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International Journal of Molecular... Feb 2023Ubiquitination and deubiquitination are reversible processes that modify the characteristics of target proteins, including stability, intracellular localization, and... (Review)
Review
Ubiquitination and deubiquitination are reversible processes that modify the characteristics of target proteins, including stability, intracellular localization, and enzymatic activity. Ubiquitin-specific proteases (USPs) constitute the largest deubiquitinating enzyme family. To date, accumulating evidence indicates that several USPs positively and negatively affect metabolic diseases. USP22 in pancreatic β-cells, USP2 in adipose tissue macrophages, USP9X, 20, and 33 in myocytes, USP4, 7, 10, and 18 in hepatocytes, and USP2 in hypothalamus improve hyperglycemia, whereas USP19 in adipocytes, USP21 in myocytes, and USP2, 14, and 20 in hepatocytes promote hyperglycemia. In contrast, USP1, 5, 9X, 14, 15, 22, 36, and 48 modulate the progression of diabetic nephropathy, neuropathy, and/or retinopathy. USP4, 10, and 18 in hepatocytes ameliorates non-alcoholic fatty liver disease (NAFLD), while hepatic USP2, 11, 14, 19, and 20 exacerbate it. The roles of USP7 and 22 in hepatic disorders are controversial. USP9X, 14, 17, and 20 in vascular cells are postulated to be determinants of atherosclerosis. Moreover, mutations in the and loci in pituitary tumors cause Cushing syndrome. This review summarizes the current knowledge about the modulatory roles of USPs in energy metabolic disorders.
Topics: Humans; Ubiquitin-Specific Proteases; Ubiquitination; Hepatocytes; Non-alcoholic Fatty Liver Disease; Ubiquitin Thiolesterase; Ubiquitin-Specific Peptidase 7; Endopeptidases
PubMed: 36834633
DOI: 10.3390/ijms24043219 -
Journal of Clinical Medicine Nov 2022The purpose of this article is to improve recognition and treatment of Wernicke-Korsakoff syndrome. It is well known that Korsakoff syndrome is a chronic amnesia... (Review)
Review
The purpose of this article is to improve recognition and treatment of Wernicke-Korsakoff syndrome. It is well known that Korsakoff syndrome is a chronic amnesia resulting from unrecognized or undertreated Wernicke encephalopathy and is caused by thiamine (vitamin B1) deficiency. The clinical presentation of thiamine deficiency includes loss of appetite, dizziness, tachycardia, and urinary bladder retention. These symptoms can be attributed to anticholinergic autonomic dysfunction, as well as confusion or delirium, which is part of the classic triad of Wernicke encephalopathy. Severe concomitant infections including sepsis of unknown origin are common during the Wernicke phase. These infections can be prodromal signs of severe thiamine deficiency, as has been shown in select case descriptions which present infections and lactic acidosis. The clinical symptoms of Wernicke delirium commonly arise within a few days before or during hospitalization and may occur as part of a refeeding syndrome. Wernicke encephalopathy is mostly related to alcohol addiction, but can also occur in other conditions, such as bariatric surgery, hyperemesis gravidarum, and anorexia nervosa. Alcohol related Wernicke encephalopathy may be identified by the presence of a delirium in malnourished alcoholic patients who have trouble walking. The onset of non-alcohol-related Wernicke encephalopathy is often characterized by vomiting, weight loss, and symptoms such as visual complaints due to optic neuropathy in thiamine deficiency. Regarding thiamine therapy, patients with hypomagnesemia may fail to respond to thiamine. This may especially be the case in the context of alcohol withdrawal or in adverse side effects of proton pump inhibitors combined with diuretics. Clinician awareness of the clinical significance of Wernicke delirium, urinary bladder retention, comorbid infections, refeeding syndrome, and hypomagnesemia may contribute to the recognition and treatment of the Wernicke-Korsakoff syndrome.
PubMed: 36431232
DOI: 10.3390/jcm11226755 -
Revue Medicale de Liege May 2019Chronic alcohol consumption results in multiple peripheral and central nervous system dysfunctions. Some are due to the direct action of alcohol or its derivatives,... (Review)
Review
Chronic alcohol consumption results in multiple peripheral and central nervous system dysfunctions. Some are due to the direct action of alcohol or its derivatives, others are induced by the vitamin deficiencies associated with alcoholism, others are eventually related to the failure of other vital organs, such as the liver. In this short review, we describe alcohol-induced neuropathy, Gayet-Wernicke syndrome, Korsakoff syndrome, alcoholic dementia, Marchiafava-Bignami syndrome, hepatic encephalopathy, alcoholic epilepsy and manifestations of alcohol withdrawal.
Topics: Alcoholism; Dementia; Hepatic Encephalopathy; Humans; Wernicke Encephalopathy
PubMed: 31206272
DOI: No ID Found -
Cell Metabolism Mar 2021The nervous system instructs the body's metabolism, including that in the liver. However, the neural anatomy of the liver under either normal or metabolically stressed...
The nervous system instructs the body's metabolism, including that in the liver. However, the neural anatomy of the liver under either normal or metabolically stressed conditions remains to be unequivocally assessed. Here, we examined neural distributions in the mouse, nonhuman primate, and human livers with advanced 3D imaging. We observed that neural innervations within the liver are predominantly sympathetic, but not parasympathetic, inputs. Moreover, we discovered the profound and reversible loss of such sympathetic innervations during metabolic challenges. This hepatic sympathetic neuropathy was caused by TNFα derived from CD11b F4/80 immune cells under high-fat-diet (HFD) condition. We further demonstrated that the Sarm1 deletion mitigated the hepatic sympathetic neuropathy and improved metabolic parameters in HFD-challenged mice. Mechanistically, the sympathetic neurotransmitter norepinephrine attenuated the immune-cell inflammation that would otherwise trigger the insulin insensitivity of hepatocytes. These results together reveal the previously unrecognized neuropathic event in the liver with metabolic relevance.
Topics: Animals; Armadillo Domain Proteins; Cytoskeletal Proteins; Diet, High-Fat; Humans; Liver; Lymphocytes; Macaca mulatta; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Norepinephrine; Stress, Physiological; Tumor Necrosis Factor-alpha
PubMed: 33545051
DOI: 10.1016/j.cmet.2021.01.012 -
Critical Reviews in Food Science and... 2023Age-related diseases are associated with increased morbidity in the past few decades and the cost associated with the treatment of these age-related diseases exerts a... (Review)
Review
Age-related diseases are associated with increased morbidity in the past few decades and the cost associated with the treatment of these age-related diseases exerts a substantial impact on social and health care expenditure. Anti-aging strategies aim to mitigate, delay and reverse aging-associated diseases, thereby improving quality of life and reducing the burden of age-related pathologies. The natural dietary antioxidant supplementation offers substantial pharmacological and therapeutic effects against various disease conditions. Astaxanthin is one such natural carotenoid with superior antioxidant activity than other carotenoids, as well as well as vitamins C and E, and additionally, it is known to exhibit a plethora of pharmacological effects. The present review summarizes the protective molecular mechanisms of actions of astaxanthin on age-related diseases of multiple organs such as Neurodegenerative diseases [Alzheimer's disease (AD), Parkinson's disease (PD), Stroke, Multiple Sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Status Epilepticus (SE)], Bone Related Diseases [Osteoarthritis (OA) and Osteoporosis], Cancers [Colon cancer, Prostate cancer, Breast cancer, and Lung Cancer], Cardiovascular disorders [Hypertension, Atherosclerosis and Myocardial infarction (MI)], Diabetes associated complications [Diabetic nephropathy (DN), Diabetic neuropathy, and Diabetic retinopathy (DR)], Eye disorders [Age related macular degeneration (AMD), Dry eye disease (DED), Cataract and Uveitis], Gastric Disorders [Gastritis, Colitis, and Functional dyspepsia], Kidney Disorders [Nephrolithiasis, Renal fibrosis, Renal Ischemia reperfusion (RIR), Acute kidney injury (AKI), and hyperuricemia], Liver Diseases [Nonalcoholic fatty liver disease (NAFLD), Alcoholic Liver Disease (AFLD), Liver fibrosis, and Hepatic Ischemia-Reperfusion (IR) Injury], Pulmonary Disorders [Pulmonary Fibrosis, Acute Lung injury (ALI), and Chronic obstructive pulmonary disease (COPD)], Muscle disorders (skeletal muscle atrophy), Skin diseases [Atopic dermatitis (ATD), Skin Photoaging, and Wound healing]. We have also briefly discussed astaxanthin's protective effects on reproductive health.
Topics: Male; Humans; Quality of Life; Antioxidants; Aging; Carotenoids; Ischemia
PubMed: 35708049
DOI: 10.1080/10408398.2022.2084600 -
Journal of Neurology Dec 2019The primary aim of this systematic review was to establish the prevalence, character, and risk factors of peripheral neuropathy amongst chronic alcohol abusers and to... (Meta-Analysis)
Meta-Analysis
The primary aim of this systematic review was to establish the prevalence, character, and risk factors of peripheral neuropathy amongst chronic alcohol abusers and to identify the most appropriate management strategies. In this review, possible pathogenetic mechanisms are also discussed. A systematic, computer-based search was conducted using the PubMed database. Data regarding the above parameters were extracted. 87 articles were included in this review, 29 case-control studies, 52 prospective/retrospective cohort studies and 2 randomised control trials, 1 cross sectional study, and 3 population-based studies. The prevalence of peripheral neuropathy amongst chronic alcohol abusers is 46.3% (CI 35.7- 57.3%) when confirmed via nerve conduction studies. Alcohol-related peripheral neuropathy generally presents as a progressive, predominantly sensory axonal length-dependent neuropathy. The most important risk factor for alcohol-related peripheral neuropathy is the total lifetime dose of ethanol, although other risk factors have been identified including genetic, male gender, and type of alcohol consumed. At present, it is unclear what the pathogenetic mechanisms for the development of neuropathy amongst those who chronically abuse alcohol are, and therefore, it is unknown whether it is attributed to the direct toxic effects of ethanol or another currently unidentified factor. There is presently sparse data to support a particular management strategy in alcohol-related peripheral neuropathy, but the limited data available appears to support the use of vitamin supplementation, particularly of B-vitamin regimens inclusive of thiamine.
Topics: Alcoholic Neuropathy; Humans; Peripheral Nervous System Diseases
PubMed: 30467601
DOI: 10.1007/s00415-018-9123-1 -
Presse Medicale (Paris, France : 1983) Mar 2017Thiamine deficiency (vitamin B1) is common in patients with alcohol dependence. Cognitive impairments may be an early consequence of thiamine deficiency. Wernicke's... (Review)
Review
Thiamine deficiency (vitamin B1) is common in patients with alcohol dependence. Cognitive impairments may be an early consequence of thiamine deficiency. Wernicke's encephalopathy is underdiagnosed and undertreated. In patients with established Wernicke's encephalopathy, parenteral thiamine 200-500mg three times a day should be given for 3-5 days, followed by oral thiamine 250-1000mg/day. In patients with suspected Wernicke's encephalopathy, parenteral thiamine 250-300mg should be given two times a day for 3-5 days, followed by oral thiamine 250-300mg/day. In patients at high risk of thiamine deficiency, parenteral thiamine 250-500mg/day should be given for 3-5 days, followed by oral thiamine 250-300mg/day. In patients at low risk (with uncomplicated alcohol dependence), oral thiamine 250-500mg/day should be given for 3-5 days, followed by oral thiamine 100-250mg/day.
Topics: Alcoholic Neuropathy; Alcoholism; Cardiomyopathy, Alcoholic; Diagnosis, Differential; Drug Administration Routes; Drug Administration Schedule; Humans; Korsakoff Syndrome; Malnutrition; Symptom Assessment; Thiamine; Thiamine Deficiency; Wernicke Encephalopathy
PubMed: 27818067
DOI: 10.1016/j.lpm.2016.07.025 -
The Lancet. Diabetes & Endocrinology Sep 2019Cluster analyses have proposed different diabetes phenotypes using age, BMI, glycaemia, homoeostasis model estimates, and islet autoantibodies. We tested whether...
BACKGROUND
Cluster analyses have proposed different diabetes phenotypes using age, BMI, glycaemia, homoeostasis model estimates, and islet autoantibodies. We tested whether comprehensive phenotyping validates and further characterises these clusters at diagnosis and whether relevant diabetes-related complications differ among these clusters, during 5-years of follow-up.
METHODS
Patients with newly diagnosed type 1 or type 2 diabetes in the German Diabetes Study underwent comprehensive phenotyping and assessment of laboratory variables. Insulin sensitivity was assessed using hyperinsulinaemic-euglycaemic clamps, hepatocellular lipid content using magnetic resonance spectroscopy, hepatic fibrosis using non-invasive scores, and peripheral and autonomic neuropathy using functional and clinical criteria. Patients were reassessed after 5 years. The German Diabetes Study is registered with ClinicalTrials.gov, number NCT01055093, and is ongoing.
FINDINGS
1105 patients were classified at baseline into five clusters, with 386 (35%) assigned to mild age-related diabetes (MARD), 323 (29%) to mild obesity-related diabetes (MOD), 247 (22%) to severe autoimmune diabetes (SAID), 121 (11%) to severe insulin-resistant diabetes (SIRD), and 28 (3%) to severe insulin-deficient diabetes (SIDD). At 5-year follow-up, 367 patients were reassessed, 128 (35%) with MARD, 106 (29%) with MOD, 88 (24%) with SAID, 35 (10%) with SIRD, and ten (3%) with SIDD. Whole-body insulin sensitivity was lowest in patients with SIRD at baseline (mean 4·3 mg/kg per min [SD 2·0]) compared with those with SAID (8·4 mg/kg per min [3·2]; p<0·0001), MARD (7·5 mg/kg per min [2·5]; p<0·0001), MOD (6·6 mg/kg per min [2·6]; p=0·0011), and SIDD (5·5 mg/kg per min [2·4]; p=0·0035). The fasting adipose-tissue insulin resistance index at baseline was highest in patients with SIRD (median 15·6 [IQR 9·3-20·9]) and MOD (11·6 [7·4-17·9]) compared with those with MARD (6·0 [3·9-10·3]; both p<0·0001) and SAID (6·0 [3·0-9·5]; both p<0·0001). In patients with newly diagnosed diabetes, hepatocellular lipid content was highest at baseline in patients assigned to the SIRD cluster (median 19% [IQR 11-22]) compared with all other clusters (7% [2-15] for MOD, p=0·00052; 5% [2-11] for MARD, p<0·0001; 2% [0-13] for SIDD, p=0·0083; and 1% [0-3] for SAID, p<0·0001), even after adjustments for baseline medication. Accordingly, hepatic fibrosis at 5-year follow-up was more prevalent in patients with SIRD (n=7 [26%]) than in patients with SAID (n=5 [7%], p=0·0011), MARD (n=12 [12%], p=0·012), MOD (n=13 [15%], p=0·050), and SIDD (n=0 [0%], p value not available). Confirmed diabetic sensorimotor polyneuropathy was more prevalent at baseline in patients with SIDD (n=9 [36%]) compared with patients with SAID (n=10 [5%], p<0·0001), MARD (n=39 [15%], p=0·00066), MOD (n=26 [11%], p<0·0001), and SIRD (n=10 [17%], p<0·0001).
INTERPRETATION
Cluster analysis can characterise cohorts with different degrees of whole-body and adipose-tissue insulin resistance. Specific diabetes clusters show different prevalence of diabetes complications at early stages of non-alcoholic fatty liver disease and diabetic neuropathy. These findings could help improve targeted prevention and treatment and enable precision medicine for diabetes and its comorbidities.
FUNDING
German Diabetes Center, German Federal Ministry of Health, Ministry of Culture and Science of the state of North Rhine-Westphalia, German Federal Ministry of Education and Research, German Diabetes Association, German Center for Diabetes Research, Research Network SFB 1116 of the German Research Foundation, and Schmutzler Stiftung.
Topics: Adult; Cluster Analysis; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Gas Chromatography-Mass Spectrometry; Germany; Glucose Clamp Technique; Humans; Insulin Resistance; Male; Middle Aged; Phenotype; Time Factors
PubMed: 31345776
DOI: 10.1016/S2213-8587(19)30187-1 -
Clinics in Liver Disease Feb 2019Chronic alcohol use induces silent changes in the structure and function of the central and peripheral nervous systems that eventually result in irreversible,... (Review)
Review
Chronic alcohol use induces silent changes in the structure and function of the central and peripheral nervous systems that eventually result in irreversible, debilitating repercussions. Once identified, nutritional supplementation and cessation measures are critical in preventing further neurologic damage. The proposed mechanisms of neuronal injury in chronic alcohol abuse include direct toxic effects of alcohol and indirect effects, including those resulting from hepatic dysfunction, nutritional deficiencies, and neuroinflammation. Clinical manifestations include cerebellar ataxia, peripheral neuropathy and Wernicke-Korsakoff encephalopathy. Continued exploration of the pathophysiologic mechanisms may lead to the discovery of early interventions that can prevent permanent neurologic injury.
Topics: Alcohol-Induced Disorders, Nervous System; Alcohol-Related Disorders; Alcoholic Korsakoff Syndrome; Alcoholic Neuropathy; Alcoholism; Cerebellar Ataxia; Humans; Neurotransmitter Agents
PubMed: 30454828
DOI: 10.1016/j.cld.2018.09.010