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There are several reports, which suggest that the consumption of foods rich in flavonoids is associated with a lower incidence of certain degenerative diseases, including cardiovascular disease. Flavones, of Seabuckthorn (SBT) (Hippophae rhamnoides L.) fruit berry can modulate the production and level of several signaling molecules associated with immune function and inflammation in vitro, including several cytokines. We have evaluated the immunomodulatory activity of ethanolic solution of SBT flavone (FLV) in human peripheral blood mononuclear cells (PBMCs). The SBT flavone was found to stimulate production of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in PBMCs. However, increased expressions of p-IkappaB, NF-kappaB, and p-p38 were found in flavone-treated human PBMCs with significantly suppressed expression of CD25 (IL-2R). There was no alteration found in the nitric oxide (NO) production in mouse macrophage cell line RAW 264.7. These observations suggest that stimulation of IL-6 and TNF-alpha secretion may contribute to the putative beneficial effects of dietary flavone against microbial infection. [ABSTRACT FROM AUTHOR]

The gastrointestinal (GI) tract is susceptible to damage under high altitude hypoxic conditions, leading to gastrointestinal discomfort and intestinal barrier injury. Sodium butyrate, a short-chain fatty acid present as a metabolite in the gut, has emerged as a promising therapeutic agent due to its ability to act as an immunomodulatory agent and restore intestinal barrier integrity. This study aimed to explore the mechanism by which sodium butyrate exhibits anti inflammatory effect on intestinal epithelial cells. In vitro, Caco-2 epithelial cells and RAW 264.7 macrophages were used to investigate the protective role of sodium butyrate on Lipopolysaccharide (LPS) induced inflammation. Cell viability assays demonstrated that 1 mM (110.86 μg/mL) of sodium butyrate did not exhibit cytotoxicity on cells in vitro. Treatment with sodium butyrate suppressed reactive oxygen species levels and TNF-α production in LPS-stimulated macrophages, indicating its efficacy in mitigating inflammatory responses. Western blot analysis revealed that sodium butyrate attenuated the expression of iNOS in RAW 264.7 macrophage cells. Moreover, sodium butyrate also reversed the LPS induced over expression of HIF-1α, NLRP3, IL-1β as well as NF-kB in Caco-2 epithelial cells and also had a suppressive effect on IL-8 secretion after LPS stimulation. Immunocytochemistry demonstrated that sodium butyrate enhanced tight junction protein occludin expression in Caco-2 cells while also restoring the decreased permeability of the Caco-2 monolayer due to LPS. These results indicate that sodium butyrate may influence immune responses by suppressing inflammatory mediators and improving the integrity of the epithelial barrier. Understanding the intricate interactions between gut metabolites and host immune responses may help in the development of innovative therapeutic strategies to alleviate intestinal inflammation in high altitude environments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulates the plasma B cells to secrete specific antibodies against the viral antigen. However, not all antibodies can prevent the virus from entering the cells. The subpopulation of antibodies which blocks the entry of the virus into host cells is termed neutralizing antibodies (NAbs). The gold standard test for the detection of NAbs is the viral plaque reduction and neutralization test; however, various other methods can also be utilized to detect NAbs. In this study, we have developed an Enzyme Linked Immunosobent Assay (ELISA)-based protocol for rapid detection of SARS CoV-2 NAb by inhibiting the binding of the spike protein receptor-binding domain to angiotensin converting enzyme 2 and compared it with cPASS neutralizing antibody kit, which was approved by the Food and Drug Administration (FDA). The results obtained suggest that the in-house ELISA developed for the detection of NAbs against SARS-CoV-2 is rapid and reliable. Compared to FDA-approved GenScript's cPass assay, the specificity and the sensitivity of the in-house-developed ELISA kit were 100% (95% confidence intervals of 69.15-100.00) and 96% (95% confidence intervals of 86.29-99.51), respectively. Thus, the ELISA protocol developed to test the neutralizing activities of antibodies is rapid, which requires a BSL-2 infrastructure facility and can be easily performed. It has very high potential applications in the rapid screening of NAb against SARS-CoV-2.

Platelets or thrombocytes play an important role in thrombosis and maintaining hemostasis. Thrombocytes help in forming blood clots at the site of the wound. When the level of platelets decreases, uncontrolled bleeding occurs which can result in mortality. A decrease in the blood platelet level is known as thrombocytopenia which can be caused due to various reasons. A variety of treatment options are available for thrombocytopenia like platelet transfusion, splenectomy, platelet management with various types of corticosteroids, and recombinant interleukin-11 (rhIL-11). The use of rhIL-11 is approved by FDA for the treatment of thrombocytopenia. rhIL-11 is a recombinant cytokine that is administered to patients suffering from chemotherapy-induced thrombocytopenia as it enhances megakaryocytic proliferation which aids in platelet production. But this treatment has various side effects and is costly. Hence, there is a crucial need to identify cost-effective alternative strategies that present no side effects. The majority of the population in low-income countries requires a functional and cost-effective treatment for low thrombocyte count. Carica papaya is a tropical herbaceous plant that has been reported in recovering low platelet count during dengue virus infection. Even though multiple benefits of the Carica papaya leaf extract (CPLE) are popular, the active compound present in it, which mediates these benefits, remains to be identified. This review aims to highlight the different aspects of rhIL-11 and CPLE-induced platelet counts and their limitations and benefits in the treatment of thrombocytopenia. The literature related to the treatment of thrombocytopenia using rhIL-11 and CPLE from 1970 to 2022 was searched using PubMed and Google Scholar databases with the keywords Recombinant Interleukin-11, Papaya Leaf Extract, Thrombocytopenia, and Platelets., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s), under exclusive licence to Association of Clinical Biochemists of India 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

When sojourners visit to high altitude, various symptoms may appear in the body including gastrointestinal symptoms such as poor appetite or nausea, vomiting, and incapacitating. The gastrointestinal tract is a key organ involved in the development of acute mountain sickness (AMS). The intestinal epithelial lining is covered by mucus layer. Mucosal barrier is considered as first line of protection of the gut wall which not only helps in lubricating and facilitating progression of bolus but also protects intestinal epithelial lining. Gut microbes play a major role in alterations of mucus barrier and may have important role in curtailing gastrointestinal symptoms at high altitude. In our previous study, we have reported ~ 17% decrease in Akkermansia muciniphila bacteria under hypobaric hypoxia exposure in Sprague-Dawley rats. A. muciniphila is a mucin-degrading bacterium. Its presence in the human intestine is inversely associated to a number of diseases. A. muciniphila is found in the mucus layer, where it helps to maintain intestinal integrity and protects from various inflammatory diseases. Hypoxia decreases A. muciniphila bacterium in gut leading to gastrointestinal barrier injury. It could be an important probiotic that may have physiological benefits in high-altitude hypoxia induced clinical scenarios. A large-scale clinical experiments, production feasibility, and regulatory clearances need to be resolved to develop it as next generation probiotic. In this review, we have searched various databases including PubMed and Google Scholar with keywords Akkermansia muciniphila, A. muciniphila, human physiology, etc. to comprehensively highlight the importance of this gut bacterium. KEY POINTS: • High-altitude hypoxia leads to gastrointestinal barrier injury. • Hypoxia decreases Akkermansia muciniphila bacterium in gut. • A. muciniphila as probiotic may help to maintain intestinal integrity., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Flavonoids are polyphenolic phytochemicals, which occur naturally in plants and possess both anti-oxidant and pro-oxidant properties. Flavonoids are gaining increasing popularity in the pharmaceutical industry as healthy and cost-effective compounds. Flavonoids show beneficial pharmacological activities in the treatment and prevention of various types of diseases. They are natural and less toxic agents for cancer chemotherapy and radiotherapy via regulation of multiple cell signaling pathways and pro-oxidant effects. In this review, we have summarized the mechanisms of action of selected flavonoids, and their pharmacological implications and potential therapeutic applications in cancer therapy.

Coronavirus disease 2019 (COVID-19) continuously affecting the lives of millions of people. The virus is spread through the respiratory route to an uninfected person, causing mild-to-moderate respiratory disease-like symptoms that sometimes progress to severe form and can be fatal. When the host is infected with the virus, both innate and adaptive immunity comes into play. The effector T cells act as the master player of adaptive immune response in eradicating the virus from the system. But during cancer and chronic viral infections, the fate of an effector T cell is altered, and the T cell may enters a state of exhaustion, which is marked by loss of effector function, depleted proliferative capacity and cytotoxic effect accomplished by an increased expression of numerous inhibitory receptors such as programmed cell death protein 1 (PD-1), lymphocyte-activation protein 3 (LAG-3), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on their surface. Various other transcriptional and epigenetic changes take place inside the T cell when it enters into an exhausted state. Latest studies point toward the induction of an abnormal immune response such as lymphopenia, cytokine storm, and T cell exhaustion during SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. This review sheds light on the dysfunctional state of T cells during chronic viral infection and COVID-19. Understanding the cause and the effect of T cell exhaustion observed during COVID-19 may help resolve new therapeutic potentials for treating chronic infections and other diseases.

Over the last twenty months, the attention of the world has been focusing on managing the unprecedented and devastating wave of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) and mitigating its impacts. Recent findings indicated that high levels of pro-inflammatory cytokines are leading cause of poor prognosis in severely ill COVID-19 patients. Presently, the multiple variants and highly contagious nature of virus makes challenge humongous. The shortage and vaccine hesitancy also prompted to develop antiviral therapeutic agents to manage this pandemic. Nanocurcumin has potential antiviral activities and also beneficial in post COVID inflammatory complications. We have developed nanocurcumin based formulation using pyrroloquinoline quinone (PQQ) which protects cardio-pulmonary function and mitochondrial homeostasis in hypobaric hypoxia induced right ventricular hypertrophy in animal model and human ventricular cardiomyocytes. Nanocurcumin based formulation (NCF) with improved bioavailability, has proven several holistic therapeutic effects including myocardial protection, and prevents edema formation, anti-inflammatory and antioxidant properties, maintaining metabolic and mitochondrial homeostasis under hypoxic condition. The post COVID-inflammatory syndrome also reported to cause impaired heart function, lung injuries and increased C-reactive protein level in severely ill patients. Thus, we speculate that NCF could be a new treatment option to manage post COVID-19 inflammatory syndrome.

Hypobaric hypoxia at higher altitudes usually impairs cognitive function. Previous studies suggested that epigenetic modifications are the culprits for this condition. Here, we set out to determine how hypobaric hypoxia mediates epigenetic modifications and how this condition worsens neurodegeneration and memory loss in rats. In the current study, different duration of hypobaric hypoxia exposure showed a discrete pattern of histone acetyltransferases and histone deacetylases (HDACs) gene expression in the hippocampus when compared with control rat brains. The level of acetylation sites in histone H2A, H3 and H4 was significantly decreased under hypobaric hypoxia exposure compared to the control rat's hippocampus. Additionally, inhibiting the HDAC family with sodium butyrate administration (1.2 g/kg body weight) attenuated neurodegeneration and memory loss in hypobaric hypoxia-exposed rats. Moreover, histone acetylation increased at the promoter regions of brain-derived neurotrophic factor (BDNF); thereby its protein expression was enhanced significantly in hypobaric hypoxia exposed rats treated with HDAC inhibitor compared with hypoxic rats. Thus, BDNF expression upregulated cAMP-response element binding protein (CREB) phosphorylation by stimulation of PI3K/GSK3β/CREB axis, which counteracts hypobaric hypoxia-induced spatial memory impairment. In conclusion, these results suggested that sodium butyrate is a novel therapeutic agent for the treatment of spatial memory loss associated with hypobaric hypoxia, and also further studies are warranted to explore specific HDAC inhibitors in this condition., (© 2021 Wiley Periodicals LLC.)

Innate immune memory, a crucial mechanism of epigenetically mediated myeloid cell plasticity, alters subsequent immune responses majorly by two types of immunological imprinting, training, and tolerance. Recent pioneer studies provided proof-of-principle for generation of both types of innate immune memory in brain macrophage, microglial cells. This novel study was designed to investigate whether the pattern of immune response generation, induced by peripheral administration of recombinant alarmin HMGB1, alone and in combination with other recombinant cytokines, is affected by prior exposure. The experimental outcomes revealed that full length recombinant HMGB1 exposure for seven consecutive days exhibit inflammatory response as evidenced by enhanced expression of inflammatory biomarkers and neurodegeneration. In contrary, combined doses of HMGB1 and IL-1β, for three and seven consecutive days, exhibited lower inflammatory state compared to its alone HMGB1 counterpart. The immune tolerance state was evident by microglial polarization towards non-reactive M2 state, lower astrocyte activation, epigenetic reprogramming, and decreased neurodegeneration. This is the first demonstration that HMGB1 and IL-1β priming can differentially affect inflammation in the brain when a host is confronted with a second, third stimulus or so on. The findings were further validated by suppressing major regulators of epigenetic reprogramming, by intranasal delivery of specific siRNAs targeting those regulators. These results may provide new evidence for the involvement of recombinant endogenous cytokine induced generation of innate immune tolerance within microglial cells and indicated the possible potential role in mediating cognitive and behavioural alterations during inflammatory diseases., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Soots are known to cause many diseases in humans, but their underlying mechanisms of toxicity are still not known. Here, we report that soots induce cell proliferation of lung epithelial cells via modulating autophagy pathways., Results: Fullerene soot and diesel exhaust particles (DEP) induced cell proliferation of lung epithelial, A549 cells via distinct autophagic mechanisms and did not cause cell death. Exposure of fullerene soot protected the cell death of A549 cells, caused by hydrogen peroxide, and inhibited LPS-induced autophagy. Fullerene soot co-localized with the autophagic proteins and inhibited starvation-induced autophagy (downregulated ATG-5, beclin-1, p62, and LC3 expressions) independent of its antioxidant properties. Similarly, it decreased the expression profile of autophagic genes and upregulated the proliferation-responsive gene, Ki-67, in mice. We observed that expressions of fullerene soot-responsive genes (Beclin-1, ATG-5, and p62) were reverted by Akt Inhibitor X, indicating an important role of the Akt pathway. At an elemental level, we found that elemental carbon of fullerene soot may be converted into organic carbon, as measured by OCEC, which may point fullerene soot as a source of carbon. On the other hand, DEP upregulated the expressions of autophagy genes. Akt Inhibitor X did not attenuate DEP-induced cell proliferation and autophagic response. However, an autophagic inhibitor, chloroquine, and significantly inhibited DEP-induced cell proliferation., Conclusion: It can be said that distinct autophagic mechanisms are operational in cell proliferation of lung epithelial cells due to soots, which may be responsible for different diseases. Understanding the mechanism of these pathways provides some important targets, which can be utilized for the development of future therapeutics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Niranjan, Mishra, Tripathi and Thakur.)

Khanna, Kunjan, Kamla Prasad Mishra, Sudipta Chanda, Lilly Ganju, Shashi Bala Singh, and Bhuvnesh Kumar. Effect of synbiotics on amelioration of intestinal inflammation under hypobaric hypoxia. High Alt Med Biol . 22:32-44, 2021. Aim: High-altitude exposure alters the gastrointestinal (GI) system, which may be a cause of hypobaric hypoxia (HH)-induced microbial dysbiosis. Therefore, we investigated the effect of a combination of beneficial bacteria and nondigestible fiber popularly known as "synbiotics" (Syn) to mitigate intestinal inflammation and microbial dysbiosis post-HH exposure. Methods: Syn, that is, a combination of probiotics and prebiotics, was given to male Sprague-Dawley rats 3 days prior and along with the HH exposure to assess its effect on mucosal barrier injury and inflammation. Changes in the gut microbiota and functional analysis were assessed using 16S rRNA and whole-genome sequencing (WGS) analysis. Results: Syn treatment significantly improved mucosal barrier injury in terms of decreased serum fluorescein isothiocyanate dextran from 96.1 ± 7.95 μg/ml in HH-alone group to 38.35 ± 4.55 μg/ml in HH + Syn group ( p  < 0.01) and decreased serum zonulin levels, that is, from 134.7 ± 19.05 ng/ml (HH alone) to 64.02 ± 7.33 ng/ml (HH + Syn) ( p  < 0.05), along with improvement in the intestinal villi under HH exposure. Levels of proinflammatory cytokines and chemokines significantly reduced upon Syn treatment, indicating attenuation of inflammation and immune cell migration. Syn treatment significantly reduced Th17 biased immune response preventing interleukin (IL)-17-induced inflammatory response with 8.1 ± 0.5 ng/mg protein in HH exposure group, while treatment with Syn in HH-exposed group reduced IL-17 levels to 2.01 ± 0.3 ng/mg protein ( p  < 0.001). Analysis of 16S rRNA showed significant ( p  < 0.05) alterations in Deferribacteres, Firmicutes, and Verrucomicrobia at the phylum levels, whereas Prevotella , Paenibacillus , Clostridium , Turicibacter , Bacillus , Anoxybacillus , Enterococcus , SMB53 , Mucispirillum , Allobaculum , and Lactococcus were significantly altered ( p  < 0.05) in abundance at the genus level. WGS analysis revealed improvement in GI health by regulating functional pathways post-Syn treatment. Conclusion: Our findings indicate that Syn treatment improves intestinal barrier function and curtailed inflammation in the HH-exposed rat models, proving it to be a promising potential countermeasure for HH-induced gut problems.

Heat exposure is an environmental stress that causes diverse heat related pathophysiological changes under extreme conditions. The brain including hippocampal region which is associated with learning and memory is significantly affected by heat stress resulting in memory impairment. However, the effect of heat on the spatial memory remains unclear. The present study aimed to explore the effect of heat stress on hippocampus and spatial memory in rats. Rat model of acute heat stress was used which was divided into two groups, viz. moderate heat stress (MHS) and severe heat stress (SHS). Redox parameters evaluation revealed that MHS and SHS exposure markedly increase the production of malondialdehyde (MDA), oxidised glutathione (GSSG), reactive oxidative species (ROS), protein oxidation level and decrease the reduced glutathione (GSH) levels in the hippocampal tissue. Furthermore, Cresyl Violet (CV) staining of hippocampal region showed higher pyknosis in rats exposed to SHS. Pronounced increase of caspase3 expression and Fluoro Jade-C (FJ-C) positive cells were observed in SHS resulting in neuronal injury and apoptosis in CA3 region of hippocampus culminating in spatial memory deficit. Our data also suggest that heat stress induces phospho Extracellular signal-regulated kinases (pERK)1/2 activation induced by Brain-derived neurotrophic factor (BDNF) leading to further activation of phospho cAMP-response element binding protein (pCREB) under MHS. However, during SHS, BDNF and pCREB expression were completely dysregulated and not sufficient to rescue cognitive decline in rats. In conclusion, SHS induces pathological alterations that include oxidative damage and apoptosis of hippocampal neurons, disturbing BDNF/ERK1/2/CREB axis that may affect spatial memory., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Chikungunya virus (CHIKV) is an arthropod-borne RNA virus which induces host Endoplasmic Reticulum (ER) stress by accumulating unfolded or misfolded proteins. ER stress activates the unfolded protein response (UPR) pathway to enable proper protein folding and maintain cellular homeostasis. There is no approved drug or vaccine available for CHIKV treatment, therefore, a pharmacological countermeasure is warranted for preventing CHIKV infection., Objective: With a view to find a treatment modality for chikungunya infection, "andrographolide", a plant-derived diterpenoid with reported antiviral, anti-inflammatory and immunomodulatory effects, was used to investigate its role in chikungunya induced unfolded protein stress and apoptosis., Methods: Cells and supernatant collected on andrographolide and VER-155008, a GRP78 inhibitor, treatment in CHIKV infected and mock-infected THP-1 cells were tested for differential expression of UPR pathway proteins including GRP78, PERK, EIF-2&#945;, IRE-1&#945;, XBP-1 and ATF6. Furthermore, the inflammasome and apoptosis pathway proteins, i.e., caspase-1, caspase-3 and PARP, were tested by immunoblotting, and cytokines, i.e., IL-1&#946;, IL-6 and IFN-&#947; were tested by ELISA., Results: Andrographolide treatment in CHIKV infected THP-1 cells significantly reduced IRE1α and downstream spliced XBP1 protein expression. Furthermore, CHIKV induced apoptosis and viral protein expression were also reduced on andrographolide treatment. A comparative analysis of andrographolide versus VER-155008, confirmed that andrographolide surpasses the effects of VER-155008 in suppressing the CHIKV induced ER stress., Conclusion: The study, therefore, confirms that andrographolide is a potential remedy for chikungunya infection and suppresses CHIKV induced ER stress and apoptosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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-1β 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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Radiobiological research continues to focus on finding newer strategies for enhanced killing of tumor cells by ionizing radiation. In recent years, chemotherapeutic drugs have been found to possess the capabilities to sensitize tumor cells without affecting the normal cells. There have been increasing research efforts to identify novel and nontoxic compounds which cause minimal or no harm to normal cells but maximize tumor toxicity response to radiation exposure. Extensive researches on flavonoids that are compounds derived from plants have shown that these have promising abilities as radioprotectors and radiosensitizers. Conclusions: In this review, we examine the role of flavonoids as potential radiosensitizers, review the underlying molecular mechanisms and discuss their potential usefulness in improving cancer radiotherapy. It is emphasized that obtaining a deeper insight into the molecular mechanisms underlying the combined action of flavonoids and ionizing radiation may provide new directions for radiobiological research applicable to the much needed enhanced selective tumor cytotoxicity to treatment agents.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) pandemic has affected millions of people worldwide. The pathophysiology of this virus is not very clearly known, thus, enormous efforts are being made by the scientific community to delineate its evading mechanism. In this review, we have summarized the hyperinflammation and humoral and cell-mediated immune response generated in human body after infection with the SARS-CoV-2 virus. The inflammatory response generated after infection by increased proinflammatory cytokines and chemokines, and complement proteins activation may likely contribute to disease severity. We also discussed the other factors that may affect immunity and could be important comorbidities in the disease severity and outcome., (© 2020 S. Karger AG, Basel.)

High mobility group box 1 (HMGB1) is an endogenous alarmin that drives the pathogenesis of neurodegenerative disorders including cognitive decline. Therefore, HMGB1 is thought to be a common biomarker as well as promising therapeutic target for neuroinflammation associated with neurocognitive disorders. Here, for the first time, we have unmasked the potential inhibitory effect of a novel receptor of HMGB1-CXCL12 complex; atypical chemokine receptor 3 (ACKR3/CXCR7) on HMGB1 induced glial phenotype switching, neuroinflammation, and subsequent memory loss. Upregulation of CXCR7 inhibits HMGB1-CXCL12 complex induced peripheral immune cells infiltration to CNS by regulating blood-brain barrier (BBB) integrity in HMGB1 induced dementia model of mice. Whereas, gene knockdown study by RNA interference (non-invasive intranasal delivery to animal model) shows CXCR7 ablation aggravates inflammatory responses in hippocampus region and immune cell infiltration to CNS tissue by breached BBB. This study also indicates the important role of CXCR7 molecule in maintaining CNS homeostasis by balancing M1/M2 microglia, A1/A2 astrocytes, long term potentiation/long term depression markers which ultimately ameliorates HMGB1 induced neurodegeneration, synaptic depression and memory loss (assessed by both radial arm maze and Morris water maze) in male mice model of dementia. Overall, the study summarizes several significant protective functions afforded by CXCR7 against HMGB1 induced disbalance in neuroimmunological axis, neurodegeneration and memory loss and thereby provides a new paradigm for strategic development of novel therapeutics against neurodegenerative diseases with dementia as a common symptom., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Exposure to hypobaric hypoxia (HH) has been reported to cause neurodegeneration and memory impairment. Hippophae rhamnoides , Prunus armeniaca , and Rhodiola imbricata , the indigenous plants of Indian Trans-Himalaya are widely used in traditional Tibetan and Amchi system of medicine. These are rich sources of diverse bioactive metabolites having prophylactic and therapeutic uses against a wide array of neurodegenerative diseases. The objective of this study was to elucidate the prophylactic and neuroprotective efficacy of formulated phytococktail (PC) against simulated HH-induced neurodegeneration in male Sprague Dawley (SD) rats. Materials and Methods: A PC containing H. rhamnoides fruit pulp, P. armeniaca fruit pulp, and R. imbricata dry root extract (100:50:1) was formulated. The neuroprotective efficacy of PC was evaluated in male SD rats following exposure to 7 day HH at simulated altitude (25,000 ft, 282 mm Hg). Rats were divided into four groups viz., normoxia group (NOR), normoxic group treated with PC (NORPC), 7 day hypoxic group treated with vehicle (7DH), and 7 day hypoxic group treated with PC (7DHPC). Memory impairment and neuromorphological alterations were measured. Targeted protein expression was analyzed by immunoblotting study. Results: PC supplementation significantly reduced the oxidative stress markers during exposure to HH. Spatial memory impairment by HH was significantly ameliorated by PC. HH-induced augmented pyknosis, decreased dendritic arborization, and increased Hoechst-positive neurons in hippocampal CA3 region were significantly ameliorated by PC. Immunoblotting study showed upregulation of BDNF and TrkB expression by PC. PC also prevented the hippocampal neurodegeneration by activating the PI3K/AKT signaling pathway, which leads to GSK-3β inactivation by its phosphorylation and alleviation of hippocampal Caspase3 expression leading to inhibition of apoptotic neuronal cell death. Conclusion: The present study advocates the potential role of PC as an effective neuroprotective supplement in preventing HH-induced neurodegeneration. Activation of the PI3K/Akt pathway through BDNF/TrkB interaction following PC supplementation after exposure to HH inhibits hippocampal neuronal apoptosis and memory impairment.

Traditional antibiotic susceptibility testing methods take several days to confirm and start disease treatment. The lack of new antibiotics or drugs warrants a need for optimization of current diagnostic tools for immediate antibiotic susceptibility testing. We present a rapid screening method to evaluate the response of bacteria to antibiotics based upon the electrochemical measurement of live bacterial cell metabolic activity using an electroactive redox dye, resazurin. A thin film of Pt deposited over a glass substrate using the direct current sputtering technique was used as a working bio-electrode for electrochemical readouts. X-ray diffraction and scanning electron microscopy was carried out to characterize the Pt thin film. We tested the efficacy of the method using two different strains, Klebsiella pneumoniae (ATCC-700603) and Escherichia coli (ATCC-25922), against ampicillin, kanamycin and tetracycline. The dye, on incubation with viable bacteria, undergoes reduction and lowers the corresponding peak current value. However, in the presence of an effective antibacterial agent, reduction did not occur due to bacterial cell death and absence of a reducing environment. The electrochemical changes in peak current values were monitored using the differential pulse voltammetry technique and interpretation of the results obtained was based upon changes in peak current values. Our results depict a new methodology where a concentration of 10 4 cells/mL cells can be detected in less than 4 h. The results were also compared with the conventional disc diffusion method for susceptibility testing which has a bacterial incubation time of 18-24 h. The method can potentially be used for monitoring the susceptibility of bacterial strains towards existing antibacterial agents in an easy, rapid, reliable and inexpensive manner without any pre-cultivation of bacteria., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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 1 st , 4 th , 7 th , 11 th and 14 th day of study. On the 14 th 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.

High altitude-induced gastrointestinal (GI) problems are potentially life-threatening. GI tract bleeding and inflammation are the major problems induced by hypobaric hypoxia (HH). In this study, effects of acute exposure to HH up to 14 days at 7620 m on GI immune function have been studied. To fulfill these objectives, Sprague-Dawley (SD) rats were divided into five groups namely Control and HH exposed (1, 3, 7, and 14 days). All groups except control were exposed to 7620 m of HH in an animal decompression chamber for the respective time intervals. Different degrees of intestinal mucosal damage in terms of increased mucosal permeability and disruption of intestinal villi were observed for different time intervals. HH exposure also upregulated secretory immunoglobulin A (sIgA) and proinflammatory cytokines in GI lavage along with proinflammatory markers such as toll-like receptor 4 (TLR4) and inducible nitric oxide synthase (iNOS). HH exposure of rats for 7 days significantly increased interleukin-17 (IL-17) and natural killer (NK) cell and dendritic cell populations compared with unexposed control rats. However, the number of naive T cells was significantly decreased in Peyer's patches. Our results connect HH to GI immune axis and highlight Th17 cells and proinflammatory molecules as potential therapeutic targets to counteract HH-induced GI dysfunction.

Hypobaric hypoxia (HH) is a major stress factor that is associated with physiological, biochemical, molecular and genomic alterations. Brain is the organ that reacts sensitively to oxygen deprivation, which leads to oxidative stress and cognitive function impairment. Our previous studies have reported that downregulation of brain derived neurotrophic factor (BDNF) leads to neurodegeneration and memory impairment. The aim of the present study was to investigate the effect of HH exposure on DNA methylation and its regulation in BDNF expression, neurodegeneration and spatial memory impairment. For this purpose, Sprague Dawley rats were exposed to HH at a simulated altitude of 25,000 feet for 14 days. Real-time polymerase chain reaction was used for transcriptional expression of DNA Methyltransferases (DNMTs) including DNMT1, DNMT3a and -DNMT3b, and immunoblotting was used for the translational expression of DNMT1, DNMT3a, DNMT3b, Methyl CpG binding protein 2 (MeCP2), pMeCP2 and BDNF in rat hippocampus. Additionally, neuronal morphology alteration and neurodegeneration in CA1 region of hippocampus were investigated though Cresyl violet (CV) staining and Fluoro-Jade C staining respectively. Results obtained suggested that HH exposure increased the expression of DNMT1 DNMT3b at the mRNA as well as protein level, whereas no significant change was observed in the level of DNMT3a. Furthermore, the level of pMeCP2 and BDNF were significantly decreased; however, the expression level of MeCP2 was significantly increased. The CV and Fluoro-Jade C-positive cells were significantly enhanced in the CA1 region of hippocampus in the HH exposed group as compared to unexposed rats. Thus, the present study concluded that HH decreases neuronal activation by the upregulation of DNA methylation and MeCP2 and decreased the expression of pMeCP2, which result in the downregulation of BDNF. The decreased BDNF expression is associated with neuronal loss and spatial memory impairment. This study highlights that DNMT inhibition could be an important therapeutic target for neurodegenerative diseases.

Context: Hippophae rhamnoides L. (Elaeagnaceae), commonly known as seabuckthorn (SBT), is known for its medicinal and nutritional properties., Objective: Evaluation of in vivo adjuvant activity of SBT leaf extract (SBTE) with inactivated rabies virus antigen (Rb)., Materials and Methods: Swiss albino mice were immunized with aqueous-alcoholic SBTE (100 mg/kg body weight) or algel (aluminium hydroxide gel) with or without Rb (5% v/v). After priming, booster was administered on day 14. Rabies virus neutralizing antibody (RVNA) titers were estimated by rapid fluorescent focus inhibition test in sera samples collected on days 7, 14, 21, 28 and 35. Effect of adjuvant administration on cytotoxic T lymphocytes (CTLs), memory T cells, plasma and CD11c + cells was studied by flow cytometry. In vitro hemolysis was assayed in human RBC., Results: RVNA titers were significantly enhanced (p < 0.05) after booster administration in mice immunized with SBTE + Rb as compared to the controls. In combination, SBTE, algel and Rb, enhanced the RVNA titers. CTLs significantly increased (p < 0.05) in SBTE + Rb immunized mice. Memory T cells and plasma cells were 27.9 and 15.9%, respectively, in SBTE + Rb immunized mice as compared to that of 20.3 and 11.3%, respectively, in Rb immunized group. SBTE + Rb enhanced peritoneal CD11c + cells (25.8%) as compared to 9.4% cells in Rb immunized mice, showed 3.2-fold increment in LPS induced IL-1β. No RBC hemolysis was observed with SBTE., Conclusions: This study demonstrates the potential adjuvant activity of SBTE with Rb by increasing RVNA titers and CTL response.

Cyclooxygenase-2 or COX-2 has been known to be crucial for Parkinson's disease (PD) pathogenesis; however, its exact role is still not known. We first time report that inhibition of COX-2 promotes 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP)-induced neuronal cell death via induction of autophagic mechanisms. We found that treatment with MPTP induced cell death of neuroblastoma cells SH-SY5Y in a dose dependent manner. Treatment of MPTP has also upregulated the expressions of autophagic proteins such as LC3, beclin, ATG-5, and p62. Interestingly, nimesulide, a preferential COX-2 inhibitor, further potentiated the MPTP-induced cell death of human neuroblastoma cells. Treatment of nimesulide with MPTP further potentiated expressions of p62, ATG-5, beclin-1, LC3 autophagic proteins. Furthermore, nimesulide with MPTP increased apoptotic protein cleaved caspase-3 and also induced expression of p53 gene. Interestingly, it was observed that Akt inhibitor significantly increased MPTP-induced cell death of neuroblastoma cells. However, (-) deprenyl, a monoamine oxidase B (MAO B) inhibitor, attenuated MPTP-induced autophagic response and protected cell death. The prior treatment with prostaglandin E2 protected against nimesulide induced-death of neuronal cells. This study confirms that neuroinflammation is associated to the autophagy and may be one of the main pathological mechanisms in Parkinson's disease and other inflammation-associated disorders.

Brain, being the highest consumer of oxygen, is prone to increased risk of hypoxia-induced neurological insults. In response to hypoxia, microglia, the major resident immune cells of brain switches to an activated phenotype and promote inflammatory responses leading to tissue damage and loss of cognitive functions including working memory impairment. Till date, no proven clinical therapeutics is available to retard the progression of neurodegenerative memory impairment. In the present study, we investigated the therapeutic potential of intranasal small interfering RNA (siRNA) delivery in a mouse model of hypoxia-induced working memory impairment using microglial receptor, Mac-1 as a target gene. Here, we implicate Mac-1 scavenger receptor in microglial phenotype switching, neurodegeneration in prefrontal cortex, hippocampus and working memory impairment. RNA mediated silencing of Mac-1 in both in vitro and in vivo model showed significant impact of it on hypoxia induced altered expression of Mac-1 endogenous ligand, signaling cascade proteins, transcription factors and NADPH oxidase pathway. Efficient degradation of Mac-1 mRNA suppressed expression of M1 phenotypic markers, inflammatory chemokines, and cytokines, but on the other hand, it upregulated M2 phenotypic markers and anti-inflammatory cytokines. Neuronal viability and synaptic plasticity markers were also modulated significantly by this strategy. Behavioral study revealed significant downregulation in the number of working memory errors at a time-dependent manner after silencing the Mac-1 gene during continuous hypoxic exposure. The novel findings of this study for the very first time, unmasked the role of Mac-1 receptor in neurodegenerative disease progression under hypoxic condition and at the same time indicated the potential therapeutic value of this non-invasive siRNA delivery approach for treating working memory loss., (Copyright © 2018 Elsevier Ltd. All rights reserved.)