The combined use of acetazolamide and Rhodiola in the prevention and treatment of altitude sickness.

Background: Altitude sickness (AS), which is caused by rapid exposure to low amounts of oxygen at high elevations, poses a great threat to humans working and traveling in these conditions. Acute mountain sickness includes high-altitude pulmonary edema and high-altitude cerebral edema. Acetazolamide (AZ) is often used to treat pulmonary edema caused by hypoxia. Additionally, the medicinal plant Rhodiola rosea L. (Rh) is often used to prevent AS in the Qinghai-Tibet plateau. However, the mechanisms of action of Rh and AZ in the treatment of AS remain unclear. To date, no research has been conducted to determine whether their combined use has better efficacy in the treatment and prevention of AS than their separate use. Methods: We used the method of network pharmacology to analyze the mechanisms of Rh and AZ in combination in the prevention and treatment of AS, and also verified our results. Results: The hypoxia-inducible factor (HIF)-1 signaling pathway, which is related to hypoxia, and other pathways related to pulmonary hypertension, became more enriched after the combined use of the 2 drugs. Additionally, Rh and AZ regulated most nodes in the AS network. Further, compared to their separate use, the combined use of Rh and AZ further downregulated the gene expression of HIF-1α and improved hemodynamics in rats, and thus helped the body to reduce its sensitivity to hypoxic environments and pulmonary artery pressure. Conclusions: This study provides evidence supporting the combined use of AZ and Rh in the treatment of AS.

The role of pulmonary mast cells activation and degranulation in the process of increased pulmonary artery pressure.

Hypoxia exposure often cause the increases of pulmonary arterial pressure (PAP). Studies reported that mast cells (MCs) participate in pulmonary vascular remodeling and promote the formation of chronic pulmonary hypertension. Current studies mainly focus on the change of MCs under chronic hypoxia, but few studies on the regulatory role and mechanism of MCs under acute hypoxia. Therefore, present study investigated the dynamic change of MCs in lung tissues under acute hypoxia and the role of MCs activation in the increasement of PAP. In our study, we established an experimental rat model of acute hypobaric hypoxia using a hypobaric chamber (simulated altitude of 7,000 m) and pretreated with MCs degranulation inhibitor sodium cromoglycate (SCG) to study the MCs changes under acute hypoxic exposure. We found that acute hypobaric hypoxia contributed to the increased quantity, activity, and degranulation of MCs and SCG pretreatment showed attenuated PAP elevation under acute hypoxia. Our findings implied that there is a possible mechanism of acute hypoxia cause rapid recruitment of MCs, activation, and explosive degranulation to release Tryptase, Chymase, IL-6, His, 5-HT, and Ang II, which further contributed to pulmonary microvascular contraction and increase in PAP. This work extends the knowledge about MCs, providing a potential profile of MCs as an alternative treatment for high-altitude pulmonary edema (HAPE)-related increased pulmonary artery pressure.

MiR-195 alleviates oxygen-glucose deprivation/reperfusion-induced cell apoptosis via inhibition of IKKα-mediated NF-κB pathway.

OBJECTIVES: Increasing evidence confirmed that miRNA plays a critical role in the occurrence and development of ischemic stroke. Here, the aim of this study was to examine the function and mechanisms of miR-195 in vascular endothelial cell apoptosis induced by oxygen-glucose deprivation (OGD). METHODS: This study intended to use OGD to simulate ischemia in vitro. The mRNA expression of miR-195, IKKα and NF-κB in human umbilical vein endothelial cells (HUVECs) were detected by RT-qPCR. The proliferation and apoptosis ability of HUVECs were evaluated using MTT assay, colony formation assay and flow cytometry, respectively. Western blot was applied to examine related protein expression. The interaction between miR-195 and IKKα was verified by dual-luciferase reporter gene assay. RESULTS: OGD significantly inhibited cell viability and induced cell apoptosis in HUVECs. Meanwhile, OGD treatment notably decreased the expression of miR-195, as well as enhanced NF-κB expression. Moreover, miR-195 directly interacted with IKKα and suppressed its expression. Mechanically, overexpression of miR-195 exhibited pro-proliferation and anti-apoptotic effect on HUVECs treated with OGD through targeting IKKα-mediated NF-κB pathway. At the molecular level, through suppressing IKKα/NF-κB pathway, miR-195 inhibited the expression of pro-apoptotic protein Bax and active caspase-3, but increased the expression of anti-apoptotic Bcl-2 in HUVECs. CONCLUSIONS: Our finding uncovers the protective effect of miR-195 on the biological behavior of HUVECs via suppression of the NF-κB pathway induced by IKKα, which may provide a new potential strategy for ischemic stroke clinical treatment.

Effects of hypoxic exposure on immune responses of intestinal mucosa to Citrobacter colitis in mice.

OBJECTIVE: The pathogenesis and mechanism of colitis may be related to intestinal flora, genetic susceptibility, environmental and immune factors. Among these various factors, the importance of environmental factors in the pathogenesis of colitis has been increasingly recognized. The purpose of this study was to investigate the effects of hypoxia on intestinal mucosal immunity. METHODS: Experimental colitis was induced by oral gavage of Citrobacter rodentium (C. rodentium) in mice, then divided into normoxia group and hypoxia group. Mice were sacrificed after 2 weeks. Physiological and blood biochemical indicators were monitored to verify the hypoxia model. The body weight, fecal bacterial output, colon length and colon histopathology were observed to evaluate severity of colitis. The concentration of cytokines in colonic tissues were detected by ELISA. The percentage of CD4+ IFN-γ+ (Th1) and CD4+ IL-17+ (Th17) cells in mesenteric lymph nodes (MLN) were detected by flow cytometry. The levels of mucosal antimicrobial peptides (AMPs), related inflammatory factors and transcription factors in colon tissues were detected by qRT-PCR. RESULTS: Mice in hypoxic C. rodentium infection (Hypoxia + C.r.) group exhibited significant decrease in body weight, increase in fecal bacterial pathogen output, and more severe histopathological damage in the colon compared with the C. rodentium infection (Nomoxia + C.r.) group. Meanwhile, the level of NF-κB, TLR4, COX-2, IL-6 and TNF-α of colonic tissue were increased, while IL17, IL-22, and Reg3γ were decreased. The percentage of CD4+ IFN-γ+ (Th1) and CD4+ IL-17+ (Th17) cells in MLN were significantly decreased in mice of Hypoxia + C.r. group, accompanied by the decreased of IFN-γ and IL-17. In addition, the level of the T-bet, RORγt, IL-12 and IL-23 were decreased in mice of Hypoxia + C.r. group. CONCLUSIONS: Hypoxic exposure significantly exacerbates the symptoms and the pathological damage of mice with colitis and influences the immune function by down-regulating Th1 and Th17 responses in C. rodentium-induced colitis in mice.

Effects of ß-adrenoceptor activation on haemodynamics during hypoxic stress in rats.

NEW FINDINGS: What is the central question of this study? The acute hypoxic compensatory reaction is based on haemodynamic changes, and ß-adrenoceptors are involved in haemodynamic regulation. What is the role of ß-adrenoceptors in haemodynamics during hypoxic exposure? What is the main finding and its importance? Activation of ß2 -adrenoceptors attenuates the increase in pulmonary artery pressure during hypoxic exposure. This compensatory reaction activated by ß2 -adrenoceptors during hypoxic stress is very important to maintain the activities of normal life. ABSTRACT: The acute hypoxic compensatory reaction is accompanied by haemodynamic changes. We monitored the haemodynamic changes in rats undergoing acute hypoxic stress and applied antagonists of ß-adrenoceptor (ß-ARs) subtypes to reveal the regulatory role of ß-ARs on haemodynamics. Sprague-Dawley rats were randomly divided into control, atenolol (ß1 -AR antagonist), ICI 118,551 (ß2 -AR antagonist) and propranolol (non-selective ß-AR antagonist) groups. Rats were continuously recorded for changes in haemodynamic indexes for 10 min after administration. Then, a hypoxic ventilation experiment [15% O2 , 2200 m a.sl., 582 mmHg (0.765 Pa), PO2 87.3 mmHg; Xining, China] was conducted, and the indexes were monitored for 5 min after induction of hypoxia. Plasma catecholamine concentrations were also measured. We found that, during normoxia, the mean arterial pressure, heart rate, ascending aortic blood flow and pulmonary artery pressure were reduced in the propranolol and atenolol groups. Catecholamine concentrations were increased significantly in the atenolol group compared with the control group. During hypoxia, mean arterial pressure and total peripheral resistance were decreased in the control, propranolol and ICI 118,551 groups. Pulmonary arterial pressure and pulmonary vascular resistance were increased in the propranolol and ICI 118,551 groups. During hypoxia, catecholamine concentrations were increased significantly in the control group, but decreased in ß-AR antagonist groups. In conclusion, the ß2 -AR is involved in regulation of pulmonary haemodynamics in the acute hypoxic compensatory reaction, and the activation of ß2 -ARs attenuates the increase in pulmonary arterial pressure during hypoxic stress. This compensatory reaction activated by ß2 -ARs during hypoxic stress is very important to maintain activities of normal life.

[Protective effects of endogenous carbon monoxide against myocardial ischemia-reperfusion injury in rats].

The present study is aimed to explore the effects of endogenous carbon monoxide on the ischemia-reperfusion in rats. Wistar rats were intraperitoneally injected with protoporphyrin cobalt chloride (CoPP, an endogenous carbon monoxide agonist, 5 mg/kg), zinc protoporphyrin (ZnPP, an endogenous carbon monoxide inhibitor, 5 mg/kg) or saline. Twenty-four hours after injection, the myocardial ischemia-reperfusion model was made by Langendorff isolated cardiac perfusion system, and cardiac function parameters were collected. Myocardial cGMP content was measured by ELISA, and the endogenous carbon monoxide in plasma and myocardial enzymes in perfusate at 10 min after reperfusion were measured by colorimetry. The results showed that before ischemia the cardiac functions of CoPP, ZnPP and control groups were stable, and there were no significant differences. After reperfusion, cardiac functions had significant differences among the three groups (P < 0.05). Compared with pre-ischemia, the cardiac function decreased and obvious cardiac arrest was shown in control and ZnPP groups, while the cardiac function in CoPP group did not change significantly, maintaining a relatively stable level. At the same time, three groups' carbon monoxide level, myocardial enzymology and the cardiac function recovery time after reperfusion also had significant differences (P < 0.05). Compared with those in control group, recovery after reperfusion was faster, activities of creatine kinase and lactic dehydrogenase were significantly decreased, plasma CO and myocardial cGMP contents were significantly increased in CoPP group, while these changes were completely opposite in ZnPP group. It is concluded that endogenous carbon monoxide can maintain cardiac function, shorten the time of cardiac function recovery, and play a protective role in cardiac ischemia-reperfusion.

[Intervention of Tibetan medicine--twenty wei chenxiang pill on elevation of hypoxic pulmonary arterial pressure in rats].

OBJECTIVE: To investigate the role of Tibetan medicine-Twenty Wei Chenxiang Pill interfering with serum ET-1 level, in order to confirm that ET-1 is involved to the pathogenesis of hypoxic pulmonary hypertension. METHODS: 165 Wistar rats were randomly divided into high altitude control group,Tibetan medicine-Twenty Wei Chenxiang Pill group and plain control group. The physiological signal acquisition system was used to record pulmonary arterial pressure, and RV/(LV + S) ratio were caculated. Serum HIF-1alpha and ET-1 protein levels were determined by the method of ELISA, and ETA protein levels in lung tissue were determined by Western Blot method. RESULTS: Compared with the high altitude group,in the rats of Tibetan medicine-Twenty Wei Chenxiang Pill group,the pulmonary arterial pressure decreased significantly from the seventh day and the seventh day (P < 0.01), the RV/(LV + S) ratio and serum HIF-1alpha levels decreased significantly from the third day (P < 0.05 or P < 0.01), the serum ET-1 levels decreased significantly from the third day (P < 0.05 or P < 0.01), and the expression of ETA protein decreased significantly from the beginning (P < 0.01 or P < 0.001). CONCLUSION: ET-1 is one of the important factors causing pulmonary artery pressure increasing and right ventricular wall thickening, which plays a role in hypoxic pulmonary artery only involved in the early period hypoxia, but not in the later period. Tibetan medicine--twenty Wei Chenxiang Pill can prevent the pulmonary artery hypertension and the right ventricular wall thickening in rats, and its mechanism may be related to the direct inhibition of ET-1 and protein levels of ETA or the indirect downregulation of ET-1 level and ETA through inhibition of HIF-la level.

Associations between interleukin-1 polymorphisms and gastric cancers among three ethnicities.

AIM: To investigate the associations between interleukin (IL)-1B and IL-1RN polymorphisms and gastric cancers among the Tibet, Hui and Han ethnicities. METHODS: Genomic DNA was extracted from peripheral blood of 210, 205, and 202 healthy volunteers and from 155, 158, and 197 gastric cancer patients from the Tibet, Hui, and Han populations, respectively. Polymorphisms in IL-1B and IL-1RN were analyzed by denaturing high-performance liquid chromatography. RESULTS: Carriers of the IL-1B-31 CC genotype had an increased risk of intestinal type gastric cancer [odds ratio (OR) = 2.17, P = 0.037] in the Tibet ethnicity. Carriers of the IL-1B 2/L genotype had an increased risk of both intestinal and diffuse types of gastric cancer (OR = 2.08, 2.31, P = 0.007, 0.016, respectively) in the Hui ethnicity. In the Han population, carriers of the IL-1B-31 CC, IL-1B-511CT, TT genotypes had increased risk of intestinal type gastric cancer (OR = 2.51, 2.74, 5.66, P = 0.005, 0.002, 0.000, respectively). CONCLUSION: IL-1B and IL-RN genotypes may differentially contribute to gastric cancer among the Tibet, Hui, and Han ethnicities in the Qinghai area of China.