RESUMEN
BACKGROUND: Nonalcoholic Steatohepatitis (NASH) results from complex liver conditions involving metabolic, inflammatory, and fibrogenic processes. Despite its burden, there has been a lack of any approved food-and-drug administration therapy up till now. PURPOSE: Utilizing machine learning (ML) algorithms, the study aims to identify reliable potential genes to accurately predict the treatment response in the NASH animal model using biochemical and molecular markers retrieved using bioinformatics techniques. METHODS: The NASH-induced rat models were administered various microbiome-targeted therapies and herbal drugs for 12 weeks, these drugs resulted in reducing hepatic lipid accumulation, liver inflammation, and histopathological changes. The ML model was trained and tested based on the Histopathological NASH score (HPS); while (0-4) HPS considered Improved NASH and (5-8) considered non-improved, confirmed through rats' liver histopathological examination, incorporates 34 features comprising 20 molecular markers (mRNAs-microRNAs-Long non-coding-RNAs) and 14 biochemical markers that are highly enriched in NASH pathogenesis. Six different ML models were used in the proposed model for the prediction of NASH improvement, with Gradient Boosting demonstrating the highest accuracy of 98% in predicting NASH drug response. FINDINGS: Following a gradual reduction in features, the outcomes demonstrated superior performance when employing the Random Forest classifier, yielding an accuracy of 98.4%. The principal selected molecular features included YAP1, LATS1, NF2, SRD5A3-AS1, FOXA2, TEAD2, miR-650, MMP14, ITGB1, and miR-6881-5P, while the biochemical markers comprised triglycerides (TG), ALT, ALP, total bilirubin (T. Bilirubin), alpha-fetoprotein (AFP), and low-density lipoprotein cholesterol (LDL-C). CONCLUSION: This study introduced an ML model incorporating 16 noninvasive features, including molecular and biochemical signatures, which achieved high performance and accuracy in detecting NASH improvement. This model could potentially be used as diagnostic tools and to identify target therapies.
Asunto(s)
Modelos Animales de Enfermedad , Aprendizaje Automático , Enfermedad del Hígado Graso no Alcohólico , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Ratas , Hígado/patología , Hígado/metabolismo , Hígado/efectos de los fármacos , Masculino , Proteínas Señalizadoras YAP/genética , Biomarcadores/sangre , MicroARNs/genéticaRESUMEN
Diabetic osteoporosis is a common health problem that is associated with a disruption in bone metabolism. A2A adenosine receptor (A2AAR) signaling seems to play a critical role in bone homeostasis. This study aimed to evaluate the effect of A2AAR stimulation on the treatment of diabetic-induced osteoporosis versus insulin treatment. Forty adult male rats were allocated into control (C), untreated diabetic-induced osteoporosis (DIO), insulin-treated DIO (I-DIO), and A2AAR agonist-treated DIO (A-DIO) groups. Both insulin and A2AAR agonist treatments significantly increased serum insulin level, glutathione peroxidase (GPx) activity, bone expression of osteoprotegerin (Opg) and ß-catenin (Ctnnb1), and cortical and trabecular bone thickness, whereas they decreased serum fasting glucose, malondialdehyde (MDA), tumor necrosis factor α (TNF-α), bone expression of receptor activator of nuclear factor kappa-B ligand (Rankl), runt-related transcription factor-2 (Runx2), and sclerostin (Sost) versus the untreated DIO groups. A2AAR agonist treatment was more effective than insulin in ameliorating diabetic osteoporosis. This might be attributed to the upregulation of ß-catenin gene expression, enhancing its anabolic effect on bone, in addition to the A2AAR agonist's anti-oxidative, anti-inflammatory, and anti-diabetic effects.
Asunto(s)
Diabetes Mellitus Experimental , Osteoporosis , Animales , Masculino , Ratas , Agonistas del Receptor de Adenosina A2/farmacología , Agonistas del Receptor de Adenosina A2/uso terapéutico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Insulina/metabolismo , Osteoporosis/metabolismo , Osteoporosis/etiología , Osteoporosis/tratamiento farmacológico , Ratas Wistar , Receptor de Adenosina A2A/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: Common bile duct ligation (BDL) is a rat experimental model to induce biliary cirrhosis. Lung fibrosis and pulmonary vascular angiogenesis and congestion are the most common complications of biliary cirrhosis that is known as hepatopulmonary syndrome. The aim of the present work is to investigate the acute lung injury in a BDL model and to investigate the possible protective effect of quercetin on this injury. METHODS: Twenty-four adult male albino rats of the Wister strain (weighing 150-250 g). Animals were divided into 3 groups, with 8 rats each: Group I: Sham-operated group (control). Group II: Bile duct ligation group (BDL) sacrificed after 28 days from the surgery. Group III: Quercetin-treated bile duct ligation group (Q-BDL) was given orally by gastric gavage in a dose of 50 mg/kg/day, starting from the 4th day of the operation until the 28th day. At the end of the experiment, at day 28, all rats were sacrificed. Lung specimens were processed to measure Endothelin B receptor gene expression by PCR, lung surfactant by ELISA, "eNO" s by immunohistochemistry. Histological assessment was done using; H&E, Masson's trichrome, PAS, toluidine blue-stained semi-thin sections, transmission electron microscope. Histomorphometric and statistical studies were done. RESULTS: BDL group showed significant increase in lung index together with mononuclear cellular infiltration denoting lung inflammatory state. Also, the significant increase in pulmonary endothelial nitric oxide synthase ("eNO" s) area percent and endothelin B receptor (ETB) gene expression indicates enhanced angiogenesis. Pulmonary surfactant concentration was significantly decreased together with thickening of interalveolar septa denoting lung injury and fibrosis. Quercetin led to significant decrease in lung index, pulmonary "eNO" s area percent, ETB gene expression and significant increase in pulmonary surfactant concentration. Quercetin treatment improved histological changes and morphometric measurements, limited mononuclear cellular infiltration and decreased perivascular and perialveolar collagen deposition. CONCLUSION: Quercetin ameliorates the hepatopulmonary syndrome-induced lung injury through its anti-inflammatory, antioxidative and antifibrotic effects.