-inflammatory properties with the tint of performance enhancer

Nanocurcumin Prevents Hypoxia Induced Stress in Primary Human Ventricular Cardiomyocytes by Maintaining Mitochondrial Homeostasis

<div><p>Hypoxia induced oxidative stress incurs pathophysiological changes in hypertrophied cardiomyocytes by promoting translocation of p53 to mitochondria. Here, we investigate the cardio-protective efficacy of nanocurcumin in protecting primary human ventricular cardiomyocytes (HVCM) from hypoxia induced damages. Hypoxia induced hypertrophy was confirmed by FITC-phenylalanine uptake assay, atrial natriuretic factor (ANF) levels and cell size measurements. Hypoxia induced translocation of p53 was investigated by using mitochondrial membrane permeability transition pore blocker cyclosporin A (blocks entry of p53 to mitochondria) and confirmed by western blot and immunofluorescence. Mitochondrial damage in hypertrophied HVCM cells was evaluated by analysing bio-energetic, anti-oxidant and metabolic function and substrate switching form lipids to glucose. Nanocurcumin prevented translocation of p53 to mitochondria by stabilizing mitochondrial membrane potential and de-stressed hypertrophied HVCM cells by significant restoration in lactate, acetyl-coenzyme A, pyruvate and glucose content along with lactate dehydrogenase (LDH) and 5' adenosine monophosphate-activated protein kinase (AMPKα) activity. Significant restoration in glucose and modulation of GLUT-1 and GLUT-4 levels confirmed that nanocurcumin mediated prevention of substrate switching. Nanocurcumin prevented of mitochondrial stress as confirmed by c-fos/c-jun/p53 signalling. The data indicates decrease in p-300 histone acetyl transferase (HAT) mediated histone acetylation and GATA-4 activation as pharmacological targets of nanocurcumin in preventing hypoxia induced hypertrophy. The study provides an insight into propitious therapeutic effects of nanocurcumin in cardio-protection and usability in clinical applications.</p></div

Exogenous sphingosine-1-phosphate boosts acclimatization in rats exposed to acute hypobaric hypoxia: assessment of haematological and metabolic effects.

The physiological challenges posed by hypobaric hypoxia warrant exploration of pharmacological entities to improve acclimatization to hypoxia. The present study investigates the preclinical efficacy of sphingosine-1-phosphate (S1P) to improve acclimatization to simulated hypobaric hypoxia.Efficacy of intravenously administered S1P in improving haematological and metabolic acclimatization was evaluated in rats exposed to simulated acute hypobaric hypoxia (7620 m for 6 hours) following S1P pre-treatment for three days.Altitude exposure of the control rats caused systemic hypoxia, hypocapnia (plausible sign of hyperventilation) and respiratory alkalosis due to suboptimal renal compensation indicated by an overt alkaline pH of the mixed venous blood. This was associated with pronounced energy deficit in the hepatic tissue along with systemic oxidative stress and inflammation. S1P pre-treatment improved blood oxygen-carrying-capacity by increasing haemoglobin, haematocrit, and RBC count, probably as an outcome of hypoxia inducible factor-1α mediated erythropoiesis and renal S1P receptor 1 mediated haemoconcentation. The improved partial pressure of oxygen in the blood could further restore aerobic respiration and increase ATP content in the hepatic tissue of S1P treated animals. S1P could also protect the animals from hypoxia mediated oxidative stress and inflammation.The study findings highlight S1P's merits as a preconditioning agent for improving acclimatization to acute hypobaric hypoxia exposure. The results may have long term clinical application for improving physiological acclimatization of subjects venturing into high altitude for occupational or recreational purposes

Effect of nanocurcumin on ΔΨ_m in HVCM cells under hypoxia:

<p>(A) Hypoxia insult disrupted ΔΨ_m as early as 1 h of exposure caused in HVCM cells as depicted by FACS. (B) Curcumin treatment did not show any significant improvement in ΔΨ_m till 6 h of hypoxia and maximum protection was observed by 24 h of hypoxia. (C) Nanocurcumin treatment significantly restored the ΔΨ_m by 3 h of hypoxia than curcumin treated cells and maximum restoration was achieved by 24 h of hypoxia.</p

Effect of nanocurcumin on p-300 HAT and HDAC activities in HVCM cells under hypoxia:

<p>Histone acetylation by p-300 was up-regulated with a corresponding decline in HDAC activity in cardiomyocytes under hypoxia depicting that hypoxia induced hypertrophy dependent upon p-300 HAT and HDAC activity (A and C). Nanocurcumin treatment significantly down-regulated p-300 HAT and up-regulated HDAC activity in HVCM cells under hypoxia compared to cells exposed to hypoxia only. This was further confirmed by western blot analysis of GATA-4 and p-GATA-4 levels along with acetylated histone 3 and 4 (B). However, curcumin treatment did not prevent histone acetylation under hypoxia. Also, nanocurcumin or curcumin treated cells did not show change in p-300 HAT activity under normoxia. Values are mean ± SD, significant values represented as ^@@ p≤0.01 <i>vs</i> normoxia, *p≤0.05 <i>vs</i> hypoxia and ^#p≤0.01 <i>vs</i> hypoxia. Non-significant changes are depicted as ns. Scale bar represents 50μm.</p

Hypoxia induced hypertrophy is independent of translocation of p53 to mitochondria:

<p>The dependency of translocation of p53 to mitochondria on induction of hypertrophy in HVCM cells under hypoxia was estimated by blocking entry of p53 to mitochondria by treatment with CsA. Treatment of HVCM cells with CsA prevented p53 translocation to mitochondria but did not affect ANF levels in HVC cells exposed to hypoxia for 24 h. However, treatment HVCM cells with nanocurcumin significantly reduced p53 translocation to mitochondria and down-regulated ANF levels. Values are mean ± SD, significant values represented as ^@@p≤0.01 <i>vs</i> normoxia, ^#p≤0.01 <i>vs</i> hypoxia, *p≤0.05 <i>vs</i> hypoxia.</p