A bioactive and biodegradable vitamin C stearate-based injectable hydrogel alleviates experimental inflammatory arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory joint disorder affecting nearly 1% of the global population. In RA, synovial joints are infiltrated by inflammatory mediators and enzymes, leading to articular cartilage deterioration, joint damage, and bone erosion. Herein, the 9-aminoacridine-6-O-stearoyl-L-ascorbic acid hydrogel (9AA-SAA hydrogel) was formulated by the heat-cool method and further characterized for surface charge, surface morphology, rheology, and cytocompatibility. Furthermore, we evaluated the therapeutic efficacy of the 9AA-SAA hydrogel, an enzyme-responsive drug delivery system with on-and-off switching capabilities based on disease severity against collagen-induced experimental arthritis in Wistar rats. The anti-inflammatory action of the US FDA-approved drug 9-aminoacridine (9AA) was revealed which acted through nuclear receptor subfamily 4 group A member 1 (NR4A1), an anti-inflammatory orphan nuclear receptor that inhibits nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). Furthermore, we have explored the role of ascorbic acid, an active moiety of 6-O-stearoyl-L-ascorbic acid (SAA), in promoting the production of collagen production through ten-eleven translocation-2 (TET2) upregulation. Targeting through NR4A1 and TET2 could be the probable mechanism for the treatment of experimental arthritis. The combination of 9AA and ascorbic acid demonstrated enhanced therapeutic efficacy in the 9AA-SAA hydrogel, significantly reducing the severity of experimental arthritis. This approach, in contrast to existing treatments with limited effectiveness, presents a promising and more effective strategy for RA treatment by mitigating inflammation in experimental arthritis.

Novel Flow Cytometry-Based Method for Detection of Anti-HLA Complement Activating Donor-Specific Antibodies in Renal Transplant Recipients and Its Comparison With Other Conventional Detection Methods.

BACKGROUND: Presence of preformed donor specific antibodies (DSAs) detected by complement-dependent cytotoxicity (CDC-XM) is a strong contraindication for transplant. However, it has limitations including its sensitivity and its inability to distinguish between HLA-specific and other non-HLA-specific antibodies. In this study, we standardized CDC-XM by flow cytometry and determined its relevance by comparing its results with other methods of DSA detection, such as routine CDC-XM, antibody binding assay by flow cytometry (FC-XM), and Luminex-based crossmatch assays, such as Luminex crossmatch (LXM) and virtual crossmatch (VXM). MATERIALS AND METHODS: A total of 79 serum samples were tested for DSAs by the flow cytometric complement-dependent cytotoxicity crossmatch assay (FC-CDC-XM) and then the results of FC-CDC-XM were compared with other detection methods such as CDC-XM, FC-XM, LXM, and VXM. RESULTS: We found that the FC-CDC-XM assay is more sensitive than routine CDC-XM. Out of total 79 sera, 24 sera were detected positive (T cells positive: 1 case and B cells positive: 23) by FC-CDC-XM as compared with 3 sera using CDC-XM; these 3 sera also showed positivity by FC-CDC-XM. After FC-XM assay, 23 samples were positive by FC-XM and out of these 23 samples, 13 were also positive by FC-CDC-XM. On comparing the FC-CDC-XM results with VXM and LXM, 10 sera of 24 FC-CDC-XM positive had HLA class II antibodies detected on a Luminex platform. CONCLUSIONS: The FC-CDC-XM is a more sensitive and specific method for detection of HLA-specific complement-fixing antibodies than CDC-XM and FC-XM. FC-CDC-XM should be used in tissue-typing laboratories after intra- and inter- laboratory validation.

Unique mutations in mitochondrial DNA and associated pathways involved in high altitude pulmonary edema susceptibility in Indian lowlanders.

High altitude pulmonary edema (HAPE) is a life threatening non-cardiogenic pulmonary edema that occurs in an otherwise healthy individuals travelling to altitude above 2500 m. Earlier studies have reported association of mutations in nuclear (nDNA) and mitochondrial DNA (mtDNA) with HAPE susceptibility. However, the molecular mechanisms involved in the pathobiology of HAPE have not been fully understood. The present study investigates the genetic predisposition to HAPE by analyzing the mtDNA mutations in HAPE susceptibles (n = 23) and acclimatized controls (n = 23) using next generation sequencing. Structural analysis of mutations was done using SWISS Model server and stability was determined using ΔΔG values. Meta-analysis of GSE52209 dataset was done to identify differentially expressed genes (DEGs) in HAPE susceptibles and acclimatized controls. Fourteen non-synonymous, conserved and pathogenic mutations were predicted using SIFT and PolyPhen scoring in protein coding genes, whereas six mutations in mt-tRNA genes showed association with HAPE (p ≤ 0.05). The structural analysis of these mutations revealed conformational changes in critical regions in Complexes I-V which are involved in subunit assembly and proton pumping activity. The protein-protein interaction network analysis of DEGs showed that HIF1α, EGLN2, EGLN3, PDK1, TFAM, PPARGC1α and NRF1 genes form highly interconnected cluster. Further, pathway enrichment analysis using DAVID revealed that "HIF-1 signaling", "oxidative phosphorylation" and "Metabolic pathways" had strong association with HAPE. Based on the findings it appears that the identified mtDNA mutations may be a potential risk factor in development of HAPE with the associated pathways providing mechanistic insight into the understanding of pathobiology of HAPE and sites for development of therapeutic targets.Communicated by Ramaswamy H. Sarma.

Surya Namaskar: As an Alternative for Aerobic Fitness.

Context: "Surya Namaskar" (SN) may be used as a need-based short-duration aerobic activity in a confined space to establish as a substitute of an equivalent routine physical training in challenging stressful conditions. Materials and Methods: Noninvasive oxygen-kinetics metabolic responses between SN and endurance work on bicycle ergometry (BE) were compared across different phases of maximal oxygen uptake percentage (%VO2 max). SN, comprising three complete rounds per min (36 beats/min of a metronome; SN consists of 12 poses per round), was performed rhythmically and continuously for 5 min to simulate an incremental BE test (25 watts/2 min at 60 rpm). Results: SN results in a significant (P < 0.05) greater increase of arteriovenous oxygen difference at 71%-80% VO2 max while keeping a low respiratory exchange ratio (P < 0.01 and 0.001) at 41%-80% VO2 max exercising state. Conclusions: SN could be an ideal form of aerobic exercise instead of BE.

Elucidating the combined effect of intermittent hypoxia training and acetazolamide on hypoxia induced hematological and physiological changes.

As the number of people travelling to altitude increases, the risk of life threatening medical emergencies also increases. It is important that we have effective strategies to minimize the risk of altitude illness. In this study, an attempt was made to investigate the combined effect of non-pharmacological (Intermittent hypoxia training; IHT) and pharmacological (acetazolamide; ACZ) intervention as a prophylactic strategy in order to minimize the risk of high altitude hypoxic related problems using rats as an animal model. Male Sprague Dawley rats were subjected to IHT for 4 h consecutively for 5 days at 12% FiO2 under normobaric conditions with and without oral ACZ administration at 25 mg/kg body weight. Validation of the intervention was performed by exposing the rats to extreme hypoxia (EH) at 8% FiO2 to further assess the effect of IHT and ACZ on hypoxic acclimatization. The principal findings of this study is that the combined effect of IHT and ACZ improves the arterial oxygenation by alterations in hemodynamics and in blood gasometry, thereby resulting into an increase in the oxygen carrying capacity of the blood with increase in SpO2 (peripheral oxygen saturation). The present study showed that the combined effect of IHT with ACZ could be refined as a prophylactic measure for better outcomes during altitude ascent and rapid altitude acclimatization rather than IHT or ACZ alone.

Aberrant promoter hypermethylation regulates thrombomodulin in high altitude induced deep vein thrombosis.

BACKGROUND: DNA methylation regulates gene expression by inhibiting transcription factor binding to promoter and regulatory regions. Acute hypoxia during altitude exposure is associated with decreased natural anticoagulants and morbid thrombotic events. Thrombomodulin (TM) is a high affinity thrombin binding receptor protein, vital for vascular homeostasis. The purpose of this study is to determine gene expression regulation via methylation of TM gene in high altitude hypoxia induced deep vein thrombosis (DVT) patients. MATERIALS AND RESULTS: Percent 5-methyl cytosine analysis showed increased methylation in high altitude DVT patients (HAP) as compared to high altitude control (HAC) and seal level control (Control) subjects, while TM protein and mRNA levels were decreased in high altitude DVT patients as compared to other two groups. Bisulfite sequencing analysis indicated increased methylation in TM promoter in high altitude DVT patients compared to high altitude controls. Flow cytometry analysis showed decreased TM expression in hypoxia induced primary human umbilical vein endothelial cells (HUVECs). Treatment with specific DNA methyltransferase (DNMT) inhibitor-decitabine during hypoxia, restored TM expression. in vitro global methylation assay showed increased methylation in hypoxia group. Specific concentration of decitabine in hypoxia decreased global methylation showing a direct correlation between DNMTs and methylation. Selective dose of decitabine restored TM levels in HUVECs. DNMT1 and DNMT3B proteins showed to mediate the overall expression of TM. CONCLUSION: TM emerged as a potential candidate for methylation in high altitude DVT patients, regulated by hypoxia-induced epigenetic mechanism. Hypoxia culminates in methylation of DNA sequences in the promoter region of TM gene and increased the expression of DNMT1 and DNMT3B per se in primary HUVECs. Critical DNA methylation events were found to be compromised in high altitude DVT patients.

Health Risk Assessment of Heavy Metals Due to Wheat, Cabbage, and Spinach Consumption at Cold-Arid High Altitude Region.

Soil and water from the trans-Himalayan high-altitude region contain high concentrations of various heavy metals. Vegetables and cereals such as cabbage, spinach, and wheat are most prone to heavy metal accumulation from soil and water which can be toxic for human consumption. It has yet to be studied how consumption of vegetables and cereal with excess heavy metal content can affect human health in high altitude areas. To this end, the objectives of this study are (a) quantify the concentrations of Aluminum (Al), Iron (Fe), Cobalt (Co), Boron (B), Lead (Pb), Arsenic (As), Cadmium (Cd), Selenium (Se), Copper (Cu), and Zinc (Zn) in three crops (wheat, cabbage, and spinach), and (b) evaluate the health risk of excess dietary heavy metal consumption in the local adult population using non-carcinogenic and carcinogenic parameters. A total of 60 samples were analyzed for minerals and potentially toxic elements using Inductively Coupled Plasma-Optical Emission Spectrometry (ICP-OES). Results found that spinach has a high mineral content than wheat and cabbage. The estimated daily intake (EDI) of each metal in each crop was less than the limit of permissible value. The hazard index (HI) of three plant species, and target hazard quotient (THQ) were less than the threshold level (< 1). The carcinogenic risk (CR) value in all the crops was less than the unacceptable risk level (1 × 10-4). These findings suggest that consumption of wheat, spinach, and cabbage does not have any significant effect on human health due to presence of elevated heavy metals at this high altitude region. .

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.

Probiotics maintain the gut microbiome homeostasis during Indian Antarctic expedition by ship.

Ship voyage to Antarctica is a stressful journey for expedition members. The response of human gut microbiota to ship voyage and a feasible approach to maintain gut health, is still unexplored. The present findings describe a 24-day long longitudinal study involving 19 members from 38th Indian Antarctic Expedition, to investigate the impact of ship voyage and effect of probiotic intervention on gut microbiota. Fecal samples collected on day 0 as baseline and at the end of ship voyage (day 24), were analyzed using whole genome shotgun sequencing. Probiotic intervention reduced the sea sickness by 10% compared to 44% in placebo group. The gut microbiome in placebo group members on day 0 and day 24, indicated significant alteration compared to a marginal change in the microbial composition in probiotic group. Functional analysis revealed significant alterations in carbohydrate and amino acid metabolism. Carbohydrate-active enzymes analysis represented functional genes involved in glycoside hydrolases, glycosyltransferases and carbohydrate binding modules, for maintaining gut microbiome homeostasis. Suggesting thereby the possible mechanism of probiotic in stabilizing and restoring gut microflora during stressful ship journey. The present study is first of its kind, providing a feasible approach for protecting gut health during Antarctic expedition involving ship voyage.

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.

Assessment of nitric oxide (NO) potential to mitigate COVID-19 severity.

Novel coronavirus disease by SARS-CoV-2 virus (also known as COVID-19) has emerged as major health concern worldwide. While, there is no specific drugs for treating this infection till date, SARS-CoV-2 had spread to most countries around the globe. Nitric oxide (NO) gas serves as an important signaling molecule having vasodilatory effects as well as anti-microbial properties. Previous studies from the 2004 SARS-CoV infection demonstrated that NO may also help to reduce respiratory tract infection by inactivating viruses and inhibiting their replication cycle and is an effective supportive measure for treating infection in patients with pulmonary complications. NO gas inhalation is being suggested as potential therapy for managing severe acute respiratory distress syndrome in COVID-19 patients. In view of COVID-19 pandemic, several clinical trials are underway to examine the effects of NO inhalation on infected patients. Previously published reports on beneficial effects of endogenous NO and NO inhalation therapy were thoroughly searched to assess the potential of NO therapy for treating COVID-19 patients. Present report summarized the therapeutic importance of NO to reverse pulmonary hypertension, restore normal endothelial activity and produce anti-thrombotic effects. In addition to this, NO also reduces viral infection by inhibiting its replication and entry into the host cell. In absence of vaccine and effective treatment strategies, we suggest that NO inhalation therapy and NO releasing foods/compounds could be considered as an alternative measure to combat COVID-19 infection.

Potential association of COVID-19 and ABO blood group: An Indian study.

Coronavirus disease 2019 (COVID-19) transmits from person to person mainly through respiratory droplets and coughing. Infection severity ranges from asymptomatic and mild infection to those with moderate and severe symptoms which may lead to multiple organ failure and mortality. Infection severity largely depends on individual's immune response, age and co-morbidities. Present study categorized COVID-19 infected patients based on their infection severity and linked COVID-19 severity with age, gender and ABO blood group types. Clinical details of 383 COVID-19 patients were collected from Rajiv Gandhi Super Specialty hospital (RGSSH), India; divided into three groups; mild, moderate and severe patients, based on their symptoms. Present analysis revealed that age plays major role in infection severity, as the symptoms are more severe in patients above 45 years. Infection rate was higher in males compared to females. Most patients with A(+ve) and B(+ve) blood group were severely affected compared to those of blood group type O(+ve) and AB(+ve). O(+ve) blood group was least represented in severe patients. Present findings could be helpful in generating awareness amongst the population regarding susceptibility towards the COVID-19 infection. This supportive information would help clinicians and health workers to propose new strategies and tactical solution against COVID-19 infection.

Hypoxia-mediated alterations in pulmonary surfactant protein expressions: Beneficial effects of quercetin prophylaxis.

We have compared the prophylactic efficacies of quercetin and salbutamol in preventing pulmonary surfactants oxidation under hypoxia. Male SD rats supplemented orally with quercetin (50 mg/Kg BW) and salbutamol (2 mg/Kg BW) were exposed to hypobaric hypoxia (7,620 m for 6 h). Hypoxia-mediated elevation in oxidative stress, inflammation, and extravasations of LDH & albumin content in BALF of rats were assessed. Western blotting and mRNA studies determined the differential expressions of Nrf-2, HO-1, and associated surfactant proteins (SP-A, SP-B, SP-C, & SP-D) in rat lungs. Later, the lung configuration under hypoxia was assessed histopathologically. Quercetin and salbutamol pretreatment considerably restored the expressions of Nrf-2, HO-1, and surfactant proteins to normal by attenuating the increase in oxidative stress, inflammation, and extravasations of plasma proteins in the animals under hypoxia. The histopathology has also evidenced the protective effect of quercetin in retaining normal lung architecture under hypoxia over salbutamol. The present study indicates the effectiveness of quercetin prophylaxis in preventing pulmonary surfactants oxidation under hypoxia over salbutamol.

Robust immunity induced by multi-epitope DnaK peptides, potential vaccine candidates against Salmonella: An in vitro study.

Enteric fever is a common yet serious issue, most troublesome in underdeveloped and developing nations affecting all age group primarily children. Pitfalls of existing vaccines along with rapidly rising Multi-Drug-Resistant Salmonella strains necessitate the need for the development of new vaccine candidates having potential to provide complete protection. Several vaccine strategies are being pursued to stimulate protective immunity against typhoid, including conjugate vaccines for the elicitation of cellular and humoral responses as both arms of immunity are essential for complete protection. Bacterial HSPs are highly immunogenic to produce humoral and cellular immune responses. In this study, we are reporting in vitro immunostimulatory activity of immunodominant multi-epitope protective antigenic DnaK peptides identified earlier by immunoinformatics approach. Remarkable increase in antibody titer, lymphocyte proliferation, cytokines and NO level with individual /mixture of DnaK peptides as compared to control demonstrate immunogenic potential of these peptides that effectively augments both humoral and cellular immune responses. None of the peptides cause any hemolysis in human RBCs. Overall; our findings strongly elucidate the immune-stimulatory potential of DnaK peptides to be explored as potent vaccine candidates against multiple pathogens.

Mitochondrial DNA mutations contribute to high altitude pulmonary edema via increased oxidative stress and metabolic reprogramming during hypobaric hypoxia.

High altitude pulmonary edema (HAPE) is experienced by non-acclimatized sea level individuals on exposure to high altitude hypoxic conditions. Available evidence suggests that genetic factors and perturbed mitochondrial redox status may play an important role in HAPE pathophysiology. However, the precise mechanism has not been fully understood. In the present study, sequencing of mitochondrial DNA (mtDNA) from HAPE subjects and acclimatized controls was performed to identify pathogenic mutations and to determine their role in HAPE. Hypobaric hypoxia induced oxidative stress and metabolic alterations were also assessed in HAPE subjects. mtDNA copy number, mitochondrial oxidative phosphorylation (mtOXPHOS) activity, mitochondrial biogenesis were measured to determine mitochondrial functions. The data revealed that the mutations in Complex I genes affects the secondary structure of protein in HAPE subjects. Further, increased oxidative stress during hypobaric hypoxia, reduced mitochondrial biogenesis and mtOXPHOS activity induced metabolic reprogramming appears to contribute to mitochondrial dysfunctions in HAPE individuals. Haplogroup analysis suggests that mtDNA haplogroup H2a2a1 has potential contribution in the pathobiology of HAPE in lowlanders. This study also suggests contribution of altered mitochondrial functions in HAPE susceptibility.

Elucidating the role of hypoxia/reoxygenation in hippocampus-dependent memory impairment: do SK channels play role?

Professionals and mountaineers often face the problem of reperfusion injury due to re-oxygenation, upon their return to sea-level after sojourn at high altitude. Small conductance calcium-activated potassium channels (SK channels) have a role in regulating hippocampal synaptic plasticity. However, the role of SK channels under hypoxia-reoxygenation (H/R) is unknown. The present study hypothesized that SK channels play a significant role in H/R induced cognitive dysfunction. Sprague-Dawley rats were exposed to simulated HH (25,000 ft) continuously for 7 days followed by reoxygenation periods 3, 6, 24, 48, 72 and 120 h. It was observed that H/R exposure caused impairment in spatial memory as indicated by increased latency (p < 0.001) and pathlength (p < 0.001). The SK1 channel expression increased upon HH exposure (102.89 ± 7.055), which abrogated upon reoxygenation. HH exposure results in an increase in SK2 (CA3, 297.67 ± 6.69) and SK3 (CA1, 246 ± 5.13) channels which continued to increase gradually upon reoxygenation. The number of pyknotic cells (24 ± 2.03) (p < 0.01) and the expression of caspase-3 increased with HH exposure, which continued in the reoxygenation group (177.795 ± 1.264). Similar pattern was observed in lipid peroxidation (p < 0.001), LDH activity (p < 0.001) and ROS production (p < 0.001). A positive correlation of memory, cell death and oxidative stress indicates that H/R exposure increases oxidative stress coupled with SK channel expression, which may play a role in H/R-induced cognitive decline and neurodegeneration.

Health Risk Assessment of Heavy Metals Through Cow Milk Consumption in Trans-Himalayan High-Altitude Region.

Consumption of heavy metals contaminated dairy milk may affect human health. No such studies have been carried out at the high-altitude region to assess the human health risk after consuming dairy milk. To this end, this study reveals the evaluation of selected heavy metals in dairy milk in the summer and winter seasons, followed by the assessment of heavy metals health risk. Analysis of Jersey crossbred cattle's milk showed that only the zinc level was significantly higher in the summer season. All the non-carcinogenic and carcinogenic parameters were below the permissible limits. However, the carcinogenic risk (CR) level of arsenic and cadmium showed near the threshold level. Based on these findings, it might be concluded that all the studied metals do not have any significant role in health risk. In the near future, CR could be a health concern due to cow milk consumption at a high-altitude region.

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.

Association Between 17ß-Estradiol Receptors and Nitric Oxide Signaling Augments High-Altitude Adaptation of Ladakhi Highlanders.

Pooja, Vandana Sharma, Manish Sharma, Rajeev Varshney, Bhuvnesh Kumar, and Niroj Kumar Sethy. Association between 17ß-estradiol receptors and nitric oxide signaling augments high-altitude adaptation of Ladakhi highlanders. High Alt Med Biol. 22: 174-183, 2021. Background: Genomic studies have identified positive natural selection of plasma membrane estrogen receptor signaling pathway for Himalayan highlanders. We sought to investigate significance of this pathway for high-altitude adaptation by studying Ladakhi highlanders. Materials and Methods: We recruited 25 healthy Ladakhi males (age range: 19-37, height: 164 ± 6 cm, and weight 59 ± 4 kg) at Leh (altitude 3,520 m) and age matched sea level volunteers at Delhi (altitude 215 m), India. We evaluated circulatory levels of 17ß-estradiol (E2) and testosterone (T) and levels of E2 biosynthesis pathway proteins. In addition, we analyzed mRNA levels of E2 pathway genes and their association with nitric oxide (NO) availability. Results: We observed higher circulatory E2 and lower testosterone (T) in Ladakhi highlanders compared to lowlanders. Studying E2 pathway genes, we identified higher transcript levels of E2 receptors ESR1 (2.02-fold) and ESR2 (3.87-fold) in Ladakhi highlanders. Higher NOS3 mRNA, plasma level of endothelial NO synthase (eNOS), p-eNOS Ser1177, NOx (nitrate and nitrite), and cGMP were observed for Ladakhi highlanders. In addition, we observed a positive correlation between E2 with plasma NOx (r = 0.52, p = 0.002) and cGMP (r = 0.72, p = 0.007) for Ladakhi highlanders. Conclusion: Our results demonstrate higher circulatory E2 and lower T levels in Ladakhi highlanders. Higher levels of E2 and its receptors (ESR1 and ESR2) are positively associated with observed higher levels of eNOS signaling pathway metabolites. These results highlight the functional importance of E2 and its receptors for Himalayan pattern of high-altitude adaptation.

Quercetin: a savior of alveolar barrier integrity under hypoxic microenvironment.

High altitude pulmonary edema (HAPE) is generally characterized by the loss of alveolar epithelial barrier integrity. The current study was undertaken to assess the noninvasive approaches of HAPE diagnosis and to evaluate the prophylactic potential of quercetin in preventing alveolar junction impairments. Male SD rats fed with quercetin 1 h prior to hypoxia (7,620 m, for 6 h) were selected. PET/CT imaging was performed to visualize the lung uptake of 18F-FDG in animals under hypoxia. Further, oxidant status, catalase activity, hematological & blood gas parameters were evaluated. Moreover, tight junction (TJ) proteins (ZO-1, JAM-C, Claudin-4, and occludin) expression analysis was accomplished using immune-blotting. The structural differences in lung epithelia were noted by TEM imaging. Quercetin prophylaxis has significantly reduced the FDG uptake in rat lungs under hypoxia. It has also dramatically alleviated the protein oxidation followed by an elevation in catalase activity in the lungs under hypoxia. The TJ protein expression in the lungs has also been restored to normal upon quercetin pre-treatment. Concomitantly, the quercetin preconditioning has elicited the stable blood gas and hematological parameters under hypoxia. The observations from TEM imaging have also implicated the normal lung epithelial structures in the quercetin pretreated animals under hypoxia. Quercetin prophylaxis has significantly restored alveolar epithelium integrity by abating oxidative stress in the lungs under hypoxia.Abbreviations: CT- Computed Tomography18F-FDG- Fluorodeoxyglucose (18FHAPE- High Altitude Pulmonary EdemaHb- HemoglobinHCT- HematocritHCO3- BicarbonateJAM- Junctional Adhesion MoleculeKBq- Killo BecquerelPaO2- Partial pressure of arterial oxygenPaCO2- Partial pressure of arterial carbon di-oxidePET- Positron Emission TomographyRBC- Red Blood CorpusclesSD- Sprague DawleyTJ- Tight JunctionsTEM- Transmission Electron MicroscopyWBC- White Blood CorpusclesZO- Zona Occludin.