Abstract Understanding transcriptional responses to chemical perturbations is central for drug discovery, but exhaustive experimental high-throughput screening of disease and compound combinations is unfeasible. To overcome this limitation, here we present a perturbation-conditioned deep generative model named PRnet for predicting transcriptional responses to novel chemical perturbations that were never experimentally perturbed at bulk and single-cell levels. Evaluation indicated that PRnet outperformed alternative methods in predicting responses across novel compounds, pathways, and cell lines. PRnet enables gene-level response interpretation and novel compounds screening for diseases based on gene signatures. PRnet further identified and experimentally tested novel compounds candidates against small cell lung cancer and colorectal cancer. Lastly, PRnet generated a large-scale integration atlas of perturbation profiles, covering 88 cell lines and 52 tissues perturbed by various screening compound libraries. PRnet provided a robust and scalable candidate recommendation workflow and has successfully recommended drug candidates for 233 different diseases based on the atlas. Overall, PRnet is an effective and valuable tool for cell- and gene-based therapeutics screening. 

Predicting transcriptional responses to novel chemical perturbations using deep generative model

Hepatic encephalopathy (HE) is one of the most prevalent and severe hepatic and brain disorders in which escalation of the oxidative, inflammatory, and apoptotic trajectories pathologically connects acute liver injury with neurological impairment. Mirabegron (Mira) is a beta3 adrenergic receptor agonist with proven antioxidant and anti-inflammatory activity. The current research pointed to exploring Mira's hepato-and neuroprotective impacts against thioacetamide (TAA)-induced HE in rats. Rats were distributed into three experimental groups: the normal control group, the TAA group, received TAA (200 mg/kg/day for three consecutive days) and the Mira-treated group received Mira (10 mg/kg/day; oral gavage) for 15 consecutive days and intoxicated with TAA from the 13th to the 15th day of the experimental period. Mira counteracted hyperammonemia, enhanced rats' locomotor capability and motor coordination. It attenuated hepatic/neurological injuries by its antioxidant, anti-apoptotic as well as anti-inflammatory potentials. Mira predominantly targeted cyclic adenosine monophosphate (cAMP)/phosphorylated extracellular signal-regulated kinase (p-Erk1/2)/peroxisome proliferator-activated receptor gamma (PPARγ) dependent pathways via downregulation of p S536-nuclear factor kappa B p65 (p S536 NF-κB p 65)/tumor necrosis alpha (TNF-α) axis. Meanwhile, it attenuated nuclear factor erythroid 2-related factor (Nrf2) depletion in parallel with restoring of the neuroprotective defensive pathway by upregulation of cerebral cAMP/PPAR-γ/p-ERK1/2 and p-CREB/BDNF/TrkB besides reduction of GFAP immunoreactivity. Mira showed anti-apoptotic activity through inhibition of Bax immunoreactivity and elevation of Bcl2. To summarize, Mira exhibited a hepato-and neuroprotective effect against TAA-induced HE in rats via shielding antioxidant defense and mitigation of the pathological inflammatory and apoptotic axis besides upregulation of neuroprotective signaling pathways. 

Unveiling the protective potential of mirabegron against thioacetamide-induced hepatic encephalopathy in rats: Insights into cAMP/PPAR-γ/p-ERK1/2/p S536 NF-κB p 65 and p-CREB/BDNF/TrkB in parallel with oxidative and apoptotic trajectories

: Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Mirabegron is a novel, once-daily orally β3-adrenoreceptor (AR) agonist. Aim of the study: This work aimed at exploring the possible prophylactic effect of mirabegron on nonalcoholic steatohepatitis (NASH) induced experimentally by high fat diet in rats. Material and methods: Rats were divided into 5 groups: normal group serving as a control group, Mirabegron group, Untreated NASH group (received a high fat diet for 12 weeks), Low dose mirabegron pre-treated NASH group (treated with mirabegron 5 mg/kg/day orally for 12 weeks) and High dose mirabegron pretreated NASH group (treated with mirabegron 10 mg/kg/day orally for 12 weeks). Results: Mirabegron produced significant reduction of liver enzymes, total cholesterol, triglycerides and Low-density lipoprotein cholesterol (LDL-c) and significant elevation of high-density lipoprotein-cholesterol (HDL-c),the serum level of glycosylated hemoglobin (HbA1c), fasting glucose and insulin levels were significantly decreased with significant improvement of insulin sensitivity observed by lowering of insulin resistance index (HOMA-IR), serum adiponectin level also showed significant elevation. These results were supported by marked improvement of liver histopathology compared to non-treated group, with the best results obtained by using the high dose of mirabegron. Conclusions: These data suggest that mirabegron may have a potential usefulness in the prevention of NASH as regard to liver enzymes, lipid profile, serum HbA1c, fasting insulin and blood glucose, insulin resistance index, and serum adiponectin levels with improvement of liver histopathological changes.

/pdf/possible-protective-effects-of-mirabegron-on-experimentally-1t1fvlgw.pdf

Possible Protective Effects of Mirabegron on Experimentally Induced Non-alcoholic Steatohepatitis in Rats

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Possible Protective Effects of Mirabegron on Experimentally Induced Non-alcoholic Steatohepatitis in Rats