Currently,more than 55 million people have dementia worldwide and Alzheimer’s disease(AD)is one of the most common causes of dementia in aging.However,no effective therapies are currently available for the prevention...Currently,more than 55 million people have dementia worldwide and Alzheimer’s disease(AD)is one of the most common causes of dementia in aging.However,no effective therapies are currently available for the prevention and treatment of AD.This is largely due to our limited understanding of the mechanisms underlying the neuropathogenesis of AD.It has widely been recognized that AD is heterogeneous and that multi-factors are contributing to the pathogenesis of AD.Accumulated evidence suggests that traumatic brain injury(TBI)is an important risk factor for the development of AD and dementia later in life(Guo et al.,2000;Johnson et al.,2010).However,the precise mechanism by which TBI contributes to developing AD has yet to be elucidated.展开更多
AIM: To understand the role of mitochondrial-produced superoxide(O 2 ?) in the regulation of iron-regulatory hormone, hepcidin by alcohol in the liver. METHODS: For alcohol experiments, manganese superoxide dismutase ...AIM: To understand the role of mitochondrial-produced superoxide(O 2 ?) in the regulation of iron-regulatory hormone, hepcidin by alcohol in the liver. METHODS: For alcohol experiments, manganese superoxide dismutase knockout mice heterozygous for Sod2 gene expression(Sod2 +/) and age-matched littermate control mice(LMC), expressing Sod2 gene on both alleles, were exposed to either 10%(w/v) ethanol in the drinking water or plain water(control) for 7 d. Total cellular O 2 ? levels in hepatocytes isolated from the livers of mice were measured by electron paramagnetic resonance spectroscopy. The mitochondrial-targeted, O 2 ?-sensitive fluorogenic probe, MitoSOX Red and flow cytometry were utilized to measure O 2 ? in mitochondria. Gene and protein expression were determined by Taqman Real-time quantitative PCR and Western blotting, respectively. RESULTS: Sod2 +/- mice expressed 40% less MnSOD protein(SOD2) in hepatocytes compared to LMC mice. The deletion of Sod2 allele did not alter the basal expression level of hepcidin in the liver. 10% ethanol exposure for 1 wk inhibited hepatic hepcidin mRNA expression three-fold both in Sod2 +/ and LMC mice. O 2 ? levels in hepatocytes of untreated Sod2 +/ mice were three-fold higher than in untreated LMC mice, as observed by electron paramagnetic resonance spectroscopy. O 2 ? levels in mitochondria of Sod2 +/ mice were four-fold higher than in mitochondria of untreated LMC mice, as measured by MitoSOX Red fluorescence and flow cytometry. Alcohol induced a two-fold higher increase in O 2 ? levels in hepatocytes of LMC mice than in Sod2 +/ mice compared to respective untreated counterparts. In contrast, 1 wk alcohol exposure did not alter mitochondrial O 2 ? levels in both Sod2 +/- and control mice. CONCLUSION: Mitochondrial O2 ? is not involved in the inhibition of liver hepcidin transcription and thereby regulation of iron metabolism by alcohol. These findings also suggest that short-term alcohol consumption significantly elevates O 2 ? levels in hepatocytes, which appears not to originate from mitochondria.展开更多
Trivalent chromium has long been recognized to benefit carbohydrate and lipid metabolism. Given emerging evidence that suggests chromium improves insulin sensitivity through the maintenance of an optimal level of plas...Trivalent chromium has long been recognized to benefit carbohydrate and lipid metabolism. Given emerging evidence that suggests chromium improves insulin sensitivity through the maintenance of an optimal level of plasma membrane (PM) cholesterol, we delineated the role of this micronutrient in attenuating hyperinsulinemia-induced cholesterol biosynthesis and insulin resistance. Exposing 3T3-L1 adipocytes to physiological hyperinsulinemia (500 pM 12 h), resulted in a marked impairment in insulin-stimulated glucose transport. Concurrent treatment with chromium in the picolinate form (CrPic, 10 nM 16 h) prevented against glucose transport dysfunction. Insulin signaling was neither impaired by hyperinsulinemia nor amplified by chromium to promote this protective action. Instead, it was found that hyperinsulinemia promoted an increase in PM cholesterol content that was observed to impair the acute ability of insulin to stimulate GLUT4 redistribution to the PM. Chromium prevented against the accumulation of PM cholesterol. Mechanistically, hyperinsulinemia promoted increases in O-GlcNAc modification of specificity protein 1 (Sp1), known to engage a cholesterolgenic response. Subsequent chromatin immunoprecipitation and luciferase assays revealed that hyperinsulinemia increased the binding affinity of Sp1 to the promoter region of Hmgcr, encoding 3-hydroxy 3-methyl-glutaryl-CoA reductase (HMGR), as well as HMGR promoter activity. This resulted in gains in mRNA and protein content of HMGR, with resulting elevations in PM cholesterol content. Moreover, treatment with chromium prevented this transcriptional response. Together, these data suggest a mechanism whereby CrPic affords glycemic health through inhibition of a transcriptional cholesterolgenic program detrimental to insulin action.展开更多
Traumatic brain injury(TBI)is a temporary or permanent disruption of brain function caused by external forces.TBI has been recognized as an important risk factor for the development of Alzheimer’s disease and dementi...Traumatic brain injury(TBI)is a temporary or permanent disruption of brain function caused by external forces.TBI has been recognized as an important risk factor for the development of Alzheimer’s disease and dementia later in life.However,the mechanisms by which TBI contributes to developing Alzheimer’s disease are largely unknown.展开更多
Evolving data show a variable expression of clinical neurological manifestations in patients suffering with coronavirus disease 2019(COVID-19)from early disease onset.The most frequent symptoms and signs are fatigue,d...Evolving data show a variable expression of clinical neurological manifestations in patients suffering with coronavirus disease 2019(COVID-19)from early disease onset.The most frequent symptoms and signs are fatigue,dizziness,impaired consciousness,ageusia,anosmia,radicular pain,and headache,as well as others.Based on the high number of series of cases reported,there is evidence for the implication of the immune system in the pathological mechanism of COVID-19.Although the exact role of the immunological mechanism is not elucidated,two main mechanisms are suggested which implicate the direct effect of severe acute respiratory syndrome coronavirus 2 infection in the central nervous system and neuroinflammation.In the context of neurological manifestations associated with COVID-19,neuropsychiatric disorders show an exacerbation and are described by symptoms and signs such as depression,anxiety,mood alterations,psychosis,post-traumatic stress disorder,delirium,and cognitive impairment,which appear to be common in COVID-19 survivors.A worsened score on psychopathological measures is seen in those with a history of psychiatric comorbidities.We review the neuropsychiatric manifestations associated with COVID-19 and some critical aspects of the innate and adaptive immune system involved in mental health disorders occurring in COVID-19.展开更多
Alzheimer’s disease(AD)is the most common cause of dementia in the elderly.Unfortunately,there are no effective therapies currently available for prevention and treatment of AD.As it is clear now,the etiology of AD i...Alzheimer’s disease(AD)is the most common cause of dementia in the elderly.Unfortunately,there are no effective therapies currently available for prevention and treatment of AD.As it is clear now,the etiology of AD is multifactorial and complex.This means that development of AD is linked to multiple mechanisms or signaling pathways and that a single-target therapy for AD is likely insufficient to achieve therapeutic goals.Therefore,an ideal therapy for AD should be able to modify the disease through multiple signaling pathways.2-Arachidonoylglycerol(2-AG)is an endogenous cannabinoid(endocannabinoid)displayinganti-inflammator y a n d neuroprotective properties,while its metabolites are arachidonic acid(AA)and AA-derived prostaglandins and leukotrienes,which are proinflammatory and neurotoxic(Figure 1).展开更多
Background: The impact of Roux-en-Y gastric bypass (RYGB) on type 2 diabetes mellitus is thought to result from upper and/or lower gut hormone alterations. Evidence supporting these mechanisms is incomplete, in part b...Background: The impact of Roux-en-Y gastric bypass (RYGB) on type 2 diabetes mellitus is thought to result from upper and/or lower gut hormone alterations. Evidence supporting these mechanisms is incomplete, in part because of limitations in relevant bariatric-surgery animal models, specifically the lack of naturally insulin-resistant large animals. With overfeeding, Ossabaw swine develop a robust metabolic syndrome, and may be suitable for studying post-surgical physiology. Whether bariatric surgery is feasible in these animals with acceptable survival is unknown. Methods: Thirty-two Ossabaws were fed a high-fat, high-cholesterol diet to induce obesity and insulin resistance. These animals were assigned to RYGB (n = 8), RYGB with vagotomy (RYGB-V, n = 5), gastrojejunostomy (GJ, n = 10), GJ with duodenal exclusion (GJD, n = 7), or sham operation (n = 2) and were euthanized 60 days post-operatively. Post-operative changes in weight and food intake are reported. Results: Survival to scheduled necropsy among surgical groups was 77%, living an average of 57 days post-operatively. Cardiac arrest under anesthesia occurred in 4 pigs. Greatest weight loss (18.0% ± 6%) and food intake decrease (57.0% ± 20%) occurred following RYGB while animals undergoing RYGB-V showed only 6.6% ± 3% weight loss despite 50.8% ± 25% food intake decrease. GJ (12.7% ± 4%) and GJD (1.2% ± 1%) pigs gained weight, but less than sham controls (13.4% ± 10%). Conclusions: A survival model of metabolic surgical procedures is feasible, leads to significant weight loss, and provides the opportunity to evaluate new interventions and subtle variations in surgical technique (e.g. vagus nerve sparing) that may provide new mechanistic insights.展开更多
Dear Editor,Tumor-associated macrophages(TAMs)are critical pro-tumor immunocytes and depletion of TAMs has been exploited for cancer therapy.1 However,the phenotypes and functions of TAMs are plastic,TAMs can also be ...Dear Editor,Tumor-associated macrophages(TAMs)are critical pro-tumor immunocytes and depletion of TAMs has been exploited for cancer therapy.1 However,the phenotypes and functions of TAMs are plastic,TAMs can also be effector cells by engulfing tumor cells and recruiting cytotoxic T cells,thus shaping the actions of TAMs is more scientific rational than depleting them indiscriminately.2 To promote the entry of reorienting TAMs into the clinical treatments of tumors,it is essential to explore the underline mechanisms controlling the anti-and pro-tumor activities of TAMs.展开更多
A recent study by Zoufaly et al.published in The Lancet Respiratory Medicine describes encouraging data from the first severe COVID-19 patient successfully treated with human recombinant soluble angiotensin-converting...A recent study by Zoufaly et al.published in The Lancet Respiratory Medicine describes encouraging data from the first severe COVID-19 patient successfully treated with human recombinant soluble angiotensin-converting enzyme-2(hrsACE2).1 The published data document upon treatment of an adaptive immune response,the disappearance of the virus swiftly from the serum,the nasal cavity and lungs,and a reduction of inflammatory cytokine levels that are critical for COVID-19 pathology.Notably,the use of hrsACE2 did not impede the generation of neutralizing antibodies,leading to a significant clinical improvement of the treated patient.展开更多
基金supported by National Institutes of Health grants RF1NS076815 and R01AG058621.
文摘Currently,more than 55 million people have dementia worldwide and Alzheimer’s disease(AD)is one of the most common causes of dementia in aging.However,no effective therapies are currently available for the prevention and treatment of AD.This is largely due to our limited understanding of the mechanisms underlying the neuropathogenesis of AD.It has widely been recognized that AD is heterogeneous and that multi-factors are contributing to the pathogenesis of AD.Accumulated evidence suggests that traumatic brain injury(TBI)is an important risk factor for the development of AD and dementia later in life(Guo et al.,2000;Johnson et al.,2010).However,the precise mechanism by which TBI contributes to developing AD has yet to be elucidated.
基金Supported by Grant to Harrison-Findik DD,No.NIH R01AA017738University of Nebraska Medical Center Undergraduate Scholarship to Lu S EPR spectroscopy studies were conducted in the EPR Core Facility,which is supported by the University of Nebraska-Lincoln Redox Biology Center,No.NIH 1 P30 GM103335
文摘AIM: To understand the role of mitochondrial-produced superoxide(O 2 ?) in the regulation of iron-regulatory hormone, hepcidin by alcohol in the liver. METHODS: For alcohol experiments, manganese superoxide dismutase knockout mice heterozygous for Sod2 gene expression(Sod2 +/) and age-matched littermate control mice(LMC), expressing Sod2 gene on both alleles, were exposed to either 10%(w/v) ethanol in the drinking water or plain water(control) for 7 d. Total cellular O 2 ? levels in hepatocytes isolated from the livers of mice were measured by electron paramagnetic resonance spectroscopy. The mitochondrial-targeted, O 2 ?-sensitive fluorogenic probe, MitoSOX Red and flow cytometry were utilized to measure O 2 ? in mitochondria. Gene and protein expression were determined by Taqman Real-time quantitative PCR and Western blotting, respectively. RESULTS: Sod2 +/- mice expressed 40% less MnSOD protein(SOD2) in hepatocytes compared to LMC mice. The deletion of Sod2 allele did not alter the basal expression level of hepcidin in the liver. 10% ethanol exposure for 1 wk inhibited hepatic hepcidin mRNA expression three-fold both in Sod2 +/ and LMC mice. O 2 ? levels in hepatocytes of untreated Sod2 +/ mice were three-fold higher than in untreated LMC mice, as observed by electron paramagnetic resonance spectroscopy. O 2 ? levels in mitochondria of Sod2 +/ mice were four-fold higher than in mitochondria of untreated LMC mice, as measured by MitoSOX Red fluorescence and flow cytometry. Alcohol induced a two-fold higher increase in O 2 ? levels in hepatocytes of LMC mice than in Sod2 +/ mice compared to respective untreated counterparts. In contrast, 1 wk alcohol exposure did not alter mitochondrial O 2 ? levels in both Sod2 +/- and control mice. CONCLUSION: Mitochondrial O2 ? is not involved in the inhibition of liver hepcidin transcription and thereby regulation of iron metabolism by alcohol. These findings also suggest that short-term alcohol consumption significantly elevates O 2 ? levels in hepatocytes, which appears not to originate from mitochondria.
文摘Trivalent chromium has long been recognized to benefit carbohydrate and lipid metabolism. Given emerging evidence that suggests chromium improves insulin sensitivity through the maintenance of an optimal level of plasma membrane (PM) cholesterol, we delineated the role of this micronutrient in attenuating hyperinsulinemia-induced cholesterol biosynthesis and insulin resistance. Exposing 3T3-L1 adipocytes to physiological hyperinsulinemia (500 pM 12 h), resulted in a marked impairment in insulin-stimulated glucose transport. Concurrent treatment with chromium in the picolinate form (CrPic, 10 nM 16 h) prevented against glucose transport dysfunction. Insulin signaling was neither impaired by hyperinsulinemia nor amplified by chromium to promote this protective action. Instead, it was found that hyperinsulinemia promoted an increase in PM cholesterol content that was observed to impair the acute ability of insulin to stimulate GLUT4 redistribution to the PM. Chromium prevented against the accumulation of PM cholesterol. Mechanistically, hyperinsulinemia promoted increases in O-GlcNAc modification of specificity protein 1 (Sp1), known to engage a cholesterolgenic response. Subsequent chromatin immunoprecipitation and luciferase assays revealed that hyperinsulinemia increased the binding affinity of Sp1 to the promoter region of Hmgcr, encoding 3-hydroxy 3-methyl-glutaryl-CoA reductase (HMGR), as well as HMGR promoter activity. This resulted in gains in mRNA and protein content of HMGR, with resulting elevations in PM cholesterol content. Moreover, treatment with chromium prevented this transcriptional response. Together, these data suggest a mechanism whereby CrPic affords glycemic health through inhibition of a transcriptional cholesterolgenic program detrimental to insulin action.
基金supported by National Institutes of Health grants No. R01NS076815, R01MH113535, and R01AG058621。
文摘Traumatic brain injury(TBI)is a temporary or permanent disruption of brain function caused by external forces.TBI has been recognized as an important risk factor for the development of Alzheimer’s disease and dementia later in life.However,the mechanisms by which TBI contributes to developing Alzheimer’s disease are largely unknown.
文摘Evolving data show a variable expression of clinical neurological manifestations in patients suffering with coronavirus disease 2019(COVID-19)from early disease onset.The most frequent symptoms and signs are fatigue,dizziness,impaired consciousness,ageusia,anosmia,radicular pain,and headache,as well as others.Based on the high number of series of cases reported,there is evidence for the implication of the immune system in the pathological mechanism of COVID-19.Although the exact role of the immunological mechanism is not elucidated,two main mechanisms are suggested which implicate the direct effect of severe acute respiratory syndrome coronavirus 2 infection in the central nervous system and neuroinflammation.In the context of neurological manifestations associated with COVID-19,neuropsychiatric disorders show an exacerbation and are described by symptoms and signs such as depression,anxiety,mood alterations,psychosis,post-traumatic stress disorder,delirium,and cognitive impairment,which appear to be common in COVID-19 survivors.A worsened score on psychopathological measures is seen in those with a history of psychiatric comorbidities.We review the neuropsychiatric manifestations associated with COVID-19 and some critical aspects of the innate and adaptive immune system involved in mental health disorders occurring in COVID-19.
基金supported by National Institutes of Health grants R01NS076815,R01MH113535,and R01AG058621(to CC).
文摘Alzheimer’s disease(AD)is the most common cause of dementia in the elderly.Unfortunately,there are no effective therapies currently available for prevention and treatment of AD.As it is clear now,the etiology of AD is multifactorial and complex.This means that development of AD is linked to multiple mechanisms or signaling pathways and that a single-target therapy for AD is likely insufficient to achieve therapeutic goals.Therefore,an ideal therapy for AD should be able to modify the disease through multiple signaling pathways.2-Arachidonoylglycerol(2-AG)is an endogenous cannabinoid(endocannabinoid)displayinganti-inflammator y a n d neuroprotective properties,while its metabolites are arachidonic acid(AA)and AA-derived prostaglandins and leukotrienes,which are proinflammatory and neurotoxic(Figure 1).
文摘Background: The impact of Roux-en-Y gastric bypass (RYGB) on type 2 diabetes mellitus is thought to result from upper and/or lower gut hormone alterations. Evidence supporting these mechanisms is incomplete, in part because of limitations in relevant bariatric-surgery animal models, specifically the lack of naturally insulin-resistant large animals. With overfeeding, Ossabaw swine develop a robust metabolic syndrome, and may be suitable for studying post-surgical physiology. Whether bariatric surgery is feasible in these animals with acceptable survival is unknown. Methods: Thirty-two Ossabaws were fed a high-fat, high-cholesterol diet to induce obesity and insulin resistance. These animals were assigned to RYGB (n = 8), RYGB with vagotomy (RYGB-V, n = 5), gastrojejunostomy (GJ, n = 10), GJ with duodenal exclusion (GJD, n = 7), or sham operation (n = 2) and were euthanized 60 days post-operatively. Post-operative changes in weight and food intake are reported. Results: Survival to scheduled necropsy among surgical groups was 77%, living an average of 57 days post-operatively. Cardiac arrest under anesthesia occurred in 4 pigs. Greatest weight loss (18.0% ± 6%) and food intake decrease (57.0% ± 20%) occurred following RYGB while animals undergoing RYGB-V showed only 6.6% ± 3% weight loss despite 50.8% ± 25% food intake decrease. GJ (12.7% ± 4%) and GJD (1.2% ± 1%) pigs gained weight, but less than sham controls (13.4% ± 10%). Conclusions: A survival model of metabolic surgical procedures is feasible, leads to significant weight loss, and provides the opportunity to evaluate new interventions and subtle variations in surgical technique (e.g. vagus nerve sparing) that may provide new mechanistic insights.
文摘Dear Editor,Tumor-associated macrophages(TAMs)are critical pro-tumor immunocytes and depletion of TAMs has been exploited for cancer therapy.1 However,the phenotypes and functions of TAMs are plastic,TAMs can also be effector cells by engulfing tumor cells and recruiting cytotoxic T cells,thus shaping the actions of TAMs is more scientific rational than depleting them indiscriminately.2 To promote the entry of reorienting TAMs into the clinical treatments of tumors,it is essential to explore the underline mechanisms controlling the anti-and pro-tumor activities of TAMs.
文摘A recent study by Zoufaly et al.published in The Lancet Respiratory Medicine describes encouraging data from the first severe COVID-19 patient successfully treated with human recombinant soluble angiotensin-converting enzyme-2(hrsACE2).1 The published data document upon treatment of an adaptive immune response,the disappearance of the virus swiftly from the serum,the nasal cavity and lungs,and a reduction of inflammatory cytokine levels that are critical for COVID-19 pathology.Notably,the use of hrsACE2 did not impede the generation of neutralizing antibodies,leading to a significant clinical improvement of the treated patient.
