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      Doxepin Exacerbates Renal Damage, Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Urinary Chromium Loss in Obese Mice

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          Abstract

          Doxepin is commonly prescribed for depression and anxiety treatment. Doxepin-related disruptions to metabolism and renal/hepatic adverse effects remain unclear; thus, the underlying mechanism of action warrants further research. Here, we investigated how doxepin affects lipid change, glucose homeostasis, chromium (Cr) distribution, renal impairment, liver damage, and fatty liver scores in C57BL6/J mice subjected to a high-fat diet and 5 mg/kg/day doxepin treatment for eight weeks. We noted that the treated mice had higher body, kidney, liver, retroperitoneal, and epididymal white adipose tissue weights; serum and liver triglyceride, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and creatinine levels; daily food efficiency; and liver lipid regulation marker expression. They also demonstrated exacerbated insulin resistance and glucose intolerance with lower Akt phosphorylation, GLUT4 expression, and renal damage as well as higher reactive oxygen species and interleukin 1 and lower catalase, superoxide dismutase, and glutathione peroxidase levels. The treated mice had a net-negative Cr balance due to increased urinary excretion, leading to Cr mobilization, delaying hyperglycemia recovery. Furthermore, they had considerably increased fatty liver scores, paralleling increases in adiponectin, FASN, PNPLA3, FABP4 mRNA, and SREBP1 mRNA levels. In conclusion, doxepin administration potentially worsens renal injury, nonalcoholic fatty liver disease, and diabetes.

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          Most cited references 85

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          Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease

          Non-alcoholic fatty liver disease (NAFLD) is currently the world’s most common liver disease, estimated to affect up to one-fourth of the population. Hallmarked by hepatic steatosis, NAFLD is associated with a multitude of detrimental effects and increased mortality. This narrative review investigates the molecular mechanisms of hepatic steatosis in NAFLD, focusing on the four major pathways contributing to lipid homeostasis in the liver. Hepatic steatosis is a consequence of lipid acquisition exceeding lipid disposal, i.e., the uptake of fatty acids and de novo lipogenesis surpassing fatty acid oxidation and export. In NAFLD, hepatic uptake and de novo lipogenesis are increased, while a compensatory enhancement of fatty acid oxidation is insufficient in normalizing lipid levels and may even promote cellular damage and disease progression by inducing oxidative stress, especially with compromised mitochondrial function and increased oxidation in peroxisomes and cytochromes. While lipid export initially increases, it plateaus and may even decrease with disease progression, sustaining the accumulation of lipids. Fueled by lipo-apoptosis, hepatic steatosis leads to systemic metabolic disarray that adversely affects multiple organs, placing abnormal lipid metabolism associated with NAFLD in close relation to many of the current life-style-related diseases.
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            Association of depressive disorders, depression characteristics and antidepressant medication with inflammation

            Growing evidence suggests that immune dysregulation may be involved in depressive disorders, but the exact nature of this association is still unknown and may be restricted to specific subgroups. This study examines the association between depressive disorders, depression characteristics and antidepressant medication with inflammation in a large cohort of controls and depressed persons, taking possible sex differences and important confounding factors into account. Persons (18–65 years) with a current (N=1132) or remitted (N=789) depressive disorder according to DSM-IV criteria and healthy controls (N=494) were selected from the Netherlands Study of Depression and Anxiety. Assessments included clinical characteristics (severity, duration and age of onset), use of antidepressant medication and inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α)). After adjustment for sociodemographics, currently depressed men, but not women, had higher levels of CRP (1.33 versus 0.92 mg l−1, P<0.001, Cohen's d=0.32) and IL-6 (0.88 versus 0.72 pg ml−1, P=0.01, Cohen's d=0.23) than non-depressed peers. Associations reduced after considering lifestyle and disease indicators — especially body mass index — but remained significant for CRP. After full adjustment, highest inflammation levels were found in depressed men with an older age of depression onset (CRP, TNF-α). Furthermore, inflammation was increased in men using serotonin–norepinephrine reuptake inhibitors (CRP, IL-6) and in men and women using tri- or tetracyclic antidepressants (CRP), but decreased among men using selective serotonin reuptake inhibitors (IL-6). In conclusion, elevated inflammation was confirmed in depressed men, especially those with a late-onset depression. Specific antidepressants may differ in their effects on inflammation.
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              Medical comorbidity in women and men with schizophrenia: a population-based controlled study.

              Persons with persistent mental illness are at risk for failure to receive medical services. In order to deliver appropriate preventive and primary care for this population, it is important to determine which chronic medical conditions are most common. We examined chronic medical comorbidity in persons with schizophrenia using validated methodologies. Retrospective analysis of longitudinal administrative claims data from Wellmark Blue Cross/Blue Shield of Iowa. Subjects with schizophrenia or schizoaffective disorder (N=1,074), and controls (N=726,262) who filed at least 1 claim for medical services, 1996 to 2001. Case subjects had schizophrenia as the most clinically predominant psychotic disorder, based on psychiatric hospitalization, psychiatrist diagnoses, and outpatient care. Controls had no claims for any psychiatric comorbidity. Using a modified version of the Elixhauser Comorbidity Index, inpatient and outpatient claims were used to determine the prevalence of 46 common medical conditions. Odds ratios (ORs) were adjusted for age, gender, residence, and nonmental health care utilization using logistic regression. Subjects with schizophrenia were significantly more likely to have 1 or more chronic conditions compared with controls. Adjusted OR (95% confidence interval [CI]) were 2.62 (2.09 to 3.28) for hypothyroidism, 1.88 (1.51 to 2.32) for chronic obstructive pulmonary disease, 2.11 (1.36 to 3.28) for diabetes with complications, 7.54 (3.55 to 15.99) for hepatitis C, 4.21 (3.25 to 5.44) for fluid/electrolyte disorders, and 2.77 (2.23 to 3.44) for nicotine abuse/dependence. Schizophrenia is associated with substantial chronic medical burden. Familiarity with conditions affecting persons with schizophrenia may assist programs aimed at providing medical care for the mentally ill.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Pharmaceuticals (Basel)
                Pharmaceuticals (Basel)
                pharmaceuticals
                Pharmaceuticals
                MDPI
                1424-8247
                16 March 2021
                March 2021
                : 14
                : 3
                Affiliations
                [1 ]Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan; leowang@ 123456mail.ncyu.edu.tw (C.-M.W.); babybelle349@ 123456gmail.com (P.-S.F.); pipi324615@ 123456gmail.com (H.-J.L.)
                [2 ]Department of Psychiatry, Taichung Veterans General Hospital, 1650 Taiwan Boulevard (Section 4), Taichung 40705, Taiwan; peterhopo2@ 123456yahoo.com.tw
                [3 ]Faculty of Medicine, National Yang-Ming University, 155 Linong Street (Section 2), Taipei 11221, Taiwan
                [4 ]School of Veterinary Medicine, National Taiwan University, 1 Roosevelt Road (Section 4), Taipei 10617, Taiwan; yangweicheng@ 123456ntu.edu.tw
                [5 ]Division of Endocrinology and Metabolism, Show Chwan Memorial Hospital, 542 Chung-Shan Road (Section 1), Changhua 50008, Taiwan
                Author notes
                [* ]Correspondence: grchang@ 123456mail.ncyu.edu.tw (G.-R.C.); s881055@ 123456gmail.com (T.-P.C.); Tel.: +886-5-2732946 (G.-R.C.); +886-4-7256166 (T.-P.C.)
                Article
                pharmaceuticals-14-00267
                10.3390/ph14030267
                8001117
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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