PRMT1 promotes hyperglycemia in a FoxO1-dependent manner, affecting glucose metabolism, during hypobaric hypoxia exposure, in rat model.

PURPOSE: High-altitude (HA) environment causes changes in cellular metabolism among unacclimatized humans. Previous studies have revealed that insulin-dependent activation of protein kinase B (Akt) regulates metabolic processes via discrete transcriptional effectors. Moreover, protein arginine methyltransferase (PRMT)1-dependent arginine modification of forkhead box other (FoxO)1 protein interferes with Akt-dependent phosphorylation. The present study was undertaken to test the involvement of PRMT1 on FoxO1 activation during hypobaric hypoxia (HH) exposure in rat model. METHODS: Samples were obtained from normoxia control (NC) and HH-exposed (H) rats, subdivided according to the duration of HH exposure. To explore the specific role played by PRMT1 during HH exposure, samples from 1d pair-fed (PF) NC, 1d acute hypoxia-exposed (AH) placebo-treated, and 1d AH TC-E-5003-treated rats were investigated. Quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) was performed to determine expressions of glycolytic, gluconeogenic enzymes, and insulin response regulating genes. Immuno-blot and enzyme linked immunosorbent assay (ELISA) were used for insulin response regulating proteins. Nuclear translocation of FoxO1 was analyzed using deoxyribonucleic acid (DNA)-binding ELISA kit. RESULTS: We observed HH-induced increase in glycolytic enzyme expressions in hepatic tissue unlike hypothalamic tissue. PRMT1 expression increased during HH exposure, causing insulin resistance and resulting increase in FoxO1 nuclear translocation, leading to hyperglycemia. Conversely, PRMT1 inhibitor treatment promoted inhibition of FoxO1 activity and increase in glucose uptake during HH exposure leading to reduction in blood-glucose and hepatic glycogen levels. CONCLUSIONS: PRMT1 might have a potential importance as a therapeutic target for the treatment of HH-induced maladies.

Alterations in different indices of skeletal health after prolonged residency at high altitude.

AIMS: The aim of this study was to evaluate the effect of prolonged residency at high altitude (HA) on different indices of bone health in sea level (SL) residents staying at an altitude of 3450 m for 4 months to 1 year. The assessment of bone health parameters included multisite quantitative bone speed of sound (SOS), and markers of bone metabolism such as serum alkaline phosphatase (ALP), bone specific alkaline phosphatase (BAP), urinary deoxypyridinoline (DPD), C-terminal propeptide of type I collagen (CICP), N-telopeptide of type I collagen (NTX), and hormonal regulators such as 25-hydroxy vitamin D3 (25Vit D), intact parathyroid hormone (i-PTH), and cortisol. RESULTS: The body weight in all the age groups was significantly lower at HA as compared to SL values. Prolonged residency at HA led to a significant decline in bone strength in terms of SOS, both at radius and phalanx. There was a significant increase in circulating Ca and ALP levels. Serum i-PTH and 25VitD levels decreased significantly. Significant decreases were also observed in CICP and BAP, bone formation markers, and serum NTX, DPD/Cr ratio, markers of bone resorption. CONCLUSION: These observations suggest that prolonged residency under hypoxic environment is associated with a decline in both bone formation and bone resorption markers, reflecting a lower bone turnover at HA.

Determination of bone mass using multisite quantitative ultrasound and biochemical markers of bone turnover during residency at extreme altitude: a longitudinal study.

A group of 221 male healthy volunteers of Indian Army were the subjects of the study. The baseline parameters of skeletal health were measured during their residency at an altitude of 3542 m. These subjects were then taken to an extreme altitude (EA, 5400-6700 m) where they stayed for about 4 months. The study parameters were repeated following their de-induction (DI) to 3542 m. On random selection, a subgroup was constituted from the above mentioned volunteers for detailed investigations on various bone turnover markers. Results of this study indicate a loss of body weight after DI from EA. The bone impairment was detected at the proximal phalanx, which is known to undergo early morpho-structural changes associated with bone resorption. The intact parathyroid hormone (i-PTH) levels showed a significant increase, while alkaline phosphatase (ALP) and bone specific alkaline phosphatase (BAP) activities declined significantly after DI from EA. This elevation in i-PTH might be required for maintenance of blood Ca level. 25 (OH) Vitamin D3 (25VitD) and calcitonin (CT) also showed a significant decline, which may suggest a negative impact on bone formation during sojourn at EA. The causes of deterioration of skeletal health at EA although are poorly understood but may be due to acute hypoxemia arising from extreme hypobaric hypoxia prevalent at extreme altitude.

Individual variation in response to simulated hypoxic stress of rats.

With an aim to categorize the animals exposed to simulated hypobaric hypoxia and to evaluate the hormonal profile responsible for individual variation in response to hypoxic stress, degree of tolerance to hypobaric hypoxia was measured by exposing the animals to a simulated altitude of 10,668 m at 32 degrees C and animals were categorized as low and high tolerant groups based on their gasping time. The hormonal profiles of these groups were evaluated just after exposure to the test. The results showed a distinct individual difference in response to hypoxic tolerance test. There was a significant increase in plasma norepinephrine concentration in high tolerant group than low tolerant rats. After hypoxic tolerance test, total circulating corticosterone (CORT) level also increased but this was not significant in high tolerant rats as compared to low tolerant rats. Corticosteroid binding globulin (CBG) concentration differ significantly between high and low tolerant groups of rats resulting in significant changes in circulating free corticosterone that in turn may be responsible for individual differences in hypoxic gasping time. Significant differences were also observed in prolactin and testosterone levels of both the groups. The results established the method of differentiating the animals according their response to hypoxic tolerance test. These data indicate that multiple components rather than only plasma glucocorticoid of the stress response are providing a basis for individual differences in physiological responses to hypoxic stress.

Erythropoietin levels in lowlanders and high-altitude natives at 3450 m.

BACKGROUND: This study is aimed to determine whether short or prolonged residency at high altitude (HA) elicits erythropoietin (EPO) secretion effectively in subjects who were able to acclimatize and those who were not able to acclimatize and suffered from acute mountain sickness (AMS) and high altitude pulmonary edema (HAPE). METHODS: Plasma EPO was measured in 16 lowland residents (LLR) at sea level (SL) and during 11 d of their sojourn at an altitude of 3450 m. Identical studies were also conducted in LLR acclimatized to HA (LLR-accl), high altitude natives (HAN) and in patients of AMS and HAPE. RESULTS: In LLR at SL, the mean +/- SD EPO levels were 8.93 +/- 3.75 mU x ml(-1), increased significantly after 8 h (20.0 +/- 11.06) of arrival at HA, peaked by day 1 (27.91 +/- 10.74 mU x ml(-1)), and started declining thereafter. The hemoglobin and hematocrit also increased after 8 h of arrival at HA and the increased levels were maintained during sojourn at high altitude. The EPO levels in LLR-accl were found to be significantly higher than the LLR SL values, but were not significantly different in HAN. The EPO levels in patients of AMS were not significantly different than the LLR values during the initial 2 d after arrival at HA but were found to be increased in patients of HAPE. CONCLUSION: Short or prolonged residency at HA is associated with increased secretion of EPO. The EPO response to hypoxia is not significantly altered in AMS but is markedly enhanced in HAPE, which may be due to exaggerated hypoxemia in these patients.

Effects of Rhodiola imbricata on dermal wound healing.

Rhodiola imbricata (Crassulaceae) is a perennial herb growing at high-altitude (4000 - 5000 m) in the western Himalayas. The present study was aimed at investigating the healing efficacy of R. imbricata rhizome ethanol extract using a rat excision wound model. The extract was found to be rich in polyphenols. The extract treated wounds were found to heal much faster as indicated by the improved rate of wound contraction and decreased time taken for epithelialization (11.33 vs. 18.33 days in the untreated group). The extract treatment increased cellular proliferation and collagen synthesis at the wound site, as evidenced by the increases in DNA, protein, hydroxyproline and hexosamine contents in comparison to a positive control treated with povidone-iodine ointment. These results were also supported by histological examinations. Furthermore, the treatment also caused an increase in antioxidant and a decrease in lipid peroxide levels in the granulation tissue. The results suggest that R. imbricata rhizome ethanol extract possesses a significant wound healing activity.

Influence of sea buckthorn (Hippophae rhamnoides L.) flavone on dermal wound healing in rats.

The present investigation was undertaken to determine the efficacy of topical administration of flavone of sea buckthorn (Hippophae rhamnoides L.) on cutaneous wound healing in rats. Four full-thickness excision wounds were created on the back of rat and 1.0% w/v flavone prepared in propylene glycol was applied topically. Control animals received the vehicle alone in an identical manner. The healing of the wound was assessed by the rate of wound contraction, period of epithelialization, hydroxyproline, hexosamine, antioxidants estimation and histopathology of the granulation tissue. The sea buckthorn flavone promoted the wound healing activity as indicated by improved rate of wound contraction, decreased time taken for epithelialization (16.3 days versus 24.8 days in controls) and significant increase in hydroxyproline (26.0%) and hexosamine (30.0%) content. These findings were also confirmed by histopathological examinations. In addition, it was observed that sea buckthorn flavone possesses potent antioxidant properties as evidenced by significant increase in reduced glutathione (55.0%), vitamin C (70.0%) and catalase (20.0%) activities in wound granulation tissue. The flavone treatment also resulted in significant decrease in lipid peroxide levels (39.0%). The results suggest that the sea buckthorn flavone promotes wound healing activity.

Autonomic nervous system and adrenal response to cold in man at Antarctica.

OBJECTIVE: To evaluate the role of the autonomic nervous system and adrenal system in acclimatization to cold in tropical men during short or prolonged sojourns at Antarctica. METHODS: The study was carried out on volunteers of the 18th winter over team (WOT) and 19th summer team (ST) of an Indian Antarctic Expedition. The ST members were evaluated at Delhi; during voyage; and on days 7, 30, and 60 of their stay at Antarctica. Identical studies were performed in WOT members who had stayed at Antarctica for 14 months. The parameters examined included heart rate, blood pressure, oral temperature, index finger skin temperature, heart rate variability, urinary epinephrine and norepinephrine, and salivary cortisol. RESULTS: The resting heart rate and blood pressure in ST members significantly increased (P < .05) on days 7 and 30 of their stay at Antarctica and returned to baseline Delhi values by day 60. The index finger temperature declined (P < .05) on day 7 at Antarctica and remained at lower levels during the entire period of observations. Heart rate variability showed an imbalance of autonomic nervous system effects with predominance of low-frequency band on day 7 of stay and returned to Delhi values by day 60. The urinary excretion of epinephrine and norepinephrine and salivary cortisol were also increased on day 7 and declined to baseline Delhi values after 2 months of stay. Compared with the ST group, the WOT group showed a significantly higher (P < .05) resting heart rate, blood pressure, and low-frequency power and urinary excretion of norepinephrine. CONCLUSIONS: These observations suggest that Antarctic residency during austral summer results in gradual attenuation of sympathetic tone and a shift of autonomic balance toward the parasympathetic side. However, WOT members showed a predominance of sympathetic and adrenal activity compared with initial responses of ST members, suggesting deconditioning or possible resetting of the autonomic nervous system.

A preclinical study of the effects of seabuckthorn (Hippophae rhamnoides L.) leaf extract on cutaneous wound healing in albino rats.

Hippophae rhamnoides L. (family Elaeagnaceae), commonly known as seabuckthorn, is a wild shrub growing at high altitude (1200-4500 meters) in adverse climatic conditions. The aim of the present study was to evaluate healing potential of seabuckthorn leaves in a preclinical study on rats using a cutaneous excision-punch wound model. Four full-thickness excision-type wounds of 8.0 mm diameter were created on the dorsal surface of rats under aseptic conditions. The aqueous lyophilized extract of seabuckthorn leaves, at doses of 0.5%, 1.0%, and 1.5% w/v prepared in propylene glycol, were applied topically twice daily for 7 days. Control animals received the vehicle alone in an identical manner. Wound granulation tissues were excised on eighth day postwounding, and the hydroxyproline, hexosamine, total protein content, and antioxidant levels were determined. Wound surface area was also measured on the eighth day before wound excision to determine wound contraction. Topical application of 1.0% seabuckthorn leaf extract statistically significantly augmented the healing process, as evidenced by increases in the content of hydroxyproline and protein as well as the reduction in wound area when compared with similar effects in response to treatment using povidone-iodine ointment (standard care). The reduced glutathione, vitamin C, superoxide dismutase, catalase, and glutathione peroxidase activities showed significant increases in seabuckthorn leaf extract-treated wounds as compared to controls. The lipid peroxide levels were significantly decreased in leaf extract-treated wounds. The results suggest that aqueous leaf extract of seabuckthorn promotes wound healing, which may be due to increased antioxidant levels in the granulation tissue.

Effects of Hatha yoga and Omkar meditation on cardiorespiratory performance, psychologic profile, and melatonin secretion.

OBJECTIVES: To evaluate effects of Hatha yoga and Omkar meditation on cardiorespiratory performance, psychologic profile, and melatonin secretion. SUBJECTS AND METHODS: Thirty healthy men in the age group of 25-35 years volunteered for the study. They were randomly divided in two groups of 15 each. Group 1 subjects served as controls and performed body flexibility exercises for 40 minutes and slow running for 20 minutes during morning hours and played games for 60 minutes during evening hours daily for 3 months. Group 2 subjects practiced selected yogic asanas (postures) for 45 minutes and pranayama for 15 minutes during the morning, whereas during the evening hours these subjects performed preparatory yogic postures for 15 minutes, pranayama for 15 minutes, and meditation for 30 minutes daily, for 3 months. Orthostatic tolerance, heart rate, blood pressure, respiratory rate, dynamic lung function (such as forced vital capacity, forced expiratory volume in 1 second, forced expiratory volume percentage, peak expiratory flow rate, and maximum voluntary ventilation), and psychologic profile were measured before and after 3 months of yogic practices. Serial blood samples were drawn at various time intervals to study effects of these yogic practices and Omkar meditation on melatonin levels. RESULTS: Yogic practices for 3 months resulted in an improvement in cardiorespiratory performance and psychologic profile. The plasma melatonin also showed an increase after three months of yogic practices. The systolic blood pressure, diastolic blood pressure, mean arterial pressure, and orthostatic tolerance did not show any significant correlation with plasma melatonin. However, the maximum night time melatonin levels in yoga group showed a significant correlation (r = 0.71, p < 0.05) with well-being score. CONCLUSION: These observations suggest that yogic practices can be used as psychophysiologic stimuli to increase endogenous secretion of melatonin, which, in turn, might be responsible for improved sense of well-being.