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Ghrelin exerts key effects on islet hormone secretion to regulate blood glucose levels. Here, we sought to determine whether ghrelin's effects on islets extend to the alteration of islet size and [beta] cell mass. We demonstrate that reducing ghrelin - by ghrelin gene knockout (GKO), conditional ghrelin cell ablation, or high-fat diet (HFD) feeding - was associated with increased mean islet size (up to 62%), percentage of large islets (up to 854%), and [beta] cell cross-sectional area (up to 51%). In GKO mice, these effects were more apparent in 10- to 12-week-old mice than in 4-week-old mice. Higher [beta] cell numbers from decreased [beta] cell apoptosis drove the increase in [beta] cell cross-sectional area. Conditional ghrelin cell ablation in adult mice increased the [beta] cell number per islet by 40% within 4 weeks. A negative correlation between islet size and plasma ghrelin in HFD-fed plus chow-fed WT mice, together with even larger islet sizes in HFD-fed GKO mice than in HFD-fed WT mice, suggests that reduced ghrelin was not solely responsible for diet-induced obesity-associated islet enlargement. Single-cell transcriptomics revealed changes in gene expression in several GKO islet cell types, including upregulation of Manf, Dnajc3, and Gnas expression in [beta] cells, which supports decreased [beta] cell apoptosis and/or increased [beta] cell proliferation. These effects of ghrelin reduction on islet morphology might prove useful when designing new therapies for diabetes., Introduction Ghrelin is secreted primarily by gastric ghrelin cells (1). It is mainly via binding to CNS and pituitary growth hormone secretagogue receptors (GHSRs) that ghrelin's actions to increase GH [...]

The hormone ghrelin serves a protective role in cancer-related anorexia-cachexia syndrome (CACS)—a condition in which plasma levels of ghrelin rise, its administration lessens CACS severity, and experimentally reduced signaling by its receptor (GHSR) worsens fat loss and anorexia and accelerates death. Yet, actions for the related hormone liver-expressed antimicrobial peptide-2 (LEAP2), which is an endogenous GHSR antagonist, are unexplored in CACS. Here, we found that plasma LEAP2 and LEAP2/ghrelin ratio were lower in Lewis lung carcinoma (LLC) and RM-9 prostate cancer CACS mouse models. Ghrelin deletion exaggerated losses of tumor-free body weight and fat mass, reduced food intake, reduced soleus muscle weight, and/or lowered grip strength in LLC or RM-9 tumor-bearing mice. LEAP2 deletion lessened reductions in tumor-free body weight and fat mass and increased food intake in LLC or RM-9 tumor-bearing mice. In a 55-subject cohort of patients with CACS or weight-stable cancer, the plasma LEAP2/total ghrelin ratio was negatively correlated with 6-month weight change preceding blood collection. These data demonstrate that ghrelin deletion exacerbates CACS in the LLC and RM-9 tumor-bearing mouse models while contrastingly, LEAP2 deletion reduces measures of CACS in these tumor-bearing mouse models. Further, they suggest that lower plasma LEAP2/ghrelin ratio protects against worsened CACS. [ABSTRACT FROM AUTHOR]

Simple Summary: Blood coagulation and cancer are intrinsically related; hyper-thrombotic complications are often observed in certain types of tumors. On the other hand, coagulation proteases are shown to promote the progression of cancer in a variety of unique mechanisms. The present review highlights how coagulation protease-induced signaling contributes to the immune evasion of different cancers, leading to the development and progression of cancer. Understanding the mechanistic insights will aid developing novel therapeutics against coagulation protease-driven response, which could be used in combination with conventional immune checkpoint inhibitors to increase the efficacy of cancer treatment and patient survival. Blood coagulation and cancer are intrinsically connected, hypercoagulation-associated thrombotic complications are commonly observed in certain types of cancer, often leading to decreased survival in cancer patients. Apart from the common role in coagulation, coagulation proteases often trigger intracellular signaling in various cancers via the activation of a G protein-coupled receptor superfamily protease: protease-activated receptors (PARs). Although the role of PARs is well-established in the development and progression of certain types of cancer, their impact on cancer immune response is only just emerging. The present review highlights how coagulation protease-driven PAR signaling plays a key role in modulating innate and adaptive immune responses. This is followed by a detailed discussion on the contribution of coagulation protease-induced signaling in cancer immune evasion, thereby supporting the growth and development of certain tumors. A special section of the review demonstrates the role of coagulation proteases, thrombin, factor VIIa, and factor Xa in cancer immune evasion. Targeting coagulation protease-induced signaling might be a potential therapeutic strategy to boost the immune surveillance mechanism of a host fighting against cancer, thereby augmenting the clinical consequences of targeted immunotherapeutic regimens. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple–negative breast cancer (TNBC), an aggressive phenotype, is commonly attributed to the loss of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor, thereby posing unique challenges in treatment via conventional targeted therapies. Although present chemotherapeutic regimens show promise against TNBC morbidity; the variability in treatment outcomes among patients and emerging resistance limit their potential. Moreover, due to significant mutational burden, TNBC is considered as highly immunogenic. Extracellular vesicles (EVs) have shown to regulate multiple human pathologies including cancer due to their role in transferring bioactive molecules between cells, evading immune surveillance. Conversely, the biological novelties of EVs are also exploited to develop experimental therapies. Here, we review studies in which EVs contribute to the progression of human TNBC and their immune regulation. Understanding these mechanistic details may open up avenues for repurposing EV–based immunotherapeutic strategies in the context of human TNBC treatment. Triple–negative breast cancer (TNBC) is an aggressive subtype accounting for ~10–20% of all human BC and is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) amplification. Owing to its unique molecular profile and limited targeted therapies, TNBC treatment poses significant challenges. Unlike other BC subtypes, TNBC lacks specific molecular targets, rendering endocrine therapies and HER2–targeted treatments ineffective. The chemotherapeutic regimen is the predominant systemic treatment modality for TNBC in current clinical practice. However, the efficacy of chemotherapy in TNBC is variable, with response rates varying between a wide range of patients, and the emerging resistance further adds to the difficulties. Furthermore, TNBC exhibits a higher mutational burden and is acknowledged as the most immunogenic of all BC subtypes. Consequently, the application of immune checkpoint inhibition has been investigated in TNBC, yielding promising outcomes. Recent evidence identified extracellular vesicles (EVs) as an important contributor in the context of TNBC immunotherapy. In view of the extraordinary ability of EVs to transfer bioactive molecules, such as proteins, lipids, DNA, mRNAs, and small miRNAs, between the cells, EVs are considered a promising diagnostic biomarker and novel drug delivery system among the prospects for immunotherapy. The present review provides an in–depth understanding of how EVs influence TNBC progression, its immune regulation, and their contribution as a predictive biomarker for TNBC. The final part of the review focuses on the recent key advances in immunotherapeutic strategies for better understanding the complex interplay between EVs and the immune system in TNBC and further developing EV–based targeted immunotherapies. [ABSTRACT FROM AUTHOR]

Inflammation is the defense mechanism of the immune system against harmful stimuli such as pathogens, toxic compounds, damaged cells, radiation, etc., and is characterized by tissue redness, swelling, heat generation, pain, and loss of tissue functions. Inflammation is essential in the recruitment of immune cells at the site of infection, which not only aids in the elimination of the cause, but also initiates the healing process. However, prolonged inflammation often brings about several chronic inflammatory disorders; hence, a balance between the pro- and anti-inflammatory responses is essential in order to eliminate the cause while producing the least damage to the host. A growing body of evidence indicates that extracellular vesicles (EVs) play a major role in cell–cell communication via the transfer of bioactive molecules in the form of proteins, lipids, DNA, RNAs, miRNAs, etc., between the cells. The present review provides a brief classification of the EVs followed by a detailed description of how EVs contribute to the pathogenesis of various inflammation-associated diseases and their implications as a therapeutic measure. The latter part of the review also highlights how EVs act as a bridging entity in blood coagulation disorders and associated inflammation. The findings illustrated in the present review may open a new therapeutic window to target EV-associated inflammatory responses, thereby minimizing the negative outcomes. [ABSTRACT FROM AUTHOR]

Objective: Prader‐Willi syndrome (PWS) is a multisystem genetic disorder. Unfortunately, none of several mouse models carrying PWS mutations emulates the entirety of the human PWS phenotype, including hyperphagia plus obesity. Methods: To determine whether housing at thermoneutrality (TN, 30 °C) permits the development of hyperphagia and obesity in the Snord116del PWS mouse model, the effects of housing three different ages of Snord116del and wild‐type (WT) littermates at TN versus room temperature (RT, 22–24 °C) for 8 weeks were compared. Results: Snord116del mice born and maintained at TN exhibited lower body weight curves, lower percentage fat mass, and lower food intake than WT mice at RT. In 4‐ to 6‐month‐old high‐fat diet–fed female mice, TN raised the Snord116del body weight curve closer to that of RT‐housed WT mice although the TN‐housed Snord116del mice did not gain more adiposity or exhibit greater food intake. In 6‐ to 8‐month‐old high‐fat diet–fed male mice, body weight, adiposity, and food intake of TN‐housed Snord116del mice remained far below levels in RT‐housed WT mice. TN elicited hypotonia in Snord116del adults and exacerbated mortality of Snord116del newborns. Conclusions: In none of three tested TN protocols were greater food intake, body weight, or adiposity induced in Snord116del mice compared with RT‐housed WT mice. [ABSTRACT FROM AUTHOR]

Liver cancer, mainly hepatocellular carcinoma (HCC), remains a major cause of cancer-related death worldwide. With the global epidemic of obesity, the major HCC etiologies have been dynamically shifting from viral to metabolic liver diseases. This change has made HCC prevention difficult with increasingly elusive at-risk populations as rational target for preventive interventions. Besides ongoing efforts to reduce obesity and metabolic disorders, chemoprevention in patients who already have metabolic liver diseases may have a significant impact on the poor HCC prognosis. Hepatitis B– and hepatitis C–related HCC incidences have been substantially reduced by the new antivirals, but HCC risk can persist over a decade even after successful viral treatment, highlighting the need for HCC-preventive measures also in these patients. Experimental and retrospective studies have suggested potential utility of generic agents such as lipophilic statins and aspirin for HCC chemoprevention given their well-characterized safety profile, although anticipated efficacy may be modest. In this review, we overview recent clinical and translational studies of generic agents in the context of HCC chemoprevention under the contemporary HCC etiologies. We also discuss newly emerging approaches to overcome the challenges in clinical testing of the agents to facilitate their clinical translation. [ABSTRACT FROM AUTHOR]

Apart from being the unit of proteins, amino acids have diverse roles. Here we have shown that amino acids guide the differential transportation of a dye molecule to the cellular organelles depending upon the property of their intrinsic functionality. We have conjugated the nitrobenzofurazan (NBD) moiety with two amino acids (lysine and histidine derivatives) with a linker. Both derivates are water‐soluble and biocompatible in nature. Surprisingly, we found that lysine‐conjugated NBD (NBD‐Lys) stains lipid droplets whereas histidine‐conjugated NBD (NBD‐His) stains lysosomes. We also measured the spectral properties of these two NBD conjugates. The results depict that both conjugates are extremely stable both in air and under inert atmosphere, and the fluorescence of the derivatives remains almost unaltered at different pH. Further by altering the functionality of the side chain, we established the contribution of each functional group towards this differential organelle targeting. [ABSTRACT FROM AUTHOR]

Extended exposure to low pO2 has multiple effects on signaling cascades. Despite multiple exploratory studies, omics studies elucidating the signaling cascades essential for surviving extended low pO2 exposures are lacking. In this study, we simulated low pO2 (PB = 40 kPa; 7620 m) exposure in male Sprague–Dawley rats for 3, 7 and 14 days. Redox stress assays and proteomics based network biology were performed using lungs and plasma. We observed that redox homeostasis was achieved after day 3 of exposure. We investigated the causative events for this. Proteo-bioinformatics analysis revealed STAT3 to be upstream of lung cytoskeletal processes and systemic lipid metabolism (RXR) derived inflammatory processes, which were the key events. Thus, during prolonged low pO2 exposure, particularly those involving slowly decreasing pressures, redox homeostasis is achieved but energy metabolism is perturbed and this leads to an immune/inflammatory signaling impetus after third day of exposure. We found that an interplay of lung cytoskeletal elements, systemic energy metabolism and inflammatory proteins aid in achieving redox homeostasis and surviving extended low pO2 exposures. Qualitative perturbations to cytoskeletal stability and innate immunity/inflammation were also observed during extended low pO2 exposure in humans exposed to 14,000 ft for 7, 14 and 21 days. [ABSTRACT FROM AUTHOR]

Hypoxia, particularly hypobaric hypoxia, is a multifaceted entity which includes certain molecular, pathophysiological and biochemical aspects. Any single aspect in itself cannot help us elucidate hypobaric hypoxia in its entirety. We observed three crucial lacunae within the existing literature. These include a lack of high-throughput investigations into redox PTMs, particularly NO-based PTMs; a prophylactic supplement with proven efficacy and safety which doesn't involve medical supervision and is not contraindicated in hepatic, renal and cardiac insufficiencies; and a clinically validated rodent model of HAPE without any genetic/pharmacological manipulations. In the present study, we present an antagonistic interplay between nitrosylation and carbonylation which shows an additional NO-based network that is active in acclimatised individuals. Then we present a micronised aqueous suspension of silymarin which is efficacious at low doses in providing antioxidant, anti-inflammatory and hypoxiaadaptive vascular responses in addition to being a free radical quencher itself. Silymarin has an excellent safety and efficacy profile in humans. Finally, we create a SD rat model of HAPE which was used to reverse-translate a previously known HAPE marker in humans (SULT1A1) and elucidate the synergistic occurrence of HAPE and inflammation cascades. This is the first radiologically validated rodent HAPE model. In conclusion, we were able to elucidate the molecular, biochemical and patho-physiological aspects of hypobaric hypoxia which were left out by previous studies. [ABSTRACT FROM AUTHOR]

Altitude acclimatization describes the processes whereby lowland humans respond to decreased partial pressure of oxygen. It refers to the changes seen as beneficial and involves a series of physiological adjustments that compensate for reduced ambient P O 2 , as opposed to changes that are pathological. Although numerous reports document the physiological effects of exposure to hypobaric hypoxia of varying durations but an interesting aspect overlooked by many researchers is that of acclimatization related studies. As proteome, a dynamic entity responds immediately to external stimuli, protein markers and their trends can be studied to assess acclimatization status of an individual. Compared to blood, the use of saliva is advantageous because sample collection and processing are easy, minimally invasive, low cost and better tolerated by individuals. In this study, we employed iTRAQ based LC-MS/MS technique for comparing saliva samples from humans exposed to hypobaric hypoxia from 7 to 120 days with normoxic controls followed by analysis using Ingenuity Pathway Analysis software and validation by immunoassays. Nearly 67 proteins were found to be differentially expressed in the exposed groups as compared to normoxia indicating modulated canonical pathways as lipid metabolism; acute phase response signalling and proteins as carbonic anhydrase 6, alpha-enolase, albumin, and prolactin inducible protein. Collectively, this study provides the proof of concept for the non-invasive assessment of high altitude acclimatization. • A global proteome-based picture of saliva of human exposed to hypobaric hypoxia is provided. • Redox homeostasis, lipid metabolism and acute phase response signaling to inflammation become perturbed. • Proteins like CA 6, alpha enolase, albumin were differentially expressed and validated. • The present study provides proof of concept for the non-invasive assessment of high altitude acclimatization. [ABSTRACT FROM AUTHOR]

Hypoxia, especially altitude associated hypoxia is known to cause severe physiological alterations and life-threatening conditions. Impaired redox balance along with oxidative stress, protein carbonylation and instigation of apoptotic events are common sub-cellular events that follow the hypoxic insult. The role of nitric oxide (NO) is very dynamic and versatile in preventing the ill effects of hypoxia vis-a-vis reacting with oxidative species and causing protein nitrosylation. Although several mechanisms of NO-mediated cytoprotection are known during hypoxic insult, limited pieces of evidence are available to support the relationship between two downstream events of oxidative stress, protein carbonylation (caused by carbonyl; CO radical) and protein nitrosylation/nitration (caused by NO/peroxynitrite; ONOO radical). In this study, we investigated an entirely new aspect of NO protection in hypoxia involving crosstalk between carbonylation and nitrosylation. Using standard NO inhibitor l -NAME and simulated hypoxic conditions in hypoxia-sensitive cell line H9c2, we evaluated the levels of radicals, cell death, mitochondrial membrane potential, levels of protein nitrosylation, protein nitration and carbonylation and glutathione content. The results were then carefully analyzed in light of NO bioavailability. Our study shows that reducing NO during hypoxia caused cell death via the increased degree of carbonylation in proteins. This provides a new aspect of NO benefits which furthers opens new possibilities to explore potential mechanisms and effects of cross-talk between nitrosylation, protein nitration and carbonylation, especially through some common antioxidant mediators such as glutathione and thioredoxin. [ABSTRACT FROM AUTHOR]

Despite its extraordinary antioxidant capacity, the clinical usage of silymarin has remained restricted to amelioration of hepatic pathology. Perhaps its low bioavailability and uneven bio-distribution, owing to its poor aqueous solubility, are two main causes that have dampened the clinical applicability and scope of this preparation. We took these two challenges and suggested an unexplored application of silymarin. Apart from liver, two of the most susceptible vital organs at the highest risk of oxidative stress are brain and lung, especially during reduced oxygen saturation (hypoxia) at anatomical level. Hypoxia causes excess generation of radicals primarily in the lungs as it is the first organ at the interphase of atmosphere and organism making it the most prone and vulnerable to oxidative stress and the first responder against hypobaric hypoxia. As our first objective, we improved the silymarin formulation by restricting its size to the lower threshold and then successfully tested the prophylactic and therapeutic action in rat lung challenged with simulated hypobaric hypoxia. After dose optimization, we observed that 50 mg/kg BW silymarin as size restricted and homogenous aqueous suspension successfully minimized the reactive oxygen species and augmented the antioxidant defense by significant upregulation of catalase and superoxide dismutase and reduced glutathione. Moreover, the well-established hypoxia markers and proteins related to hypoxia adaptability, hif1a and VEGF were differentially regulated conferring significant reduction in the inflammation caused by hypobaric hypoxia. We therefore report,the unexplored potential benefits of silymarin for preventing high altitude associated pathophysiology further paving its road to clinical trials. [ABSTRACT FROM AUTHOR]

Background and Aims: Hepatocellular carcinoma (HCC) risk stratification is an urgent unmet need for cost-effective HCC screening and early detection in patients with cirrhosis to improve poor HCC prognosis., Methods: Molecular (Prognostic Liver Secretome signature with alpha-fetoprotein) and clinical (aMAP score) variable-based scores were integrated to develop PAaM, which was subsequently validated in two phase 3 biomarker validation studies: the statewide Texas HCC Consortium (THCCC) and nationwide HCC Early Detection Strategy (HEDS) prospective cohorts, following the prospective specimen collection, retrospective blinded evaluation (PRoBE) design. The associations between baseline PAaM and incident HCC were assessed using Fine-Gray regression, with overall death and liver transplantation as competing events., Results: Of 2,156 cirrhosis patients in THCCC, PAaM identified 404 (19%) high-risk, 903 (42%) intermediate-risk, and 849 (39%) low-risk patients with annual HCC incidence rates of 5.3%, 2.7%, and 0.6%, respectively. Compared to low-risk patients, high- and intermediate-risk groups had sub-distribution hazard ratios (sHRs) for incident HCC of 7.51 (95% confidence interval [CI], 4.42-12.8) and 4.20 (95%CI, 2.52-7.01), respectively. Of 1,328 cirrhosis patients in HEDS, PAaM identified 201 (15%) high-risk, 540 (41%) intermediate-risk, and 587 (44%) low-risk patients, with annual HCC incidence rates of 6.2%, 1.8%, and 0.8%, respectively. High- and intermediate risk groups were associated with sHRs for incident HCC of 6.54 (95%CI, 3.85-11.1) and 1.77 (95%CI, 1.02-3.08), respectively. Subgroup analysis showed robust risk stratification across HCC etiologies, including metabolic dysfunction-associated steatotic liver disease (MASLD) and cured hepatitis C infection., Conclusion: PAaM enables accurate HCC risk stratification in patients with cirrhosis from contemporary etiologies., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Previous studies have implicated the orexigenic hormone ghrelin as a mediator of exercise endurance and the feeding response postexercise. Specifically, plasma ghrelin levels nearly double in mice when they are subjected to an hour-long bout of high-intensity interval exercise (HIIE) using treadmills. Also, growth hormone secretagogue receptor-null (GHSR-null) mice exhibit decreased food intake following HIIE and diminished running distance (time until exhaustion) during a longer, stepwise exercise endurance protocol. To investigate whether ghrelin-responsive mediobasal hypothalamus (MBH) neurons mediate these effects, we stereotaxically delivered the inhibitory designer receptor exclusively activated by designer drugs virus AAV2-hSyn-DIO-hM4(Gi)-mCherry to the MBH of Ghsr-IRES-Cre mice, which express Cre recombinase directed by the Ghsr promoter. We found that chemogenetic inhibition of GHSR-expressing MBH neurons (upon delivery of clozapine-N-oxide) 1) suppressed food intake following HIIE, 2) reduced maximum running distance and raised blood glucose and blood lactate levels during an exercise endurance protocol, 3) reduced food intake following ghrelin administration, and 4) did not affect glucose tolerance. Further, HIIE increased MBH Ghsr expression. These results indicate that activation of ghrelin-responsive MBH neurons is required for the normal feeding response to HIIE and the usual amount of running exhibited during an exercise endurance protocol.

Apart from being the unit of proteins, amino acids have diverse roles. Here we have shown that amino acids guide the differential transportation of a dye molecule to the cellular organelles depending upon the property of their intrinsic functionality. We have conjugated the nitrobenzofurazan (NBD) moiety with two amino acids (lysine and histidine derivatives) with a linker. Both derivates are water-soluble and biocompatible in nature. Surprisingly, we found that lysine-conjugated NBD (NBD-Lys) stains lipid droplets whereas histidine-conjugated NBD (NBD-His) stains lysosomes. We also measured the spectral properties of these two NBD conjugates. The results depict that both conjugates are extremely stable both in air and under inert atmosphere, and the fluorescence of the derivatives remains almost unaltered at different pH. Further by altering the functionality of the side chain, we established the contribution of each functional group towards this differential organelle targeting., (© 2022 Wiley-VCH GmbH.)

The triple-negative phenotype is the most prevalent form of human breast cancer worldwide and is characterized by poor survival, high aggressiveness, and recurrence. Microvesicles (MV) are shredded plasma membrane components and critically mediate cell-cell communication, but can also induce cancer proliferation and metastasis. Previous studies have revealed that protease-activated receptor 2 (PAR2) contributes significantly to human triple-negative breast cancer (TNBC) progression by releasing nano-size MV and promoting cell proliferation, migration, and invasion. MV isolated from highly aggressive human TNBC cells impart metastatic potential to nonmetastatic cells. Over-expression of microRNA221 (miR221) has also been reported to enhance the metastatic potential of human TNBC, but miR221's relationship to PAR2-induced MV is unclear. Here, using isolated MV, immunoblotting, quantitative RT-PCR, FACS analysis, and enzymatic assays, we show that miR221 is translocated via human TNBC-derived MV, which upon fusion with recipient cells, enhance their proliferation, survival, and metastasis both in vitro and in vivo by inducing the epithelial-to-mesenchymal transition (EMT). Administration of anti-miR221 significantly impaired MV-induced expression of the mesenchymal markers Snail, Slug, N-cadherin, and vimentin in the recipient cells, whereas restoring expression of the epithelial marker E-cadherin. We also demonstrate that MV-associated miR221 targets phosphatase and tensin homolog (PTEN) in the recipient cells, followed by AKT Ser/Thr kinase (AKT)/NF-κB activation, which promotes EMT. Moreover, elevated miR221 levels in MV derived from human TNBC patients' blood could induce cell proliferation and metastasis in recipient cells. In summary, miR221 transfer from TNBC cells via PAR2-derived MV induces EMT and enhances the malignant potential of recipient cells., (© 2019 Das et al.)

Hypobaric hypoxia elicits several patho-physiological manifestations, some of which are known to be lethal. Among various molecular mechanisms proposed so far, perturbation in redox state due to imbalance between radical generation and antioxidant defence is promising. These molecular events are also related to hypoxic status of cancer cells and therefore its understanding has extended clinical advantage beyond high altitude hypoxia. In present study, however, the focus was to understand and propose a model for rapid acclimatization of high altitude visitors to enhance their performance based on molecular changes. We considered using simulated hypobaric hypoxia at some established thresholds of high altitude stratification based on known physiological effects. Previous studies have focused on the temporal aspect while overlooking the effects of varying pO 2 levels during exposure to hypobaric hypoxia. The pO 2 levels, indicative of altitude, are crucial to redox homeostasis and can be the limiting factor during acclimatization to hypobaric hypoxia. In this study we present the effects of acute (24h) exposure to high (3049m; pO 2 : 71kPa), very high (4573m; pO 2 : 59kPa) and extreme altitude (7620m; pO 2 : 40kPa) zones on lung and plasma using semi-quantitative redox specific transcripts and quantitative proteo-bioinformatics workflow in conjunction with redox stress assays. It was observed that direct exposure to extreme altitude caused 100% mortality, which turned into high survival rate after pre-exposure to 59kPa, for which molecular explanation were also found. The pO 2 of 59kPa (very high altitude zone) elicits systemic energy and redox homeostatic processes by modulating the STAT3-RXR-Nrf2 trio. Finally we posit the various processes downstream of STAT3-RXR-Nrf2 and the plasma proteins that can be used to ascertain the redox status of an individual., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Computational biology has opened a gateway to omics data analysis and shifted the focus from molecules to systemic molecular networks in the domain of hypobaric hypoxia (HH). Yet there are no meta-analytical investigations circumventing constraints such as organism (rat/human), HH exposure conditions (acute/chronic), and the tissues that can be investigated simultaneously in the realm of wet lab experiments., Experimental Design: We analyzed 154 differentially expressed proteins upon HH exposure using Ingenuity Pathway Analysis (IPA) tool, without the constraint of using a single organism or tissue type, to determine the most significant pathways and networks that are perturbed across a range of HH conditions., Results: We found acute phase response signaling, farsenoid X receptor/retinoid X receptor activation, liver X receptor/retinoid X receptor activation, clathrin-mediated endocytosis signaling, mitochondrial dysfunction, production of nitric oxide and ROS in macrophages, and integrin signaling to be the most significant universally perturbed pathways. Unique protein-function relationships have also been highlighted., Conclusion and Clinical Relevance: This meta-analysis provides a list of specific pathways and networks across two model organisms that are perturbed due to HH exposure irrespective of its duration/intensity. Thus, it will be a map of important pathways and proteins to look at when exploring effects of HH exposure irrespective of tissue/organism chosen, particularly in the context of prophylactic/therapeutic targets., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)