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Training robots to safely navigate (Safe-Nav) in uncertain complex environments using the RGB-D sensor is quite challenging as it involves the performance of different tasks such as obstacle avoidance, optimal path planning, and control. Traditional navigation approaches cannot generate suitable paths which guarantee enough visible features. Recent learning-based methods are still not mature enough due to their proneness to collisions and prohibitive computational cost. This paper focuses on generating safe trajectories to the desired goal while avoiding collisions and tracking failure in unknown complex environments. We present Safe-Nav, a hierarchical framework composed of the visual simultaneous localization and mapping (SLAM) module, the global planner module and the local planner module. The visual SLAM module generates the navigation map and the robot pose. The global planner module plans a local waypoint on the real-time navigation map. In the local planner module, a deep-reinforcement-learning-based (DRL-based) policy is presented for taking safe actions towards local waypoints. Our DRL-based policy can learn different navigation skills (e.g., avoiding collisions and avoiding tracking failure) through specialized modes without any supervisory signals when the PointGoal-navigation-specied reward is provided. We have demonstrated the performance of our proposed Safe-Nav in the Habitat simulation environment. Our approach outperforms the recent learning-based method and conventional navigation approach with relative improvements of over 205% (0.55 vs. 0.18) and 139% (0.55 vs. 0.23) in the success rate, respectively.

Acetaminophen (APAP), one of the most widely used antipyretic and analgesic drugs, principally contributes to drug-induced liver injury when taken at a high dose. APAP-induced liver injury (AILI) results in extensive necrosis of hepatocytes along with the occurrence of multiple intracellular events such as metabolic activation, cell injury, and signaling pathway activation. However, the specific role of the immune response in AILI remains controversial for its complicated regulatory mechanisms. A variety of inflammasomes, immune cells, inflammatory mediators, and signaling transduction pathways are activated in AILI. These immune components play antagonistic roles in aggravating the liver injury or promoting regeneration. Recent experimental studies indicated that natural products showed remarkable therapeutic effects against APAP hepatotoxicity due to their favorable efficacy. Therefore, this study aimed to review the present understanding of the immune response in AILI and attempted to establish ties among a series of inflammatory cascade reactions. Also, the immune molecular mechanisms of natural products in the treatment of AILI were extensively reviewed, thus providing a fundamental basis for exploring the potential pharmacological targets associated with immune interventions.

Linyuan Yu, Lihong Gong, Cheng Wang, Naihua Hu, Yunqiu Tang, Li Zheng, Xuyang Dai, Yunxia Li School of Pharmacy, Chengdu University of Traditional Chinese Medicine; Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education; National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu 611137, People’s Republic of ChinaCorrespondence: Yunxia LiSchool of Pharmacy, Chengdu University of Traditional Chinese Medicine; Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education; National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, No. 1166, Liu Tai Avenue, Wenjiang District, Chengdu, Sichuan, People’s Republic of ChinaTel +86-13699021135Email lyxcdutcm@126.comPurpose: Nonalcoholic fatty liver disease (NAFLD) has become a predictor of death in many diseases. This study was carried out to investigate the therapeutic effect of Radix Polygoni Multiflori Preparata (RPMP) and its main component emodin on egg yolk powder-induced NAFLD in zebrafish. Further investigation was performed to explore whether emodin was the main component of RPMP for the treatment of NAFLD as well as the underlying therapeutic mechanism of RPMP and emodin.Methods: Zebrafish were divided into control group, egg yolk powder group, RPMP group and emodin group. The obesity of zebrafish was evaluated by body weight, body length and BMI. The content of lipid was detected by triglyceride (TG), total cholesterol (TC) reagent kit and the fatty acid was detected by nonesterified free fatty acids (NEFA) reagent kit. HE staining was used to detect the histological structure of liver. Whole-mount Oil red O staining and Frozen oil red O staining were carried out to investigate the lipid accumulation in liver. KEGG and STRING databases were performed to analyze the potential role of AMPK between insulin resistance (IR) and fatty acid oxidation. Western blot and RT-qPCR were carried out for mechanism research.Results: RPMP and emodin significantly reduced zebrafish weight, body length and BMI. Both RPMP and emodin treatment could reduce the lipid deposition in zebrafish liver. RPMP significantly reduced the content of TG. However, emodin significantly reduced the contents of TG, TC and NEFA in zebrafish with NAFLD. The protein interaction network indicated that AMPK participated in both IR and fatty acid oxidation. Further investigation indicated that RPMP and emodin reduced hepatic lipogenesis via up-regulating the expressions of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT2), amp-activated protein kinase alpha (AMPKα), proliferator-activated receptor alpha (PPARα), carnitine palmitoyl transferase 1a (CPT-1a) and acyl-coenzyme A oxidase 1 (ACOX1).Conclusion: These findings suggest that emodin is the main component of RPMP for the treatment of NAFLD, which is closely related to the regulation of AMPK signaling pathway which increases IR and fatty acid oxidation.Keywords: RPMP, emodin, zebrafish, AMPK, nonalcoholic fatty liver disease

In the prescription of Traditional Chinese Medicine for lipid metabolism, Polygoni Multiflori Radix Preparata (ZhiHeShouWu, RPMP) was widely used. In recent years, RPMP ethanol extract has been reported for the treatment of non-alcoholic fatty liver disease (NAFLD). However, the role of RPMP ethanol extract in the treatment of NAFLD has not been fully elucidated. Therefore, we examined the optimal therapeutic dose of RPMP ethanol extracts. Afterward, a mouse model of non-alcoholic fatty liver induced by a high-fat diet (HFD) was treated with RPMP ethanol extract to further evaluate the mechanism of action of RPMP ethanol extract treatment. And the serum lipid metabolism indexes and liver function indexes showed that the RPMP ethanol extract in the 1.35 g/kg dose group exhibited better therapeutic effects than the 2.70 g/kg dose group. Meanwhile, RPMP ethanol extract can regulate the biochemical indicators of serum and liver to normal levels, and effectively reduce liver steatosis and lipid deposition. RPMP ethanol extract treatment restored HFD-induced disruption of the compositional structure of the intestinal microbial (IM) and bile acids (BAs) pools. And restore the reduced expression of intestinal barrier-related genes caused by HFD administration, which also effectively regulates the expression of genes related to the metabolism of BAs in mice. Thus, RPMP ethanol extract can effectively improve the abnormal lipid metabolism and hepatic lipid accumulation caused by HFD, which may be related to the regulation of IM composition, maintenance of intestinal barrier function, and normal cholesterol metabolism in the body.

Ethnopharmacological relevanceQuercetin is the active component of the higher content in PCP, which exerts various biological activities such as anti-obesity effect, anti-inflammatory and anti-oxidant activities in alcoholic liver disease (ALD). Aim of the study P2X7 receptor (P2X7R) plays an important role in health and disease, which can be activated by extracellular ATP to induce a variety of downstream events, including lipid metabolism, inflammatory molecule release, oxidative stress. However, whether the mechanism of quercetin on ethanol-induced hepatic steatosis via P2X7R-mediated haven't been elucidated. Material and methods Zebrafish transgenic (fabp10: EGFP) larvae were treated with 100 μM, 50 μM, 25 μM quercetin for 48 h at 3 days post fertilization (dpf), then soaked in 350 mmol/L ethanol for 32 h, treated with 1 mM ATP (P2X7R activator) for 30min. Serum lipids, liver steatosis, oxidative stress factors were respectively detected. The mRNA levels in the related pathways were measured by quantitative Real-Time PCR (RT-qPCR) to investigate the mechanisms. Results Quercetin improved the liver function via decreasing ALT, AST and γ-GT level of zebrafish with acute ethanol-induced hepatic steatosis and attenuated hepatic TG, TC accumulation. Additionally, quercetin significantly reduced the MDA content and suppressed the ethanol-induced reduction of hepatic oxidative stress biomarkers GSH, CAT and SOD and significantly down-regulated the expression of P2X7R, and up-regulated the expression of phosphatidylinositol 3-kinase (PI3K), Kelch like ECH associated protein1 (Keap1), Nuclear Factor E2 related factor 2 (Nrf2). Moreover, ATP stimulation activated P2X7R, which further mediated the mRNA expressions of PI3K, Keap1 and Nrf2. Conclusion Quercetin exhibited hepatoprotective capacity in zebrafish model, via regulating P2X7R-mediated PI3K/Keap1/Nrf2 oxidative stress signaling pathway.

BackgroundInflammation is a general pathological phenomenon during severe disturbances to the homeostasis. Forsythiaside A (FA) and forsythiaside B (FB), isolated from the dried fruit ofForsythia suspensa(Thunb.) Vahl, are phenylethanoid compounds that show a significant anti-inflammatory effect. However, the properties and therapeutic mechanisms of this effect have not yet been systematically elucidated.MethodsIn this study, the anti-inflammatory effects of FA and FB were investigated in CuSO4-induced inflammation in zebrafish larvae. Intracellular generation of reactive oxygen species (ROS) and nitric oxide (NO) was investigated using fluorescence probes. Metabolomic and proteomic analyses using liquid chromatography-mass spectrometry were carried out to identify the expressions of metabolites and proteins associated with the anti-inflammatory mechanism of FA and FB. Quantitative polymerase chain reaction (PCR) was performed to detect the progressive changes in gene expression.ResultsFA and FB inhibited neutrophils migration to the damaged neuromasts and remarkably reduced CuSO4-induced ROS and NO generation in zebrafish larvae. Metabolomic analysis pointed to the involvement of nicotinate and nicotinamide metabolism, energy metabolism, pyrimidine metabolism, and purine metabolism. Proteomic analysis identified 146 differentially expressed proteins between the control and model groups. These included collagen [collagen type II alpha 1b precursor (col2a1b), collagen alpha-2(IX) chain precursor (col9a2), collagen type IX alpha I precursor (col9a1b)], nucleoside diphosphate kinase 3 isoform X1 (Nme3), WD repeat-containing protein 3 (Wdr3), and 28S ribosomal protein S7 mitochondrial precursor (Mrps7). FA and FB were shown to reverse the abnormal expressions of potential metabolite and protein biomarkers and alleviate CuSO4-induced damage to the neuromasts in the zebrafish lateral line.ConclusionsOur results indicate that FA and FB possess remarkable anti-inflammatory properties, protecting against CuSO4-induced neuromasts damage in zebrafish larvae. The results also suggest a multi-component and multi-regulatory therapeutic mechanism for FA and FB.

Ethnopharmacological relevance Forsythiae Fructuse water extract (FSE) is a water-soluble component extracted from the traditional Chinese medicine Forsythiae Fructuse (The fruit of Forsythia suspensa (Thunb.) Vahl) usually used to treat inflammatory diseases. However, little is known about the therapeutic effect of FSE on liver fibrosis. Aim of the study The purpose of our study was to investigate the therapeutic effect of FSE on liver fibrosis and reveal the underlying mechanism. Materials and methods Liver fibrosis model was established by subcutaneous injection of olive oil containing 40% CCl4. Rat liver tissue morphologic pathology was investigated by using HE staining, Masson staining and Sirius red staining. Several biochemical markers including liver (ALT, AST, AKP, γ-GT), fibrosis (HA, LN, PC III, Col IV) and inflammation (IL-6, IL-1β, TNF-α) were determined by using Elisa kits. Immunohistochemistry was used to observe the distribution of α-SMA and COL1 in liver tissue. Effects of FSE on inflammatory pathway (TLR4/MyD88/NF-κB) and fibrotic pathway (TGF-β/smads) were detected by western blot and qPCR. Results The results showed that hepatic histopathological injury, abnormal liver function, fibrosis and inflammation induced by CCl4 were improved by FSE (2.5, 5 g/kg). Immunohistochemistry and western blot results indicated that the expression of α-SMA and COL1 in liver tissue was inhibited by FSE (2.5, 5 g/kg). Western blot and qPCR results further proved that FSE (2.5, 5 g/kg) inhibited the transduction of TLR4/MyD88/NF-κB and TGF-β/smads signaling pathways. Conclusion FSE can inhibit the expression of inflammatory factors and fibrotic cytokines, reduce liver injury, and inhibit the development of liver fibrosis through TLR4/MyD88/NF-κB and TGF-β/smads signaling pathways.

Additional file 2: Table S2. Metabolic pathways associated to varied influences of FA and FB in CuSO4-induced zebrafish inflammation.

Additional file 4: Figure S2. Protein-protein interactions of differentially expressed proteins.

Additional file 3: Figure S1. GO analysis of differentially-expressed proteins.

Additional file 5: Figure S3. Interactive network construction by integrated metabolomics and proteomics analysis.

Ethnopharmacological relevance: The traditional Chinese medicine Forsythiae Fructus is the dried fruit of Forsythia suspensa (Thunb.) Vahl. It is commonly used to clear heat and detoxify, reduce swelling and disperse knot, and evacuate wind and heat. Aim of the study: Inflammation is involved in liver fibrosis. Phillygenin (PHI) is a kind of lignans extracted and separated from Forsythiae Fructus, which has been reported to have a good anti-inflammatory effect. Therefore, we aimed to explore whether PHI has a therapeutic effect on liver fibrosis caused by inflammation. Materials and methods: Firstly, the induction of the LX2 cells inflammatory model and fibrosis model by LPS with different concentrations were studied. Then, high, medium and low doses PHI was given for intervention therapy. The secretion of IL-6, IL-1β and TNF-α inflammatory factors were detected by ELISA kit, and the expression of collagen I and α-SMA was detected by Western blot and RT-qPCR. The possible mechanism of PHI on TLR4/MyD88/NF-κB signal pathway was studied by computer-aided drug design software and the results were further verified by Western blot and RT-qPCR experiments. Results: The results showed that LPS could promote the expression of IL-6, IL-1β and TNF-α and the expression of collagen I and α-SMA, indicating that LPS could induce inflammation and fibrosis in LX2 cells. PHI could inhibit LX2 cell activation and fibrotic cytokine expression by inhibiting LPS-induced pro-inflammatory reaction. Molecular docking results showed that PHI could successfully dock with TLR4, MyD88, IKKβ, p65, IκBα, and TAK1 proteins. Subsequently, Western blot and qPCR results further proved that PHI could inhibit the proteins expression in TLR4/MyD88/NF-κB signal pathway which were consistent with the molecular docking results. Conclusion: PHI can inhibit LPS-induced pro-inflammatory reaction and LX2 cell activation through TLR4/MyD88/NF-κB signaling pathway, thereby inhibiting liver fibrosis.

With the improvement of people's living standards and the change of dietary habits, Non-alcoholic fatty liver disease (NAFLD) has gradually become one of the liver diseases that endanger human health around the world. However, there are no particularly effective drugs for NAFLD in the current market. Therefore, new drug candidates which could provide high efficacy and low toxicity are needed valuable for the prevention and treatment of NAFLD. 2,3,5,4'-tetrahydroxystilbence-2-O-β-D-glucoside (TSG) is extracted from Polygonum multiflorum Thunb., and has been widely used to treat a variety of chronic diseases in China. Recently, TSG has been reported to exert various biological activities in many studies, such as lipid-lowering, anti-inflammatory and anti-oxidant activities, which indicate that TSG may have the effect of improving NAFLD. After feeding 5% high cholesterol diet to 5 days post fertilization larval zebrafish for 10 days, hepatic steatosis larval zebrafish model was established successfully. Then the effect of TSG on the improvement of hepatic steatosis larval zebrafish was studied. Moreover, the potential mechanism of TSG on anti-NAFLD effect were studied using RT-qPCR methods from multiple pathogenesis aspects of lipogenesis, lipid-lowering, inflammation, and oxidant stress. To conclude, TSG attenuates hepatic steatosis via regulating lipid metabolism related pathway, IKKβ/NF-κB anti-inflammatory pathway and Keap1-Nrf2 anti-oxidant pathway.