Avtar Meena | University of Tennessee Health Science Center (original) (raw)
Papers by Avtar Meena
phosphorylation of p53 expressed in HeLa cells
Alcohol, 2018
Disruption of intestinal epithelial tight junctions (TJ), gut barrier dysfunction and endotoxemia... more Disruption of intestinal epithelial tight junctions (TJ), gut barrier dysfunction and endotoxemia play important role in the pathogenesis of alcoholic liver disease (ALD). Our previous study showed that Ca2+ influx and TRPV6 channel play crucial role in ethanol (EtOH) and acetaldehyde induced TJ disruption and barrier dysfunction in Caco-2 cell monolayers. In the present study, we evaluated the effect of EtOH feeding on gut and liver injury in TRPV6 knockout (TRPV6-/-) mice. Wild type (WT) and TRPV6-/mice were fed 1e6% EtOH (0% 2d, 1% 2d, 2% 2d, 4% 1 wk, 5% 1 wk and 6% 1 wk) in Lieber-DeCarli liquid diet; control mice were pair fed iso-caloric maltodextrin. Colon length was slightly, but significantly, increased by EtOH feeding in WT mice, but not in TRPV6-/-mice. EtOH feeding elevated inulin permeability in the distal colon in vivo in WT mice, which was associated with redistribution of TJ proteins from the junctions. EtOH failed to alter colonic epithelial permeability and TJ disruption in TRPV6-/mice. Plasma endotoxin level was increased by EtOH feeding in WT mice, but not in TRPV6-/-mice. Actin cytoskeletal architecture in the colonic epithelium was disrupted by EtOH feeding in WT mice, which was associated with activation of cofilin. EtOH feeding increased liver triglyceride level, which was associated with histological lesions and elevated plasma AST/ALT in WT mice. EtOH-induced liver injury and plasma AST/ALT elevation were minimal in TRPV6-/-mice. In WT mice, EtOH depleted reduced protein thiols and elevated oxidized protein thiols in colonic epithelium and liver, which was associated with down regulation of antioxidant genes (SOD1, SOD2, Trx1, catalase, GPX1 & Nrf2); these effects of EtOH were minimal in TRPV6-/-mice. EtOH feeding up regulated inflammatory cytokine (IL-1b & TNFa) and chemokine (MCP-1, CCL5, CXCL1 & CXCL2) gene expression in WT mice, but not in TRPV6-/-mice. These data demonstrate that TRPV6 plays an important role in EtOH-induced colonic epithelial TJ disruption, mucosal barrier dysfunction, endotoxemia and liver damage, and that TRPV6 channel blockers may bear therapeutic value in the treatment of ALD and other alcohol-related diseases. (Supported by NIH R01 AA12307 (RKR) and R01 DK55532 (RKR).) 20. Impact of repeated binge drinking on resistance to bacterial pneumonia
The FASEB Journal, 2021
This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmer... more This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Nutritional Neuroscience, 2020
ABSTRACT Neuroinflammation is implicated in the pathogenesis of alcohol use disorders. We investi... more ABSTRACT Neuroinflammation is implicated in the pathogenesis of alcohol use disorders. We investigated the role of Gut-Brain interactions in alcohol-induced neuroinflammation by probiotic-mediated manipulation of intestinal dysbiosis in mice. Chronic ethanol feeding induced dysbiosis, as evidenced by an increase in Firmicutes/Bacteroidetes ratio and depletion of Lactobacillus species in the colon. Ethanol increased the levels of IL-1β, IL-6, and TNFα in plasma and the mRNA for IL-1β, IL-6, TNFα, and MCP1 genes in the cerebral cortex and hippocampus. Ethanol feeding increased inulin flux from the circulation into different brain regions, accompanied by the increase in TLR4 mRNA levels in the cerebral cortex and hippocampus. The immunofluorescence confocal microscopy showed that ethanol elevates the expression of microglial activation marker TMEM119 in the cerebral cortex. Feeding L. plantarum suppressed the ethanol-induced dysbiosis to some extent, as evidenced by attenuation of ethanol effects on Firmicutes/Bacteroidetes ratio and abundance of Lactobacillus spp. L. plantarum blocked ethanol-induced elevation of plasma cytokines, inulin permeability to the brain, mRNA for TLR4, IL-1β, IL-6, TNFα, and MCP1 in brain regions, and the expression of TMEM119 in the cerebral cortex. The L. plantarum effect was absent in mice that express a dominant-negative EGFR, suggesting that the EGFR receptor plays an essential role in the protective effect of L. plantarum against ethanol-induced neuroinflammation. L. plantarum, when administered after chronic ethanol-induced injury, rescued the ethanol-induced systemic inflammation and neuroinflammation. This study demonstrates that L. plantarum in the gut prevents and mitigates ethanol-induced neuroinflammation by an EGFR-dependent mechanism.
Biophysical Journal, 2022
Molecular specific photonic localization is a sensitive technique to probe the structural alterat... more Molecular specific photonic localization is a sensitive technique to probe the structural alterations or abnormalities in a cell such as abnormalities due to alcohol or other drugs. Alcohol consumption during pregnancy by mother, or fetal alcoholism, is one of the major factors of mental retardation in children. Fetal alcohol syndrome and alcohol related neurodevelopmental disorder are awful outcomes of the maternal alcohol consumption linked with notable cognitive and behavioral defects. Alcohol consumed by the pregnant mother, being teratogenic, interferes with the fetal health resulting brain damage and other birth defects. This might affect the brain cells at the very nanolevel which cannot be predicted by the present histopathological procedures. We perform quantification of nanoscale spatial structural alterations in two different spatial molecular components, DNA and histone molecular mass densities, in brain cell nuclei of fetal alcohol effected (FAE) pups at postnatal day 6...
Frontiers in Aging Neuroscience, 2021
The spectrum of health complications instigated by coronavirus disease 2019 (COVID-19, caused by ... more The spectrum of health complications instigated by coronavirus disease 2019 (COVID-19, caused by the novel severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2) pandemic has been diverse and complex. Besides the evident pulmonary and cardiovascular threats, accumulating clinical data points to several neurological complications, which are more common in elderly COVID-19 patients. Recent pieces of evidence have marked events of neuro infection and neuroinvasion, producing several neurological complications in COVID-19 patients; however, a systematic understanding of neuro-pathophysiology and manifested neurological complications, more specifically in elderly COVID-19 patients is largely elusive. Since the elderly population gradually develops neurological disorders with aging, COVID-19 inevitably poses a higher risk of neurological manifestations to the aged patients. In this report, we reviewed SARS-CoV-2 infection and its role in neurological manifestations with an emphasi...
The FASEB Journal, 2020
The tight junction (TJ) and barrier function of colonic epithelium is highly sensitive to ionizin... more The tight junction (TJ) and barrier function of colonic epithelium is highly sensitive to ionizing radiation. We evaluated the effect of lysophosphatidic acid (LPA) and its analog, Radioprotein-1, on γ-radiation-induced colonic epithelial barrier dysfunction using Caco-2 and m-IC C12 cell monolayers in vitro and mice in vivo. Mice were subjected to either total body irradiation (TBI) or partial body irradiation (PBI-BM5). Intestinal barrier function was assessed by analyzing immunofluorescence localization of TJ proteins, mucosal inulin permeability, and plasma lipopolysaccharide (LPS) levels. Oxidative stress was analyzed by measuring protein-thiol oxidation and antioxidant mRNA. In Caco-2 and m-IC C12 cell monolayers, LPA attenuated radiation-induced redistribution of TJ proteins, which was blocked by a Rho-kinase inhibitor. In mice, TBI and PBI-BM5 disrupted colonic epithelial tight junction and adherens junction, increased mucosal permeability, and elevated plasma LPS; TJ disruption by TBI was more severe in Lpar2 −/− mice compared to wild type mice. RP1, administered before or after irradiation, alleviated TBI and PBI-BM5-induced TJ disruption, barrier dysfunction, and endotoxemia accompanied by protein thiol oxidation and downregulation of antioxidant gene expression, cofilin activation, and remodeling of the actin cytoskeleton. These data demonstrate that LPAR2 receptor
Scientific Reports, 2021
Alcohol use disorders are associated with altered stress responses, but the impact of stress or s... more Alcohol use disorders are associated with altered stress responses, but the impact of stress or stress hormones on alcohol-associated tissue injury remain unknown. We evaluated the effects of chronic restraint stress on alcohol-induced gut barrier dysfunction and liver damage in mice. To determine whether corticosterone is the stress hormone associated with the stress-induced effects, we evaluated the effect of chronic corticosterone treatment on alcoholic tissue injury at the Gut-Liver-Brain (GLB) axis. Chronic restraint stress synergized alcohol-induced epithelial tight junction disruption and mucosal barrier dysfunction in the mouse intestine. These effects of stress on the gut were reproduced by corticosterone treatment. Corticosterone synergized alcohol-induced expression of inflammatory cytokines and chemokines in the colonic mucosa, and it potentiated the alcohol-induced endotoxemia and systemic inflammation. Corticosterone also potentiated alcohol-induced liver damage and ne...
Pathogens, 2020
The rapidly evolving coronavirus disease 2019 (COVID-19, caused by severe acute respiratory syndr... more The rapidly evolving coronavirus disease 2019 (COVID-19, caused by severe acute respiratory syndrome coronavirus 2- SARS-CoV-2), has greatly burdened the global healthcare system and led it into crisis in several countries. Lack of targeted therapeutics led to the idea of repurposing broad-spectrum drugs for viral intervention. In vitro analyses of hydroxychloroquine (HCQ)’s anecdotal benefits prompted its widespread clinical repurposing globally. Reports of emerging cardiovascular complications due to its clinical prescription are revealing the crucial role of angiotensin-converting enzyme 2 (ACE2), which serves as a target receptor for SARS-CoV-2. In the present settings, a clear understanding of these targets, their functional aspects and physiological impact on cardiovascular function are critical. In an up-to-date format, we shed light on HCQ’s anecdotal function in stalling SARS-CoV-2 replication and immunomodulatory activities. While starting with the crucial role of ACE2, we...
Authorea
Background and Purpose The colonic epithelium is highly sensitive to ionizing radiation, leading ... more Background and Purpose The colonic epithelium is highly sensitive to ionizing radiation, leading to impaired barrier function. Lysophosphatidic acid (LPA) is protective against radiation-induced intestinal mucosal injury and genotoxic stress. We evaluated the effect of LPA and its analog, Radioprotein-1 in radiation-induced colonic epithelial barrier dysfunction. Experimental approach Caco-2 and m-ICC12 cell monolayers were exposed up to g-radiation, and the barrier function was evaluated by measuring and unidirectional flux of FITC-inulin. Mice were subjected to either total body irradiation (TBI) or partial body irradiation (PBI-BM5). Intestinal barrier function was analyzed by evaluating mucosal permeability to inulin and measuring plasma lipopolysaccharide (LPS) levels. Tight junction and adherens junction integrity was examined by confocal microscopy. Oxidative stress was assessed by measuring protein thiol oxidation and antioxidant mRNA. Key Results In Caco-2 and m-ICC12 cell monolayers, LPA attenuates radiation-induced redistribution of tight junction proteins from the junctions, which was blocked by Rho-kinase inhibitor. In mice, TBI and PBI-BM5 disrupt colonic epithelial tight junction and adherens junction, increases mucosal inulin permeability and elevates plasma LPS. RP1 administered 30 min pre-irradiation or 24 hours post-irradiation alleviates TBI and PBI-BM5-induced tight junction disruption, barrier dysfunction, and endotoxemia. The RP1 effects on radiation-induced colonic injury was associated with protein thiol oxidation, suppression of antioxidant gene expression, cofilin activation and remodeling of actin cytoskeleton. Conclusion and Implications These data demonstrate that LPA2 receptor agonists prevent and mitigate g-irradiation-induced colonic mucosal barrier dysfunction and endotoxemia, indicating their potential therapeutic benefit in the treatment of the gastrointestinal acute radiation syndrome.
Alcohol, 2019
The meeting consisted of plenary sessions with oral presentations and a poster presentation sessi... more The meeting consisted of plenary sessions with oral presentations and a poster presentation session. There were four plenary sessions that covered a wide range of topics relating to alcohol use: Alcohol and Liver Disease; Alcohol, Inflammation and Immune Response; Alcohol and Organ Injury; Heath Consequences and Alcohol Drinking. The meeting provided a forum for the presentation and discussion of novel research findings regarding alcohol use and immunology.
Alcohol, 2018
Fetal alcohol spectrum disorders (FASD) are associated with social interaction behavior and gastr... more Fetal alcohol spectrum disorders (FASD) are associated with social interaction behavior and gastrointestinal (GI) abnormalities. These abnormal behaviors and GI abnormalities overlap with autism spectrum disorder (ASD). We investigated the effect of fetal alcohol exposure (FAE) on social interaction deficits (hallmark of autism). Evidence indicates that exogenous lipopolysaccharide (LPS) administration during gestation induces autism-like behavior in the litters. LPS regulates the expression of genes underlying differentiation, immune function, myelination and synaptogenesis in fetal brain by the LPS receptor, TLR-4-dependent mechanism. In this study, we evaluated the role of TLR-4 in FAE-induced social behavior deficit. WT and TLR4 −/− pregnant mice were fed Lieber-DeCarli liquid diet with or without EtOH. Control group was pair-fed with isocaloric diet. Social behavior was tested in the adult litters at postnatal day 60. Frontal cortex mRNA expression of autistic candidate genes (Ube3a, Gabrb3, Mecp2) and inflammatory cytokine genes (IL-1β, IL-6, TNF-α) were measured by RT-qPCR. Adult male litters of EtOH-fed WT dams showed low birth weight compared to litters of pair-fed WT dams. However, their body weights at adulthood were greater compared to the body weights of litters of pair-fed WT dams. There were no body weight differences in litters of TLR4 −/− dams. Social interaction deficit was observed only in male litters of EtOH-fed WT dams, but it was not observed in both male and female litters of EtOH-fed TLR4 −/− dams. Expressions of autism candidate genes, Gabrb3 and Ube3a were elevated, while that of Mecp2 gene was suppressed in *
The Journal of Nutritional Biochemistry, 2018
, EGF receptor plays a role in the mechanism of glutamine-mediated prevention of alcohol-induced ... more , EGF receptor plays a role in the mechanism of glutamine-mediated prevention of alcohol-induced gut barrier dysfunction and liver injury. Jnb (2018),
Experimental biology and medicine (Maywood, N.J.), Jan 25, 2018
Diarrheal disease is a severe global health problem. It is estimated that secretory diarrhea caus... more Diarrheal disease is a severe global health problem. It is estimated that secretory diarrhea causes 2.5 million deaths annually among children under the age of five in the developing world. A critical barrier in treating diarrheal disease is lack of easy-to-use effective treatments. While antibiotics may shorten the length and severity of diarrhea, oral rehydration remains the primary approach in managing secretory diarrhea. Existing treatments mostly depend on reconstituting medicines with water that is often contaminated which can be an unresolved problem in the developing world. Standard treatments for secretory diarrhea also include drugs that decrease intestinal motility. This approach is less than ideal because in cases where infection is the cause, this can increase the incidence of bacterial translocation and the potential for sepsis. Our goal is to develop a safe, effective, easy-to-use, and inexpensive treatment to reduce fluid loss in secretory diarrhea. We have developed...
Journal of cell science, Jan 6, 2018
The apical junctional complex (AJC), which includes tight junctions (TJs) and adherens junctions ... more The apical junctional complex (AJC), which includes tight junctions (TJs) and adherens junctions (AJs), determines the epithelial polarity, cell-cell adhesion and permeability barrier. An intriguing characteristic of a TJ is the dynamic nature of its multiprotein complex. Occludin is the most mobile TJ protein, but its significance in TJ dynamics is poorly understood. On the basis of phosphorylation sites, we distinguished a sequence in the C-terminal domain of occludin as a regulatory motif (ORM). Deletion of ORM and expression of a deletion mutant of occludin in renal and intestinal epithelia reduced the mobility of occludin at the TJs. ORM deletion attenuated Ca depletion, osmotic stress and hydrogen peroxide-induced disruption of TJs, AJs and the cytoskeleton. The double point mutations T403A/T404A, but not T403D/T404D, in occludin mimicked the effects of ORM deletion on occludin mobility and AJC disruption by Ca depletion. Both Y398A/Y402A and Y398D/Y402D double point mutations...
Gastroenterology, 2017
Cation exchange (CE) has been recognized as a particularly powerful tool for the synthesis of het... more Cation exchange (CE) has been recognized as a particularly powerful tool for the synthesis of heterogeneous nanocrystals. At present, CE can be divided into two categories, namely ion solvation-driven CE reaction and thermally activated CE reaction. Here we report an electrically driven CE reaction to prepare individual nanostructures inside a transmission electron microscope. During the process, Cd is eliminated due to Ohmic heating, whereas Cu þ migrates into the crystal driven by the electrical field force. Contrast experiments reveal that the feasibility of electrically driven CE is determined by the structural similarity of the sulfur sublattices between the initial and final phases, and the standard electrode potentials of the active electrodes. Our experimental results demonstrate a strategy for the selective growth of individual nanocrystals and provide crucial insights into understanding of the microscopic pathways leading to the formation of heterogeneous structures.
phosphorylation of p53 expressed in HeLa cells
Alcohol, 2018
Disruption of intestinal epithelial tight junctions (TJ), gut barrier dysfunction and endotoxemia... more Disruption of intestinal epithelial tight junctions (TJ), gut barrier dysfunction and endotoxemia play important role in the pathogenesis of alcoholic liver disease (ALD). Our previous study showed that Ca2+ influx and TRPV6 channel play crucial role in ethanol (EtOH) and acetaldehyde induced TJ disruption and barrier dysfunction in Caco-2 cell monolayers. In the present study, we evaluated the effect of EtOH feeding on gut and liver injury in TRPV6 knockout (TRPV6-/-) mice. Wild type (WT) and TRPV6-/mice were fed 1e6% EtOH (0% 2d, 1% 2d, 2% 2d, 4% 1 wk, 5% 1 wk and 6% 1 wk) in Lieber-DeCarli liquid diet; control mice were pair fed iso-caloric maltodextrin. Colon length was slightly, but significantly, increased by EtOH feeding in WT mice, but not in TRPV6-/-mice. EtOH feeding elevated inulin permeability in the distal colon in vivo in WT mice, which was associated with redistribution of TJ proteins from the junctions. EtOH failed to alter colonic epithelial permeability and TJ disruption in TRPV6-/mice. Plasma endotoxin level was increased by EtOH feeding in WT mice, but not in TRPV6-/-mice. Actin cytoskeletal architecture in the colonic epithelium was disrupted by EtOH feeding in WT mice, which was associated with activation of cofilin. EtOH feeding increased liver triglyceride level, which was associated with histological lesions and elevated plasma AST/ALT in WT mice. EtOH-induced liver injury and plasma AST/ALT elevation were minimal in TRPV6-/-mice. In WT mice, EtOH depleted reduced protein thiols and elevated oxidized protein thiols in colonic epithelium and liver, which was associated with down regulation of antioxidant genes (SOD1, SOD2, Trx1, catalase, GPX1 & Nrf2); these effects of EtOH were minimal in TRPV6-/-mice. EtOH feeding up regulated inflammatory cytokine (IL-1b & TNFa) and chemokine (MCP-1, CCL5, CXCL1 & CXCL2) gene expression in WT mice, but not in TRPV6-/-mice. These data demonstrate that TRPV6 plays an important role in EtOH-induced colonic epithelial TJ disruption, mucosal barrier dysfunction, endotoxemia and liver damage, and that TRPV6 channel blockers may bear therapeutic value in the treatment of ALD and other alcohol-related diseases. (Supported by NIH R01 AA12307 (RKR) and R01 DK55532 (RKR).) 20. Impact of repeated binge drinking on resistance to bacterial pneumonia
The FASEB Journal, 2021
This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmer... more This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Nutritional Neuroscience, 2020
ABSTRACT Neuroinflammation is implicated in the pathogenesis of alcohol use disorders. We investi... more ABSTRACT Neuroinflammation is implicated in the pathogenesis of alcohol use disorders. We investigated the role of Gut-Brain interactions in alcohol-induced neuroinflammation by probiotic-mediated manipulation of intestinal dysbiosis in mice. Chronic ethanol feeding induced dysbiosis, as evidenced by an increase in Firmicutes/Bacteroidetes ratio and depletion of Lactobacillus species in the colon. Ethanol increased the levels of IL-1β, IL-6, and TNFα in plasma and the mRNA for IL-1β, IL-6, TNFα, and MCP1 genes in the cerebral cortex and hippocampus. Ethanol feeding increased inulin flux from the circulation into different brain regions, accompanied by the increase in TLR4 mRNA levels in the cerebral cortex and hippocampus. The immunofluorescence confocal microscopy showed that ethanol elevates the expression of microglial activation marker TMEM119 in the cerebral cortex. Feeding L. plantarum suppressed the ethanol-induced dysbiosis to some extent, as evidenced by attenuation of ethanol effects on Firmicutes/Bacteroidetes ratio and abundance of Lactobacillus spp. L. plantarum blocked ethanol-induced elevation of plasma cytokines, inulin permeability to the brain, mRNA for TLR4, IL-1β, IL-6, TNFα, and MCP1 in brain regions, and the expression of TMEM119 in the cerebral cortex. The L. plantarum effect was absent in mice that express a dominant-negative EGFR, suggesting that the EGFR receptor plays an essential role in the protective effect of L. plantarum against ethanol-induced neuroinflammation. L. plantarum, when administered after chronic ethanol-induced injury, rescued the ethanol-induced systemic inflammation and neuroinflammation. This study demonstrates that L. plantarum in the gut prevents and mitigates ethanol-induced neuroinflammation by an EGFR-dependent mechanism.
Biophysical Journal, 2022
Molecular specific photonic localization is a sensitive technique to probe the structural alterat... more Molecular specific photonic localization is a sensitive technique to probe the structural alterations or abnormalities in a cell such as abnormalities due to alcohol or other drugs. Alcohol consumption during pregnancy by mother, or fetal alcoholism, is one of the major factors of mental retardation in children. Fetal alcohol syndrome and alcohol related neurodevelopmental disorder are awful outcomes of the maternal alcohol consumption linked with notable cognitive and behavioral defects. Alcohol consumed by the pregnant mother, being teratogenic, interferes with the fetal health resulting brain damage and other birth defects. This might affect the brain cells at the very nanolevel which cannot be predicted by the present histopathological procedures. We perform quantification of nanoscale spatial structural alterations in two different spatial molecular components, DNA and histone molecular mass densities, in brain cell nuclei of fetal alcohol effected (FAE) pups at postnatal day 6...
Frontiers in Aging Neuroscience, 2021
The spectrum of health complications instigated by coronavirus disease 2019 (COVID-19, caused by ... more The spectrum of health complications instigated by coronavirus disease 2019 (COVID-19, caused by the novel severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2) pandemic has been diverse and complex. Besides the evident pulmonary and cardiovascular threats, accumulating clinical data points to several neurological complications, which are more common in elderly COVID-19 patients. Recent pieces of evidence have marked events of neuro infection and neuroinvasion, producing several neurological complications in COVID-19 patients; however, a systematic understanding of neuro-pathophysiology and manifested neurological complications, more specifically in elderly COVID-19 patients is largely elusive. Since the elderly population gradually develops neurological disorders with aging, COVID-19 inevitably poses a higher risk of neurological manifestations to the aged patients. In this report, we reviewed SARS-CoV-2 infection and its role in neurological manifestations with an emphasi...
The FASEB Journal, 2020
The tight junction (TJ) and barrier function of colonic epithelium is highly sensitive to ionizin... more The tight junction (TJ) and barrier function of colonic epithelium is highly sensitive to ionizing radiation. We evaluated the effect of lysophosphatidic acid (LPA) and its analog, Radioprotein-1, on γ-radiation-induced colonic epithelial barrier dysfunction using Caco-2 and m-IC C12 cell monolayers in vitro and mice in vivo. Mice were subjected to either total body irradiation (TBI) or partial body irradiation (PBI-BM5). Intestinal barrier function was assessed by analyzing immunofluorescence localization of TJ proteins, mucosal inulin permeability, and plasma lipopolysaccharide (LPS) levels. Oxidative stress was analyzed by measuring protein-thiol oxidation and antioxidant mRNA. In Caco-2 and m-IC C12 cell monolayers, LPA attenuated radiation-induced redistribution of TJ proteins, which was blocked by a Rho-kinase inhibitor. In mice, TBI and PBI-BM5 disrupted colonic epithelial tight junction and adherens junction, increased mucosal permeability, and elevated plasma LPS; TJ disruption by TBI was more severe in Lpar2 −/− mice compared to wild type mice. RP1, administered before or after irradiation, alleviated TBI and PBI-BM5-induced TJ disruption, barrier dysfunction, and endotoxemia accompanied by protein thiol oxidation and downregulation of antioxidant gene expression, cofilin activation, and remodeling of the actin cytoskeleton. These data demonstrate that LPAR2 receptor
Scientific Reports, 2021
Alcohol use disorders are associated with altered stress responses, but the impact of stress or s... more Alcohol use disorders are associated with altered stress responses, but the impact of stress or stress hormones on alcohol-associated tissue injury remain unknown. We evaluated the effects of chronic restraint stress on alcohol-induced gut barrier dysfunction and liver damage in mice. To determine whether corticosterone is the stress hormone associated with the stress-induced effects, we evaluated the effect of chronic corticosterone treatment on alcoholic tissue injury at the Gut-Liver-Brain (GLB) axis. Chronic restraint stress synergized alcohol-induced epithelial tight junction disruption and mucosal barrier dysfunction in the mouse intestine. These effects of stress on the gut were reproduced by corticosterone treatment. Corticosterone synergized alcohol-induced expression of inflammatory cytokines and chemokines in the colonic mucosa, and it potentiated the alcohol-induced endotoxemia and systemic inflammation. Corticosterone also potentiated alcohol-induced liver damage and ne...
Pathogens, 2020
The rapidly evolving coronavirus disease 2019 (COVID-19, caused by severe acute respiratory syndr... more The rapidly evolving coronavirus disease 2019 (COVID-19, caused by severe acute respiratory syndrome coronavirus 2- SARS-CoV-2), has greatly burdened the global healthcare system and led it into crisis in several countries. Lack of targeted therapeutics led to the idea of repurposing broad-spectrum drugs for viral intervention. In vitro analyses of hydroxychloroquine (HCQ)’s anecdotal benefits prompted its widespread clinical repurposing globally. Reports of emerging cardiovascular complications due to its clinical prescription are revealing the crucial role of angiotensin-converting enzyme 2 (ACE2), which serves as a target receptor for SARS-CoV-2. In the present settings, a clear understanding of these targets, their functional aspects and physiological impact on cardiovascular function are critical. In an up-to-date format, we shed light on HCQ’s anecdotal function in stalling SARS-CoV-2 replication and immunomodulatory activities. While starting with the crucial role of ACE2, we...
Authorea
Background and Purpose The colonic epithelium is highly sensitive to ionizing radiation, leading ... more Background and Purpose The colonic epithelium is highly sensitive to ionizing radiation, leading to impaired barrier function. Lysophosphatidic acid (LPA) is protective against radiation-induced intestinal mucosal injury and genotoxic stress. We evaluated the effect of LPA and its analog, Radioprotein-1 in radiation-induced colonic epithelial barrier dysfunction. Experimental approach Caco-2 and m-ICC12 cell monolayers were exposed up to g-radiation, and the barrier function was evaluated by measuring and unidirectional flux of FITC-inulin. Mice were subjected to either total body irradiation (TBI) or partial body irradiation (PBI-BM5). Intestinal barrier function was analyzed by evaluating mucosal permeability to inulin and measuring plasma lipopolysaccharide (LPS) levels. Tight junction and adherens junction integrity was examined by confocal microscopy. Oxidative stress was assessed by measuring protein thiol oxidation and antioxidant mRNA. Key Results In Caco-2 and m-ICC12 cell monolayers, LPA attenuates radiation-induced redistribution of tight junction proteins from the junctions, which was blocked by Rho-kinase inhibitor. In mice, TBI and PBI-BM5 disrupt colonic epithelial tight junction and adherens junction, increases mucosal inulin permeability and elevates plasma LPS. RP1 administered 30 min pre-irradiation or 24 hours post-irradiation alleviates TBI and PBI-BM5-induced tight junction disruption, barrier dysfunction, and endotoxemia. The RP1 effects on radiation-induced colonic injury was associated with protein thiol oxidation, suppression of antioxidant gene expression, cofilin activation and remodeling of actin cytoskeleton. Conclusion and Implications These data demonstrate that LPA2 receptor agonists prevent and mitigate g-irradiation-induced colonic mucosal barrier dysfunction and endotoxemia, indicating their potential therapeutic benefit in the treatment of the gastrointestinal acute radiation syndrome.
Alcohol, 2019
The meeting consisted of plenary sessions with oral presentations and a poster presentation sessi... more The meeting consisted of plenary sessions with oral presentations and a poster presentation session. There were four plenary sessions that covered a wide range of topics relating to alcohol use: Alcohol and Liver Disease; Alcohol, Inflammation and Immune Response; Alcohol and Organ Injury; Heath Consequences and Alcohol Drinking. The meeting provided a forum for the presentation and discussion of novel research findings regarding alcohol use and immunology.
Alcohol, 2018
Fetal alcohol spectrum disorders (FASD) are associated with social interaction behavior and gastr... more Fetal alcohol spectrum disorders (FASD) are associated with social interaction behavior and gastrointestinal (GI) abnormalities. These abnormal behaviors and GI abnormalities overlap with autism spectrum disorder (ASD). We investigated the effect of fetal alcohol exposure (FAE) on social interaction deficits (hallmark of autism). Evidence indicates that exogenous lipopolysaccharide (LPS) administration during gestation induces autism-like behavior in the litters. LPS regulates the expression of genes underlying differentiation, immune function, myelination and synaptogenesis in fetal brain by the LPS receptor, TLR-4-dependent mechanism. In this study, we evaluated the role of TLR-4 in FAE-induced social behavior deficit. WT and TLR4 −/− pregnant mice were fed Lieber-DeCarli liquid diet with or without EtOH. Control group was pair-fed with isocaloric diet. Social behavior was tested in the adult litters at postnatal day 60. Frontal cortex mRNA expression of autistic candidate genes (Ube3a, Gabrb3, Mecp2) and inflammatory cytokine genes (IL-1β, IL-6, TNF-α) were measured by RT-qPCR. Adult male litters of EtOH-fed WT dams showed low birth weight compared to litters of pair-fed WT dams. However, their body weights at adulthood were greater compared to the body weights of litters of pair-fed WT dams. There were no body weight differences in litters of TLR4 −/− dams. Social interaction deficit was observed only in male litters of EtOH-fed WT dams, but it was not observed in both male and female litters of EtOH-fed TLR4 −/− dams. Expressions of autism candidate genes, Gabrb3 and Ube3a were elevated, while that of Mecp2 gene was suppressed in *
The Journal of Nutritional Biochemistry, 2018
, EGF receptor plays a role in the mechanism of glutamine-mediated prevention of alcohol-induced ... more , EGF receptor plays a role in the mechanism of glutamine-mediated prevention of alcohol-induced gut barrier dysfunction and liver injury. Jnb (2018),
Experimental biology and medicine (Maywood, N.J.), Jan 25, 2018
Diarrheal disease is a severe global health problem. It is estimated that secretory diarrhea caus... more Diarrheal disease is a severe global health problem. It is estimated that secretory diarrhea causes 2.5 million deaths annually among children under the age of five in the developing world. A critical barrier in treating diarrheal disease is lack of easy-to-use effective treatments. While antibiotics may shorten the length and severity of diarrhea, oral rehydration remains the primary approach in managing secretory diarrhea. Existing treatments mostly depend on reconstituting medicines with water that is often contaminated which can be an unresolved problem in the developing world. Standard treatments for secretory diarrhea also include drugs that decrease intestinal motility. This approach is less than ideal because in cases where infection is the cause, this can increase the incidence of bacterial translocation and the potential for sepsis. Our goal is to develop a safe, effective, easy-to-use, and inexpensive treatment to reduce fluid loss in secretory diarrhea. We have developed...
Journal of cell science, Jan 6, 2018
The apical junctional complex (AJC), which includes tight junctions (TJs) and adherens junctions ... more The apical junctional complex (AJC), which includes tight junctions (TJs) and adherens junctions (AJs), determines the epithelial polarity, cell-cell adhesion and permeability barrier. An intriguing characteristic of a TJ is the dynamic nature of its multiprotein complex. Occludin is the most mobile TJ protein, but its significance in TJ dynamics is poorly understood. On the basis of phosphorylation sites, we distinguished a sequence in the C-terminal domain of occludin as a regulatory motif (ORM). Deletion of ORM and expression of a deletion mutant of occludin in renal and intestinal epithelia reduced the mobility of occludin at the TJs. ORM deletion attenuated Ca depletion, osmotic stress and hydrogen peroxide-induced disruption of TJs, AJs and the cytoskeleton. The double point mutations T403A/T404A, but not T403D/T404D, in occludin mimicked the effects of ORM deletion on occludin mobility and AJC disruption by Ca depletion. Both Y398A/Y402A and Y398D/Y402D double point mutations...
Gastroenterology, 2017
Cation exchange (CE) has been recognized as a particularly powerful tool for the synthesis of het... more Cation exchange (CE) has been recognized as a particularly powerful tool for the synthesis of heterogeneous nanocrystals. At present, CE can be divided into two categories, namely ion solvation-driven CE reaction and thermally activated CE reaction. Here we report an electrically driven CE reaction to prepare individual nanostructures inside a transmission electron microscope. During the process, Cd is eliminated due to Ohmic heating, whereas Cu þ migrates into the crystal driven by the electrical field force. Contrast experiments reveal that the feasibility of electrically driven CE is determined by the structural similarity of the sulfur sublattices between the initial and final phases, and the standard electrode potentials of the active electrodes. Our experimental results demonstrate a strategy for the selective growth of individual nanocrystals and provide crucial insights into understanding of the microscopic pathways leading to the formation of heterogeneous structures.