Dioxin-like molecules have been associated with endocrine disruption and liver disease. To better understand aryl hydrocarbon receptor (AHR) biology, metabolic phenotyping and liver proteomics were performed in mice following ligand-activation or whole-body genetic ablation of this receptor. Male wild type (WT) and Ahr -/- mice (Taconic) were fed a control diet and exposed to 3,3\',4,4\',5-pentachlorobiphenyl (PCB126) (61 nmol/kg by gavage) or vehicle for two weeks. PCB126 increased expression of canonical AHR targets (Cyp1a1 and Cyp1a2) in WT but not Ahr -/-. Knockouts had increased adiposity with decreased glucose tolerance; smaller livers with increased steatosis and perilipin-2; and paradoxically decreased blood lipids. PCB126 was associated with increased hepatic triglycerides in Ahr -/-. The liver proteome was impacted more so by Ahr -/- genotype than ligand-activation, but top gene ontology (GO) processes were similar. The PCB126-associated liver proteome was Ahr-dependent. Ahr principally regulated liver metabolism (e.g., lipids, xenobiotics, organic acids) and bioenergetics, but it also impacted liver endocrine response (e.g., the insulin receptor) and function, including the production of steroids, hepatokines, and pheromone binding proteins. These effects could have been indirectly mediated by interacting transcription factors or microRNAs. The biologic roles of the AHR and its ligands warrant more research in liver metabolic health and disease.

BACKGROUND: The global social expenses of Alzheimer\'s disease (AD) have been increased to US$1 trillion due to high cost, side-effects, and low efficiency of the current AD-therapies. Another reason is the lack of preventive drugs and the low-income situation of Asian and African countries. Accordingly, patients rather prefer traditional herbal remedies. Network-pharmacology has been a well-established method for the visualization and the construction of disorder target protein-drug framework. This could aid in the identification of drugs molecular-mechanisms.
OBJECTIVE: The aim of this study is to investigate the phytochemical constituents that could target Alzheimer\'s disease from the North African plants. This could be done by exploring their possible mechanisms of action through molecular network pharmacology-based approach.
METHODS: The Phytochemical-compounds of North-African plants (NAP) have been accessed from open-databank. ADME-screening has been conducted for filtering of the NAP phytochemical-constituents utilizing Qikprop-software. The open STITCH databank has been utilized for the prediction of the phytochemical-constituents target-proteins; UniProt and TDD-DB databanks have been utilized for distinguishing AD-related proteins. Phytochemical constituent-target protein (C-T) and plant-phytochemical constituent-target protein (P-C-T) frameworks have been assembled utilizing Cytoscape to interpret the anti-Alzheimer\'s disease mechanism of action of the targeted phytochemical constituents.
RESULTS: The NAP 6842 phytochemical-constituents (from more than 1000 plants) have been exposed to ADME and CNS modulating filtration, generating 94 phytochemical-constituents which have been subjected to target-prediction investigation. The 94 phytochemical-constituents and the 4 AD-identified targets have been associated through 155 edges which formed the main pathways related to AD. Cuparene, alpha-selinene, beta-sesquiphellandrene, calamenene, 2-4-dimethylheptane, undecane, n-tetradecane, hexadecane, nonadecane, n-eicosane, and heneicosane have had C-T network highest combined-score, whilst the proteins MAO-B, HMG-CoA, BACE1, and GCR have been the most enriched ones by comprising the uppermost combined-scores of C-T. Hypericum perforatum, Piper nigrum, Juniperus communis, Levisticum officinale, Origanum vulgare acquired the uppermost number of P-C-Target interactions.
CONCLUSIONS: The phytochemical-targets prediction of NAP utilizing molecular-network pharmacology-based investigation has paved the way for networking multi-target, multi-constituent, and multi-pathway mechanisms. This may introduce potential future targets for the regulation and the management of Alzheimer\'s disease.
UNASSIGNED: Alzheimer\'s disease, Network pharmacology, In-silico computer based approach.

UNASSIGNED: The paradox of hepatic insulin resistance describes the inability for liver to respond to bioenergetics hormones in suppressing gluconeogenesis whilst maintaining lipid synthesis. Here, we report the deficiency of miR-192-3p in the livers of mice with diabetes and its role in alleviating hepatic steatosis.
UNASSIGNED: As conventional pre-microRNA (miRNA) stem-loop overexpression only boosts guiding strand (i.e. miR-192-5p) expression, we adopted an artificial AAV(DJ)-directed, RNA Pol III promoter-driven miRNA hairpin construct for star-strand-specific overexpression in the liver. Liver steatosis and insulin resistance markers were evaluated in primary hepatocytes, mice with diabetes, and mice with excessive carbohydrate consumption.
UNASSIGNED: Functional loss of miR-192-3p in liver exacerbated hepatic micro-vesicular steatosis and insulin resistance in either mice with diabetes or wild-type mice with excessive fructose consumption. Liver-specific overexpression of miR-192-3p effectively halted hepatic steatosis and ameliorated insulin resistance in these mice models. Likewise, hepatocytes overexpressing miR-192-3p exhibited improved lipid accumulation, accompanied with decreases in lipogenesis and lipid-accumulation-related transcripts. Mechanistically, glucocorticoid receptor (GCR, also known as nuclear receptor subfamily 3, group C, member 1 [NR3C1]) was demonstrated to be negatively regulated by miR-192-3p. The effect of miR-192-3p on mitigating micro-vesicular steatosis was ablated by the reactivation of NR3C1.
UNASSIGNED: The star strand miR-192-3p was an undermined glycerolipid regulator involved in controlling fat accumulation and insulin sensitivity in liver through blockade of hepatic GCR signalling; this miRNA may serve as a potential therapeutic option for the common co-mobility of diabetic mellitus and fatty liver disease.
UNASSIGNED: The potential regulatory activity of star strand microRNA (miRNA) species has been substantially underestimated. In this study, we investigate the role and mechanism of an overlooked star strand miRNA (miR-192-3p) in regulating hepatic steatosis and insulin signalling in the livers of mice with diabetes and mice under excessive carbohydrate consumption.