Endogenous dipeptide-carnosine supplementation ameliorates hypobaric hypoxia-induced skeletal muscle loss via attenuating endoplasmic reticulum stress response and maintaining proteostasis.

High altitude is an environmental stress that is accompanied with numerous adverse biological responses, including skeletal muscle weakness and muscle protein loss. Skeletal muscle wasting is an important clinical problem, progressing to critical illness, associated with increased morbidity and mortality. The present study explores the protective efficacy of endogenous dipeptide, carnosine (CAR), supplementation in ameliorating skeletal muscle protein loss under hypobaric hypoxia (HH). Male Sprague-Dawley rats (n = 5) were randomly divided into control group, HH-exposed group (3 days HH exposure equivalent to 7,620 m), and HH-exposed rats supplemented with carnosine (3 days; 150 mg/kg b.w, orally) (HH + CAR). HH-exposed rats supplemented with CAR ameliorated HH-induced oxidative protein damage, lipid peroxidation, and maintained pro-inflammatory cytokines levels. HH-associated muscle protein degradative pathways, including calpain, ubiquitination, endoplasmic reticulum stress, autophagy, and apoptosis were also regulated in carnosine-supplemented rats. Further, the muscle damage marker, the levels of serum creatine phosphokinase were also reduced in HH + CAR co-supplemented rats which proved the protective efficacy of CAR against hypobaric hypoxia-induced muscle protein loss. Altogether, CAR supplementation ameliorated HH-induced skeletal muscle protein loss via performing multifaceted ways, mainly by maintaining redox homeostasis and proteostasis in skeletal muscle.

Ginkgo biloba L. Prevents Hypobaric Hypoxia-Induced Spatial Memory Deficit Through Small Conductance Calcium-Activated Potassium Channel Inhibition: The Role of ERK/CaMKII/CREB Signaling.

Hypobaric hypoxia (HH) is a stressful condition, which is more common at high altitudes and can impair cognitive functions. Ginkgo biloba L. leaf extract (GBE) is widely used as herbal medicine against different disorders. Its ability to improve cognitive functions, reduce oxidative stress, and promote cell survival makes it a putative therapeutic candidate against HH. The present study has been designed to explore the effect of GBE on HH-induced neurodegeneration and memory impairment as well as possible signaling mechanisms involved. 220-250 gm (approximately 6- to 8-week-old) Sprague Dawley rats were randomly divided into different groups. GBE was orally administered to respective groups at a dose of 100 mg/kg/day throughout the HH exposure, i.e., 14 days. Memory testing was performed followed by hippocampus isolation for further processing of different molecular and morphological parameters related to cognition. The results indicated that GBE ameliorates HH-induced memory impairment and oxidative damage and reduces apoptosis. Moreover, GBE modulates the activity of the small conductance calcium-activated potassium channels, which further reduces glutamate excitotoxicity and apoptosis. The exploration of the downstream signaling pathway demonstrated that GBE administration prevents HH-induced small conductance calcium-activated potassium channel activation, and that initiates pro-survival machinery by activating extracellular signal-regulated kinase (ERK)/calmodulin-dependent protein kinase II (CaMKII) and the cAMP response element-binding protein (CREB) signaling pathway. In summary, the current study demonstrates the beneficial effect of GBE on conditions like HH and provides various therapeutic targets involved in the mechanism of action of GBE-mediated neuroprotection.

Coronavirus Disease 2019 (COVID-19): Research, Clinical Knowledge, and Preventive Measures.

In early December 2019, a novel coronavirus disease 2019 (COVID-19), the global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) commenced in Wuhan, China, and WHO declared the outbreak a pandemic and Public Health Emergency of International Concern. An ample number of clinical trials with multiple drugs is underway to overcome the current perilous condition. Still, the situation is alarming with no therapeutic measure in our hand at present. Keeping the present scenario in mind, this review comprises the research, clinical knowledge, and repurposed herbals with regard to COVID-19. Preventive measures such as yoga, nasal breathing, and herbal administration could also provide protection and beneficial effects against coronavirus. Innumerable clinical trials are ongoing to manage COVID-19 and the drugs were selected on the basis of life cycle of coronavirus. The selection of herbals was done on the basis of the previous reported pharmacological activities and docking study. The results concluded that garlic, liquorice, and Ashwagandha have a potential against SARS-CoV-2, which was further proved via a docking study and their reported biological functions. The very well-known fact "prevention is always better than cure" is applied to overcome with coronavirus infection. It is expected that following the preventive measures could impede or lessen the adverse effect of SARS-CoV-2.

Trace Element Zinc, a Nature's Gift to Fight Unprecedented Global Pandemic COVID-19.

With the advent of twenty-first century, we are in cruel grip of a pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the associated illness being called as COVID-19. Since its outbreak in December 2019 in Wuhan, China, there are no medicines to cure the disease till date. Based on their experience, scientists say that developing a coronavirus vaccine could take at least a year. There are many steps in place before the vaccine comes for the distribution like its safety and cost-effectiveness, especially for the developing countries. In this scenario, the only way to prevent the disease is by following certain safety guidelines and to boost up the body's immune system. Zinc, a crucial trace element involved in several biological and metabolic processes, has been found to play a pivotal role in promoting and appropriately regulating the host defense mechanisms against viral infections. Zinc is naturally present in some foods, fortified in others and also available as dietary supplement. The current RDA (Recommended Daily Allowance) of zinc is 12 and 10 mg for males and females respectively. Zinc is the second most common trace mineral after iron in the cell. It is present in all organs and tissues in the body as it forms catalytic component of all 6 classes of enzymes encompassing almost 2000 enzymes in the body. Zinc is biologically essential for cellular processes, including growth and development, as well as DNA synthesis and RNA transcription. Zinc deficiency results in a number of metabolic changes besides a compromised immune system. In this review, the role of zinc in regulating the host defense and viral replication is being discussed with the main focus on COVID-19.

Andrographolide attenuates complete freund's adjuvant induced arthritis via suppression of inflammatory mediators and pro-inflammatory cytokines.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional plant-derived medicines have enabled the mankind in curing the wide spectrum of diseases throughout the ages. Andrographis paniculata (Burm.f.) Nees, is one of the traditional plant used as a folk medicine for the management of inflammation, arthritis, viral-bacterial infections and other ailments in India, China, Malaysia and other South-East Asian countries. Its major bioactive compound; andrographolide, a diterpenoid, also exerts cytoprotective properties and is reported to be effective in neuroprotection, hepatoprotection, etc. AIM: The study is aimed to explore the role of andrographolide in treatment of complete freund's adjuvant (CFA) induced arthritis. MATERIALS AND METHODS: The influx of immune cells, release of pro-inflammatory cytokines and subsequent accumulation of synovial fluid (swelling) and pain manifest into the disease. The present study used CFA induced Balb/c mice model and treated them intraperitoneally with andrographolide and dexamethasone (used as a positive control) on alternate days for six days. After 6 days, blood and peritoneal macrophages were collected to evaluate the expression of various arthritic markers and paw edema was measured on all days. RESULTS: The in vitro and ex vivo experiments showed that andrographolide treated animal group had reduced paw edema, cell cytotoxicity and nitric oxide production than dexamethasone treated animal group. Further, the study revealed the mechanistic role of andrographolide in treatment of arthritis by suppressing battery of molecules like COX-2, NF-κB, p-p38, CD40, TNF-α, IL-1ß and IL-6 involved in arthritis. CONCLUSION: The study showed the potent anti-arthritic effects of andrographolide and warrants further investigations on andrographolide for the development of safe and effective anti-arthritic drug.

Google trend analysis of climatic zone based Indian severe seasonal sensitive population.

BACKGROUND: Our earlier Google Trend (GT) Analytics study reported that the worldwide human population severely subject to four seasonal (sensitive) comorbid lifestyle diseases (SCLD) such as asthma, obesity, hypertension and fibrosis. The human population subject to seasonal variability in these four diseases activity referred as "severe seasonal sensitive population". In India, the estimated burden of these four seasonal diseases is more than 350 million as on the year 2018. It is a growing crisis for India with a projected disease burden of 500 million in the year 2025. This study was aimed to decipher the genuine SCLD seasonal trends in the entire Indian population using GT and validate these trends in Indian climatic zones. METHODS: GT is used to study the temporal trends in web search using weekly Relative Search Volume (RSV) for the period 2004 to 2017. The relative search volume (RSV) of the four-severe seasonal comorbid diseases namely Asthma, Hypertension, Obesity and Fibrosis were collected with and without obesity as the reference. The RSV were collected using the GT selection options as (i) Whole India (ii) Jammu and Kashmir (Cold zone) (iii) Rajasthan (Hot and Dry zone) (iii) West Bengal (Hot and Humid zone) and (iv) Uttar Pradesh state (Composite zone). The time series analysis was carried out to find seasonal patterns, comorbidity, trends and periodicity in the entire India and four of its states (zones). RESULTS: Our analysis of entire India (2004-2017) revealed high significant seasonal patterns and comorbidity in all the four diseases of SCLD. The positive tau values indicated strong positive seasonal trends in the SCLD throughout the period (Table). The auto correlation analysis revealed that these diseases were subjected to 3, 4 and 6 months period seasonal variations. Similar seasonal patterns and trends were also observed in all the four Indian temperature zones. Overall study indicated that SCLD seasonal search patterns and trends are highly conserved in India even in drastic Indian climatic zones. CONCLUSIONS: The clinical outcome arise out of these observations could be of immense significance in handling the major chronic life style diseases asthma, hypertension, obesity and fibrosis. The possible strong comorbid relationship among asthma, hypertension, obesity and fibrosis may be useful to segregate Indian seasonal sensitive population. In disease activity-based chronotherapy, the search interest of segment of the population with access to Internet may be used as an indicator for public health sectors in the early detection of SCLD from a specific country or a region. As this disease population could be highly subject to the adverse effect of seasons in addition to life style and other environmental factors. Our study necessitates that these Indian populations need special attention from the Indian health care sectors.

Effects of Pulsed 810 nm Al-Ga-As Diode Laser on Wound Healing Under Immunosuppression: A Molecular Insight.

BACKGROUND AND OBJECTIVES: Dysregulated inflammation is one of the major contributing factors for the prevalence of non-healing chronic wound in immunosuppressed subjects. Photobiomodulation (PBM) has emerged as a potential non-thermal, light-based therapeutic healing intervention for the treatment of impaired wounds. STUDY DESIGN/MATERIALS AND METHODS: The present study delineates the underlying molecular mechanisms of PBM 810 nm laser-induced full-thickness cutaneous wound repair in immunosuppressed rats at continuous and pulsed wave-mode with power-density of 40 mW/cm 2 , fluence 22.6 J/cm 2 for 10 minutes daily for 7 post-wounding days. Molecular markers were assessed using biochemical, enzyme-linked immunosorbent assay quantification, enzyme kinetics and immunoblots analyses pertaining to inflammation, oxidative stress, cell survival, calcium signaling, and proliferation cascades. RESULTS: Results distinctly revealed that pulsed 810 nm (10 Hz) PBM potentially influenced the cell survival and proliferation signaling pathway by significantly upregulated phospho-protein kinase B(phospho-Akt), phospho-extracellular-signal-regulated kinase 1 (ERK1), transient receptor potential vanilloid-3 (TRPV3), Ca2+ , calmodulin, transforming growth factor-ß1 (TGF-ß1), TGF-ßR3, and Na + /K + -ATPase pump levels. PBM treatment resulted in reduction of exaggerated inflammatory responses evident by significantly repressed levels of interleukin-1ß (IL-1ß), IL-6, cyclooxygenase 2 (COX-2), and substance-P receptor (SPR), as well as inhibited apoptotic cell death by decreasing p53, cytochrome C, and caspase 3 levels (P < 0.05), which, in turn, effectively augment the wound repair in immunosuppressed rats. PBM treatment also lowered 4-hydroxynoneal (HNE) adduct level and NADP/NADPH ratio and upregulated the GRP78 expression, which might culminate into reduced oxidative stress and maintained the redox homeostasis. CONCLUSIONS: Taken together, these findings would be helpful in better understanding of the molecular aspects involved in pulsed 810 nm laser-mediated dermal wound healing in immunosuppressed rats through regulation of cell survival and proliferation via Ca2+ -calmodulin, Akt, ERK, and redox signaling. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Methanolic root extract of Codonopsis clematidea prevents hypoxia induced procoagulant state by inhibition of GPIb receptor regulated Lyn kinase activation.

BACKGROUND: The prevalence of procoagulant state under prolonged hypoxic exposures and the complications and lack of specificity associated with use of existing anti-thrombotic agents have necessitated the search for safer and natural therapeutics. Codonopsis, a widely studied medicinal herb, has been reported to decrease whole blood viscosity but the bioactive ingredients involved, and their mechanism of action therein however remain to be investigated. PURPOSE: The present study aimed at evaluating the efficacy of C. clematidea root extract and mechanism of action of its bioactive constituent flavonoid, Kaempferol, in ameliorating hypobaric hypoxia induced procoagulant state. METHODS: Fingerprinting analysis of methanolic extract of C. clematidea root was performed by RP-HPLC. In vitro toxicity study was conducted using HUVEC cell line and in vivo acute and sub-acute toxicity were done according to OECD guidelines (section-4, number-420 and 407 respectively). Adult male Sprague-Dawley rats weighing 230-250 g were exposed to global hypoxia simulating an altitude of 7600 m (282 mmHg), in animal decompression chamber for 3, 7, 14 and 21 days for in vivo studies. Dose optimisation of the extract was done by quantification of Thromboxane A2 in the serum of hypoxic rats. C. clematidea root extract was also evaluated for its in vitro and in vivo antioxidant properties. Procoagulant changes were studied by biochemical plasma coagulation assays and expression analysis of the signalling molecules of the platelet activation cascade like vWF, platelet activation marker CD41, GpIb-IX-V (CD42), Lyn kinase, p-PI3K, p-ERK and p-PLCγ were conducted to investigate C. clematidea mediated signalling mechanisms. RESULTS: Methanolic extract of C. clematidea root showed improved antioxidant status and improvement in bleeding time and in vitro coagulation assays like pT, aPTT, INR. Decreased concentrations of D-Dimers along with that of platelet activation marker CD41 and serum concentration of Thromboxane A2 were observed in C. clematidea root extract supplemented hypoxic animals. Phosphorylation of Lyn kinase, was reduced despite increase in concentration of activating ligand vWF. CONCLUSION: C. clematidea root extract was effective in preventing hypoxia induced platelet activation and resultant procoagulant state by inhibiting Lyn kinase, a serine threonine kinase effector of vWF signalling cascade.

Evaluation of anti-dengue activity of Carica papaya aqueous leaf extract and its role in platelet augmentation.

Dengue disease is characterized by a marked decrease in platelet count, which is life threatening. In the present study, we investigated the antiviral activity of an aqueous extract of Carica papaya leaves (PLE) against dengue virus (DENV) and its effect on platelet augmentation. The anti-dengue activity of PLE in DENV-infected THP-1 cells was examined by immunoblotting and flow cytometry. The effect of PLE on erythrocyte damage was investigated using hemolytic and anti-hemolytic assays. Virus-infected THP-1 cells were assayed for IFN-α secretion. The effect of PLE on platelet augmentation in rats with cyclophosphamide-induced thrombocytopenia was also investigated. The platelet count of blood from the retro-orbital plexus of rats was determined on the 1st, 4th, 7th, 11th and 14th day of study. On the 14th day, the rats were sacrificed for histopathological examination of the liver, kidney and spleen. Plasma of thrombocytopenic rats was tested for thrombopoietin (TPO) and IL-6 secretion. The data suggest that PLE significantly decreases the expression of the envelope and NS1 proteins in DENV-infected THP-1 cells. A marked decrease in intracellular viral load upon PLE treatment confirmed its antiviral activity. This also resulted in a significant decrease in erythrocyte damage and hydrogen-peroxide-induced lipid peroxidation. A significant increase in the number of platelets was found in thrombocytopenic rats treated with PLE, along with an increase in IL-6 and TPO levels. These findings suggest that PLE can potentially be used as an antiviral agent, as it helps in platelet augmentation and exhibits antiviral activity against DENV.

Hippophae rhamnoides as novel phytogenic feed additive for broiler chickens at high altitude cold desert.

Extremes of climate and hypobaric hypoxia cause poor growth performance in broiler chickens at high altitude. The present study examined the potential of Hippophae rhamnoides extract as phytogenic feed additive for broilers reared at 3500 m above mean sea level (MSL). Higher content of phytomolecules were recorded during characterization of the extract. Immunomodulatory activity of extract was observed in chicken lymphocytes through in-vitro studies. Thereafter, for in vivo study, 105 day old Rhode Island Red (RIR) Cross-bred chicks were randomly distributed in to control and treatments T1, T2, T3, T4, T5, and T6 which were supplemented with H. rhamnoides aqueous extract along with basal diet, at level of 100, 150, 200, 300, 400, and 800 mg/kg body weight of chicken, respectively. Among the experimental groups, birds in the T3 group represent the highest body weight. Furthermore, treatment group birds had shown better physio-biochemical indices as compared to control group birds. Interestingly, lower mortality rate due to ascites and coccidiosis was recorded in treatment groups and therefore, higher net return was observed. Hence, present investigation demonstrated the beneficial effect of H. rhamnoides extract (@200 mg/kg) at high altitude and therefore, may be used in formulation of feed additive for poultry ration.

Effect of seabuckthorn seed oil in reducing cardiovascular risk factors: A longitudinal controlled trial on hypertensive subjects.

BACKGROUND & AIMS: The present study aimed at investigating whether dietary supplementation of seabuckthorn seed oil which is rich in omega fatty acids at an oral dose of 0.75 ml could affect cardiovascular risk factors and reduce hypertension and systolic blood pressure. METHODS: Toxicological evaluation and efficacy of seabuckthorn seed oil in reducing high fat diet induced dyslipidemia was initially conducted on adult male Sprague Dawley rats. 32 normal and 74 hypertensive and hypercholestrolemic human subjects participated in the randomized, controlled, double blind longitudinal study. Seabuckthorn seed oil or sunflower oil placebo was orally supplemented at a daily dose of 0.75 ml for 30 days. RESULTS: Supplementation of seabuckthorn seed oil at a daily dose of 0.75 ml for 30 days resulted in normalization of blood pressure in hypertensive subjects. Dietary supplementation of seabuckthorn seed oil markedly reduces cholesterol, oxy-LDL and triglycerides in hypercholesterolemic subjects though it's effect on subjects with normal blood pressure and cholesterol is less pronounced. Seabuckthorn seed oil supplementation also improves circulatory antioxidant status in both normal and hypertensive subjects. CONCLUSION: The present study demonstrates the efficacy of seabuckthorn seed oil in reducing dyslipidemia, cardiovascular risk factors and hypertension in human population which may be due to presence of omega 3, 6 and 9 fatty acids in the oil. The improvement in antioxidant status can be attributed to presence of beta carotene and vitamin E in seabuckthorn seed oil. The trial was registered with Clinical Trial Registry of India (Clinical trial registration number - CTRI/2015/11/006368).