Role of FXR in the development of NAFLD and intervention strategies of small molecules.

Non-alcoholic fatty liver disease (NAFLD) remains a prevailing etiological agent behind hepatocyte diseases like chronic liver disease. The spectrum of processes involved in NAFLD stages includes hepatic steatosis, non-alcoholic fatty liver, and non-alcoholic steatohepatitis (NASH). Without intervention, the progression of NASH can further deteriorate into cirrhosis and ultimately, hepatocellular carcinoma. The cardinal features that characterize NAFLD are insulin resistance, lipogenesis, oxidative stress and inflammation, extracellular matrix deposition and fibrosis. Due to its complex pathogenesis, existing pharmaceutical agents fail to take a curative or ameliorative effect on NAFLD. Consequently, it is imperative to identify novel therapeutic targets and strategies for NAFLD, ideally to improve the aforementioned key features in patients. As an enterohepatic regulator of bile acid homeostasis, lipid metabolism, and inflammation, FarnesoidX receptor (FXR) is an important pharmacological target for the treatment of NAFLD. Manipulating FXR to regulate lipid metabolic signaling pathways is a potential mechanism to mitigate NAFLD. Therefore, elucidating the modulatory character of FXR in regulating lipid metabolism in NAFLD has the potential to yield groundbreaking perspectives for drug design. This review details recent advances in the regulation of lipid depletion in hepatocytes and investigates the pivotal function of FXR in the progress of NAFLD.

Flavonoids and Organic Acids Affect Phase II Metabolism based on the Regulation of UGT1A1 Expression and Function.

BACKGROUND: Exogenous substances modulate metabolism by regulating the expression and function of UDP-glycosyltransferases (UGTs). However, the exact mechanism in the intestine was rarely understood. Herein, we explored the effects of representative flavonoids and organic acids on the regulation of UGT1A1. METHODS: MTT assays and western blot analysis were used to explore the effect of polyphenols. X-ray diffraction was used to reveal the catalytic mechanisms of UGTs. RESULTS: MTT assays showed that these compounds basically had no cytotoxicity, even in concentrations up to 200 µM. Then, through western blot assays, UGT1A1 expression was increased after being treated with liquiritigenin and caffeic acid. Furthermore, liquiritigenin and caffeic acid enhanced the nuclear translocation of Nrf2. Moreover, a 2.5-Å crystal structure of the complex containing UGTs C-terminal domain and organic acid was solved, and the UDPGA binding pocket could be occupied by organic acid, suggesting the enzyme activity might be impaired by organic acid. CONCLUSION: Above all, liquiritigenin and caffeic acid maintained the metabolism balance by upregulating the expression of UGT1A1 via Nrf2 activation and inhibiting the enzyme activity in Caco-2 cells.

The effectiveness of Q6 and PIPER 6-year-old models on quantification of the change of child sitting posture with AEB and its impact on child's injures in frontal crash.

OBJECTIVE: Automatic Emergency Braking (AEB) has a direct impact on the effectiveness of the restraint systems in providing protection toward child occupants. The objective is to evaluate the effectiveness of Q6 and PIPER 6-year-old models in predicting the kinematic responses of child models, and further to quantify and analyze the child injuries during a frontal crash with and without AEB. METHODS: The finite element model of a booster seat has been validated through a full vehicle test. Based on the validated finite element model, two sled test finite element models for the rear seat booster seat with Q6 and PIPER 6-year-old models were constructed. AEB condition was imposed on above the two models and the kinematic responses of sitting posture including head, neck and chest have been compared in detail. The peak head displacement and neck curvature of Q6 dummy and PIPER 6-year-old models have been compared with the test data from child volunteers. Based on the child model with better predictive capability for kinematic response under AEB, child injuries were evaluated and analyzed for the 50 km/h frontal crash test with and without AEB. Last, this study discussed the effects of internal neck and chest structure difference between Q6 and PIPER 6-year-old models on child kinematic response and the injury risks. RESULTS: Under AEB condition, PIPER 6-year-old model has higher head displacement and lower trunk displacement than Q6 dummy model, and the peak head displacement and neck curvature of PIPER 6-year-old model are similar to the test data of child volunteers. During the 50 km/h frontal crash simulation with pre-crash AEB, the HIC15, Head acceleration 3 ms, Nij decrease 43.7%, 19.6% and 28.8%, respectively and the chest deflection increases 15.5% compared to the simulation without AEB. CONCLUSIONS: This study shows that PIPER 6-year-old model is more suitable for the quantification of sitting posture change under AEB due to its higher biofidelity. The pre-crash AEB can substantially reduce the head, neck injuries. But it also increases the chest injury due to the chest pre-compression. Future efforts are recommended to lower the child chest injury by integrating AEB with active pre-tensioning seatbelts.

Ponicidin-induced conformational changes of HSP90 regulates the MAPK pathway to relieve ulcerative colitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is a recurring chronic intestinal disease that can be debilitating and in severe cases, may further lead to cancer. However, all these treatment techniques still suffer from drug dependence, adverse effects and poor patient compliance. Therefore, there is an urgent need to seek new therapeutic strategies. In traditional Chinese medicine, Rabdosia rubescens (Hemsl.) H.Hara has the effects of clearing heat-toxin and promoting blood circulation to relieve pain, it is wildly used for treating inflammatory diseases such as sore throats and tonsillitis. Ponicidin is an important molecule for the anti-inflammatory effects of Rabdosia rubescens, but it has not been studied in the treatment of colitis. HSP90 is the most critical regulator in the development and progression of inflammatory diseases such as UC. AIM OF THE STUDY: The aim of this study was to explore the anti-inflammatory activity of ponicidin and its mechanism of effect in vitro and in vivo, as well as to identify the target proteins on which ponicidin may interact. MATERIAL AND METHODS: 2.5% (w/v) dextran sulfate sodium (DSS) was used to induce C57BL/6 mice to form an ulcerative colitis model, and then 5 mg/kg and 10 mg/kg ponicidin was given for treatment, while the Rabdosia rubescens extract group and Rabdosia rubescens diterpene extract group were set up for comparison of the efficacy of ponicidin. At the end of modeling and drug administration, mouse colon tissues were taken, and the length of colon was counted, inflammatory factors and inflammatory signaling pathways were detected. RAW264.7 cells were induced to form cell inflammation model with 1 µg/mL Lipopolysaccharide (LPS) for 24 h. 1 µM, 2 µM and 4 µM ponicidin were given at the same time, and after the end of the modeling and administration of the drug, the inflammatory factors and inflammatory signaling pathways were detected by qRT-PCR, western blotting, immunofluorescence and other methods. In vitro, target angling and combined with mass spectrometry were used to search for relevant targets of ponicidin, while isothermal titration calorimetry (ITC), protease degradation experiments and molecular dynamics simulations were used for further confirmation of the mode of action and site of action between ponicidin and target proteins. RESULTS: Ponicidin can alleviate DSS and LPS-induced inflammation by inhibiting the MAPK signaling pathway at the cellular and animal levels. In vitro, we confirmed that ponicidin can interact with the middle domain of HSP90 and induce the conformational changes in the N-terminal domain. CONCLUSION: These innovative efforts identified the molecular target of ponicidin in the treatment of UC and revealed the molecular mechanism of its interaction with HSP90.

Environmental quality assessment and spatial spillover effects of three urban agglomerations in China: A Meta-EBM approach.

The new development form of urban agglomeration has greatly promoted economic and social progress in recent years, but it is also facing severe environmental pollution problems. Understanding the status quo of environmental efficiency in urban agglomerations and its leading driving forces is an important prerequisite for formulating energy conservation and emission reduction policies. This research uses the Meta Epsilon Based Measure (Meta-EBM) model to measure the environmental emission efficiency of the Beijing-Tianjin-Hebei（BTH）, Yangtze River Delta (YRD) and Pearl River Delta (PRD) urban agglomerations in China from 2014 to 2018 so as to improve on the inability of traditional Data Envelopment Analysis (DEA) to combine linear and non-linear characteristics, and employs Moran's I index and spatial econometric methods to analyze their spatial dependence and main driving factors. The results demonstrate that the overall environmental efficiency of the three major urban agglomerations in the five years from 2014 to 2018 presents a wave-like development and then tends to be flat. The itemized efficiency of economic outputs has maintained a relatively high level with the environmental output index exhibiting the best efficiency for industrial wastewater, followed by industrial sulfur dioxide (SO2). The scores of the two indicators for inhalable fine particle emissions (PM2.5) and industrial smoke and dust in each urban agglomeration are not ideal, and there are obvious differences between regions. Among them, YRD and PRD are relatively inferior. From the perspective of spatial spillover effects, various indicators show diverse characteristics at different development stages of the regions. Population and Normalized Difference Vegetation Index (NDVI) have a positive effect on environmental efficiency, while both Gross Domestic Product (GDP) per capita and transportation tend to show greater negative effects on regional environmental optimization. This study proposes countermeasures as follows. Each urban agglomeration should set up measures suitable to local conditions and give full play to their location advantages. They can also use space radiation to promote sector economic development and optimize urban environmental benefits.

Metabolomics analyses of serum metabolites perturbations associated with Naja atra bite.

Naja atra bite is one of the most common severe snakebites in emergency departments. Unfortunately, the pathophysiological changes caused by Naja atra bite are unclear due to the lack of good animal models. In this study, an animal model of Naja atra bite in Guangxi Bama miniature pigs was established by intramuscular injection at 2 mg/kg of Naja atra venom, and serum metabolites were systematically analyzed using untargeted metabolomic and targeted metabolomic approaches. Untargeted metabolomic analysis revealed that 5045 chromatographic peaks were obtained in ESI+ and 3871 chromatographic peaks were obtained in ESI-. Screening in ESI+ modes and ESI- modes identified 22 and 36 differential metabolites compared to controls. The presence of 8 core metabolites of glutamine, arginine, proline, leucine, phenylalanine, inosine, thymidine and hippuric acid in the process of Naja atra bite was verified by targeted metabolomics significant difference (P<0.05). At the same time, during the verification process of the serum clinical samples with Naja atra bite, we found that the contents of three metabolites of proline, phenylalanine and inosine in the serum of the patients were significantly different from those of the normal human serum (P<0.05). By conducting functional analysis of core and metabolic pathway analysis, we revealed a potential correlation between changes in key metabolites after the Naja atra bite and the resulting pathophysiological alterations, and our research aims to establish a theoretical foundation for the prompt diagnosis and treatment of Naja atra bite.

Diagnostic accuracy of glioma pseudoprogression identification with positron emission tomography imaging: a systematic review and meta-analysis.

Background: Positron emission tomography (PET) imaging is a promising molecular neuroimaging technique and has been proposed as one of the criteria for glioma management. However, there is some controversy concerning the diagnostic accuracy of PET using different radiotracers to differentiate between glioma pseudoprogression (PsP) and true progression (TPR). The purpose of this meta-analysis was to systematically evaluate the methodological quality and clinical value of original studies for distinguishing PsP from TPR in glioma. Methods: The Medline, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov were searched from inception until September 1, 2022. Retrieved clinical studies only investigated the PsP cases but did not include the cases of radiation necrosis or other treatment-related changes. Eligible studies were screened for data extraction and evaluated by 2 independent reviewers using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. A random effects model was used to describe summary receiver operating characteristics. Meta-regression and subgroup analyses were applied to identify any sources of heterogeneity. Results: The meta-analysis included 20 studies, comprising 317 (30.9%) patients with PsP and 708 (69.1%) with TPR. The summary sensitivity and specificity of general PET for identifying PsP were 0.86 [95% confidence interval (CI): 0.77-0.91] and 0.84 (95% CI: 0.79-0.88), respectively. The statistical heterogeneity was explained by sample size, study design, World Health Organization (WHO) grade, gold standard, and radiotracer type. The summary sensitivity and specificity of O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET PET) were 0.80 (95% CI: 0.68-0.88) and 0.81 (95% CI: 0.75-0.85), respectively. The maximum tumor-to-brain ratio (TBRmax) and the mean tumor-to-brain ratio (TBRmean) both showed excellent diagnostic performance in 18F-FET studies, the summary sensitivity was 0.83 (95% CI: 0.72-0.91) and 0.79 (95% CI: 0.65-0.98), respectively, and the specificity was 0.76 (95% CI: 0.68-0.84) and 0.78 (95% CI: 0.64-0.88), respectively. Conclusions: PET imaging is generally accurate in identifying glioma PsP. Considering the credibility of meta-evidence and the practicability of using radiotracer, 18F-FET PET holds the highest clinical value, while TBRmax and TBRmean should be regarded as reliable parameters. PET used with the radiotracers and multiple-parameter combinations of PET with magnetic resonance imaging (MRI) and radiomics analysis have broad research and application prospects, whose diagnostic values for identifying glioma PsP warrant further investigation.

Glutamine ameliorates Bungarus multicinctus venom-induced lung and heart injury through HSP70: NF-κB p65 and P53/PUMA signaling pathways involved.

Background: Bungarus multicinctus is one of the most dangerous venomous snakes prone to cardiopulmonary damage with extremely high mortality. In our previous work, we found that glutamine (Gln) and glutamine synthetase (GS) in pig serum were significantly reduced after Bungarus multicinctus bite. In the present study, to explore whether there is a link between the pathogenesis of cardiopulmonary injury and Gln metabolic changes induced by Bungarus multicinctus venom. We investigated the effect of Gln supplementation on the lung and heart function after snakebite. Methods: We supplemented different concentrations of Gln to mice that were envenomated by Bungarus multicinctus to observe the biological behavior, survival rate, hematological and pathological changes. Gln was supplemented immediately or one hour after the venom injection, and then changes in Gln metabolism were analyzed. Subsequently, to further explore the protective mechanism of glutamine on tissue damage, we measured the expression of heat-shock protein70 (HSP70), NF-κB P65, P53/PUMA by western blotting and real-time polymerase in the lung and heart. Results: Gln supplementation delayed the envenoming symptoms, reduced mortality, and alleviated the histopathological changes in the heart and lung of mice bitten by Bungarus multicinctus. Additionally, Gln increased the activity of glutamine synthetase (GS), glutamate dehydrogenase (GDH) and glutaminase (GLS) in serum. It also balanced the transporter SLC7A11 expression in heart and lung tissues. Bungarus multicinctus venom induced the NF-κB nuclear translocation in the lung, while the HO-1 expression was suppressed. At the same time, venom activated the P53/PUMA signaling pathway and the BAX expression in the heart. Gln treatment reversed the above phenomenon and increased HSP70 expression. Conclusion: Gln alleviated the glutamine metabolism disorder and cardiopulmonary damage caused by Bungarus multicinctus venom. It may protect lungs and heart against venom by promoting the expression of HSP70, inhibiting the activation of NF-κB and P53/PUMA, thereby delaying the process of snake venom and reducing mortality. The present results indicate that Gln could be a potential treatment for Bungarus multicinctus bite.

The structural basis of conserved residue variant effect on enzyme activity of UGT2B15.

UDP-glucuronosyltransferase 2B15 (UGT2B15) is a crucial phase II drug-metabolizing enzyme, which glucuronidates various compounds, including clinical drugs and hormones. Mutants might affect glucuronidation, leading to a disruption of drug metabolism in vivo and decrease of therapeutic effect. Here, we mainly analyzed two representative mutants, H401P and L446S, on UGT2B15 activity using glucuronidation assays, molecular dynamic (MD) simulation and X-ray diffraction methods. The enzyme activity of L446S obviously increased six-fold than the wild type, although the enzyme activities of P191L, T374A, and H401P were lost apparently. Furthermore, we used MD simulations to calculate the energy change in the catalytic process of H401P and L446S, and the results indicated the free binding energies of H401P mutant to oxazepam and UDPGA were -30.98 ± 1.00 kcal/mol and -36.42 ± 1.04 kcal/mol, respectively, increased obviously compared to wild type, suggesting the mutation on position 401 had a crucial effect on the catalysis. Moreover, the three-dimensional structure of UGT2B15 C-terminal domain L446S was determined through protein crystallography and X-ray diffraction technology and the results suggested that one more hydrogen bonding between S446 and K410 was formed in the S446 crystal structure, compared to the wild type. Isothermal titration calorimetry assay further revealed the Kd values of C-terminal domain of UGT2B15 harbored L446S towards the cofactor UDPGA was similar to the value of wild type. Above all, our results pointed out that H401P and L446S affected the enzyme activity by different mechanism. Our work provided a helpful mechanism for variance explained in the UGTs catalyzation process.

Comprehensive evaluation of urban water supply security based on the VIKOR-TOPSIS method.

To determine the security status of urban water supplies, a comprehensive evaluation model of urban water supply security based on the VIKOR and TOPSIS models is proposed. The comprehensive evaluation value K is obtained as the evaluation result, and the larger K is, the higher the safety of the urban water supply. The results show that the security of the water supply in Tianjin increased from 0.2300 in 2015 to 0.8026 in 2018. Although it slightly decreased to 0.5439 in 2019, it was still at a high level and increased to 0.7508 in 2020. The urban water transmission and distribution status, the service level of the water supply industry, and the status of sewage treatment play positive roles in affecting the safety of the water supply in Tianjin, and the status of urban water sources and the urban water use status are the main factors that reduced the safety of the urban water supply. According to the results of an obstacle degree model and the actual conditions in the study area, it is suggested that Tianjin should continue to focus on the development of water resources and the utilization of unconventional water sources and actively promote the construction of a water-saving society.

Corrigendum: Effects of meteorological factors and atmospheric pollution on hand, foot, and mouth disease in Urumqi Region.

[This corrects the article DOI: 10.3389/fpubh.2022.913169.].

Discovery and Structural and Functional Characterization of a Novel A-Superfamily Conotoxin Targeting α9α10 Nicotinic Acetylcholine Receptor.

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels widely distributed in the central peripheral nervous system and muscles which participate in rapid synaptic transmission. The α9α10 nAChR is an acetylcholine receptor subtype and is involved in chronic pain. In the present study, a new A-superfamily conotoxin Bt14.12 cloned from Conus betulinus was found to selectively inhibit α9α10 nAChRs with an IC50 of 62.3 nM. Unlike α-conotoxins and other A-superfamily conotoxins, Bt14.12 contains a four Cys (C-C-C-C) framework with a unique disulfide bond connection "C1-C4, C2-C3". The structure-activity studies of Bt14.12 demonstrate that all amino acid residues contribute to its potency. Interestingly, mutation experiments show that the deletion of Asp2 or the addition of three Arg residues at the N-terminus of Bt14.12 significantly enhances its inhibitory activity (IC50 is 21.9 nM or 12.7 nM, respectively) by 2- or 4-fold compared to the wild-type Bt14.12. The NMR structure of Bt14.12 shows that it contains α-helix- and ß-turn-like elements, and further computational modelings of the interaction between Bt14.12 and the α9α10 nAChR demonstrate that Bt14.12 possesses a distinctive mode of action and displays a different structure-activity relationship from known α9α10 nAChR targeting α-conotoxins. Our findings provide a novel conotoxin that potently targets α9α10 nAChRs and a new motif for designing potent inhibitors against α9α10 nAChRs.

Effects of Meteorological Factors and Atmospheric Pollution on Hand, Foot, and Mouth Disease in Urumqi Region.

Background: Hand, foot, and mouth disease (HFMD) is a febrile rash infection caused by enteroviruses, spreading mainly via the respiratory tract and close contact. In the past two decades, HFMD has been prevalent mainly in Asia, including China and South Korea, causing a huge disease burden and putting the lives and health of children at risk. Therefore, a further study of the factors influencing HFMD incidences has far-reaching implications. In existing studies, the environmental factors affecting such incidences are mainly divided into two categories: meteorological and air. Among these studies, the former are the majority of studies on HFMD. Some scholars have studied both factors at the same, but the number is not large and the findings are quite different. Methods: We collect monthly cases of HFMD in children, meteorological factors and atmospheric pollution in Urumqi from 2014 to 2020. Trend plots are used to understand the approximate trends between meteorological factors, atmospheric pollution and the number of HFMD cases. The association between meteorological factors, atmospheric pollution and the incidence of HFMD in the Urumqi region of northwest China is then investigated using multiple regression models. Results: A total of 16,168 cases in children are included in this study. According to trend plots, the incidence of HFMD shows a clear seasonal pattern, with O3 (ug/m3) and temperature (°C) showing approximately the same trend as the number of HFMD cases, while AQI, PM2.5 (ug/m3), PM10 (ug/m3) and NO2 (ug/m3) all show approximately opposite trends to the number of HFMD cases. Based on multiple regression results, O3 (P = 0.001) and average station pressure (P = 0.037) are significantly and negatively associated with HFMD incidences, while SO2 (P = 0.102), average dew point temperature (P = 0.072), hail (P = 0.077), and thunder (P = 0.14) have weak significant relationships with them.

The spatiotemporal evolution of COVID-19 in China and its impact on urban economic resilience.

The spread of the novel coronavirus (COVID-19) has had a major political, economic, social, and cultural impact on various countries worldwide. Based on economic operation, public opinion, public health, government policies and population inflow in the affected areas, this study measures daily economic resilience during the COVID-19 outbreak in 286 prefecture-level cities in China (from 1st January to 8th February, 2020). Specifically, this study further investigates the economic resilience and the number of COVID-19 cases by analysing the evolutionary trend of their spatial distribution pattern using the standard deviation ellipse (SDE). The impact of COVID-19 on economic resilience is examined using a panel vector autoregressive model. The following are the findings. (1) The economic resilience value decreased throughout the study period, but the cities with high economic resilience showed a trend of spatial diffusion in the late study period. Wuhan's lockdown strategy was benefit to control the spread of COVID-19, and promptly stopped the decline of China's economic resilience. (2) Economic resilience and the number of COVID-19 cases influenced their future trends positively, but this effect gradually decreased over time. During the COVID-19, although the number of confirmed cases significantly influenced China's economic resilience, and the disease's spread was evident, China maintained a high level of economic development resilience. (3) The rise in economic resilience during the pandemic's early stages promoted the number of confirmed cases, but the strength of this relationship gradually declined as the pandemic progressed. Returning to work and other activities may increase the risk of infection. Numerous policies implemented at the outbreak' inception aided in laying the groundwork for economic resilience. Although the outbreak had a detrimental effect on economic resilience in the later stages of the pandemic, a convergent trend was observed at the end of the research period. (4) Using variance decomposition, we discovered that future economic resilience was significantly influenced by itself and by relatively few changes. However, the impact of confirmed cases on economic resilience becomes apparent after the fourth period. This indicates that the number of confirmed cases must be limited during the initial stages. The early support of various sectors in China facilitated the spatial expansion of economically resilient cities. The pandemic has a non-negligible negative impact on economic resilience, but this has been mitigated by Wuhan's timely closure.

The Therapeutic Potential of Targeting Hsp90-Cdc37 Interactions in Several Diseases.

Heat shock protein (Hsp) 90 is an ATP-dependent chaperone and plays a vital role in the folding, maturation, and stability of a protein. Hsp90 and its client proteins have become targets of various diseases through the regulation of disease-related proteins. Inhibition of Hsp90 production and activity prevents ATP hydrolysis, resulting in the ubiquitination and proteasome degradation of client proteins. However, the Hsp90 inhibitor has obvious toxic side effects and the inevitable heat shock response. Cell division cycle 37 (Cdc37) is a crucial Hsp90 kinase-specific co-chaperone, which forms a complex with Hsp90 to regulate kinase and non-kinase client's activities, cell communication, and signal transduction. The Hsp90-Cdc37 complex maintains cell survival by stabilizing abnormal client proteins and regulating cell growth signals. The abnormal activation of Hsp90-Cdc37 protein-protein interaction (PPI) often leads to the aggravation of diseases, such as cancer and neurodegenerative diseases. Compared with ATP competitive Hsp90 inhibitors, blocking Hsp90-Cdc37 PPI has higher selectivity, fewer toxic side effects, and better application prospects. This review detailed the biological characteristics of Hsp90-Cdc37 PPI and its role in several human diseases. Besides, the latest research progress in inhibitors is summarized and discussed to guide further research and clinical application.

Six Unusual Meroterpenoids from the Leaves of Psidium guajava L. and Their PTP1B Inhibitory Activities.

Six unusual meroterpenoids, psidiguajadiol A-J (1-6), and three known meroterpenoids (7-9) were isolated from the leaves of Psidium guajava L. Compounds 2-6 represent the first examples of 6/8-formyl-5,7-dihydroxy-4-phenylchromane-coupled sesquiterpenoids. The structures of the undescribed compounds, including their absolute configurations, were elucidated by spectroscopic analyses, X-ray diffraction, and computational calculations. Compounds 3, 4, and 6 exhibited inhibitory activities against PTP1B with IC50 values of 9.83, 18.52, and 16.87 µM, respectively. In light of these findings, we performed molecular docking studies to predict their inhibition mechanisms at the atomic level.

Serum metabolomics of Bama miniature pigs bitten by Bungarus multicinctus.

Bungarus multicinctus is one of the top ten venomous snakes in China, and its bite causes acute and severe diseases, but its pathophysiology remains poorly elucidated. Thus, an animal model of Bungarus multicinctus bite was established by intramuscular injection of 30µg/kg of Bungarus multicinctus venom, and then the serum metabolites were subsequently screened, identified and validated by ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF-MS) methods to explore the potential biomakers and possible metabolic pathways. Untargeted metabolomics analysis showed that 36 and 38 endogenous metabolites levels changed in ESI+ and ESI-, respectively, KEGG pathway analysis showed that 5 metabolic pathways, including mineral absorption, central carbon metabolism in cancer, protein digestion and absorption, aminoacyl-tRNA biosynthesis and ABC transporters might be closely related to Bungarus multicinctus bite. Targeted metabolomics analysis showed that there were significant differences in serum D-proline, L-leucine and L-glutamine after Bungarus multicinctus bite (P < 0.05). In addition, receiver operating characteristic (ROC) analysis showed that the diagnostic efficiency of L-Glutamine was superior to other potential biomarkers and the AUC value was 0.944. Moreover, we found evidence for differences in the pathophysiology of glutamine between Bungarus multicinctus bite group and normal group, specifically with the content of glutamine synthetase (GS) and glutaminase (GLS). Taken together, the current study has successfully established an animal model of Bungarus multicinctus bite, and further identified the links between the metabolic perturbations and the pathophysiology and the potential diagnostic biomakers of Bungarus multicinctus bite, which provided valuable insights for studying the mechanism of Bungarus multicinctus bite.

The tectonigral pathway regulates appetitive locomotion in predatory hunting in mice.

Appetitive locomotion is essential for animals to approach rewards, such as food and prey. The neuronal circuitry controlling appetitive locomotion is unclear. In a goal-directed behavior-predatory hunting, we show an excitatory brain circuit from the superior colliculus (SC) to the substantia nigra pars compacta (SNc) to enhance appetitive locomotion in mice. This tectonigral pathway transmits locomotion-speed signals to dopamine neurons and triggers dopamine release in the dorsal striatum. Synaptic inactivation of this pathway impairs appetitive locomotion but not defensive locomotion. Conversely, activation of this pathway increases the speed and frequency of approach during predatory hunting, an effect that depends on the activities of SNc dopamine neurons. Together, these data reveal that the SC regulates locomotion-speed signals to SNc dopamine neurons to enhance appetitive locomotion in mice.

Differences in Clinical Features and Diagnostic Strategies Between IgG4-Related Autoimmune Cholangitis and Cholangiocarcinoma.

IgG4-related autoimmune cholangitis (IgG4-AIC) is often difficult to distinguish from cholangiocarcinoma (CCA). This study aimed to determine a practical clinical strategy for distinguishing between IgG4-AIC and CCA to avoid unnecessary surgical resection. We retrospectively collected and compared the clinicopathological data between IgG4-AIC and CCA patients, including the clinical, serological, and radiological characteristics, to follow up on these patients to investigate the prognosis. Among the 377 patients who received surgical resection for suspecting CCA at the Sun Yat-Sen Memorial Hospital between June 2004 and June 2014, 14 patients were diagnosed as IgG4-AIC through histochemistry after surgery. Immunohistochemistry revealed that IgG4 was up-regulated in the plasma cells of IgG4-AIC tissues in 13 out of 14 patients. The serum CA19-9 level was significantly lower than in the CCA group. Patients with IgG4-AIC can only see slight or no enhancement under the contrast enhancement CT scan, while there are no signs of ring-like or delayed enhancement that is unique to CCA. Thirteen patients were followed up, and the time was 12 to 92 months. Three of them were regularly treated with prednisone after surgery, and original symptoms disappeared. Our study demonstrated that the combination of imaging with serum CA19-9 could improve the preoperative diagnostic value and reduce the rate of unnecessary resection.

Correction: Yan, L., et al. Combined Taurine, Epigallocatechin Gallate and Genistein Therapy Reduces HSC-T6 Cell Proliferation and Modulates the Expression of Fibrogenic Factors. Int. J. Mol. Sci. 2013, 14, 20543-20554.

The authors regret that, during the preparation of our published manuscript "Combined taurine, epigallocatechin gallate and genistein therapy reduces HSC-T6 cell proliferation and modulates the expression of fibrogenic factors" [...].