Search

The Coptidis Rhizoma and Bovis Calculus herb pair possesses clearing heat and detoxifying effects. The aim of this study was to reveal the effects and mechanisms of the herb pair in the treatment of NASH by network pharmacology and experimental verification. A network pharmacology-based approach was employed to predict the putative mechanism of the herb pair against NASH. The high-fat diet (HFD) and methionine/choline deficient (MCD) diet induced NASH models were used to evaluate efficacy and mechanism of the herb pair. Network pharmacological analysis showed that the herb pair modulated NOD-like receptor pathway. In the HFD mice, herb pair reduced body weight, blood sugar, serum ALT, AST, TBA, TC, TG and LDL-C contents, also improved the general morphology and pathological manifestations. Hepatic transcriptomics study showed that herb pair attenuated NASH by regulating NOD-like receptor signaling pathway. Western blotting showed that herb pair reduced the protein expression levels of NLRP3, cleaved Caspase-1 and cleaved IL-1β. In the MCD mice, herb pair also reduced serum ALT, ALT and TBA levels, improved liver pathological manifestations, inhibited the protein expression levels of NLRP3, cleaved Caspase-1 and cleaved IL-1β. Our findings proved that the Coptidis Rhizoma and Bovis Calculus herb pair attenuates NASH through suppression of NLRP3 inflammasome activation. This will demonstrate effective pharmacological evidence for the clinical application of herb pair.

Abstract The pathogenesis of Acute-on-chronic liver failure (ACLF) involves several forms of cell death, such as pyroptosis, apoptosis, and necroptosis, which consist of PANoptosis. To explore PANoptosis as a regulated cell death pathway in ACLF. Firstly, a bioinformatic strategy was used to observe the role of the PANoptosis pathway in ACLF and identify differentially expressed genes related to PANoptosis. Enrichment analysis showed that PANoptosis-related pathways were up-regulated in ACLF. We screened out BAX from the intersection of pyroptosis, apoptosis, necroptosis, and DEGs. Secondly, we screened articles from literature databases related to PANoptosis and liver failure, and specific forms of PANoptosis were reported in different experimental models in vitro and in vivo. Secondly, we established a model of ACLF using carbon tetrachloride-induced liver fibrosis, followed by D-galactosamine and lipopolysaccharide joint acute attacks. A substantial release of inflammatory factors(IL-6, IL-18, TNFα, and IFNγ) and the key proteins of PANoptosis (NLRP3, CASP1, GSDMD, BAX, CASP8, CASP3, CASP7, and MLKL) were detected independently in the ACLF rats. Finally, we found that combining TNF-α/INF-γ inflammatory cytokines could induce L02 cells PANoptosis. Our study highlighted the potential role of ACLF and helps drug discovery targeting PANoptosis in the future.

Abstract In this paper, we tackle the challenging problem of point cloud completion from the perspective of feature learning. Our key observation is that to recover the underlying structures as well as surface details, given partial input, a fundamental component is a good feature representation that can capture both global structure and local geometric details. We accordingly first propose FSNet, a feature structuring module that can adaptively aggregate point-wise features into a 2D structured feature map by learning multiple latent patterns from local regions. We then integrate FSNet into a coarse-to-fine pipeline for point cloud completion. Specifically, a 2D convolutional neural network is adopted to decode feature maps from FSNet into a coarse and complete point cloud. Next, a point cloud upsampling network is used to generate a dense point cloud from the partial input and the coarse intermediate output. To efficiently exploit local structures and enhance point distribution uniformity, we propose IFNet, a point upsampling module with a self-correction mechanism that can progressively refine details of the generated dense point cloud. We have conducted qualitative and quantitative experiments on ShapeNet, MVP, and KITTI datasets, which demonstrate that our method outperforms state-of-the-art point cloud completion approaches.

Objective: The Qinzhi Zhudan formula (QZZD) exhibits a prominent therapeutic effect in the treatment of vascular dementia (VaD). This study combined a network pharmacology approach and experimental validation to identify the underlying biological mechanism of QZZD against VaD. Methods: Male Wistar rats received bilateral common carotid artery occlusion (BCCAO) surgery, and after 4 weeks of intragastric administration of QZZD, the therapeutic effect was assessed using the Morris water maze test and cerebral blood flow (CBF) assessment. Hematoxylin and eosin staining, Nissl staining, and electron microscopy were used to measure the histopathological changes in the neurons of rats. The effect of QZZD treatment on hippocampal neurotransmitters was assessed by high-performance liquid chromatography with electrochemical detection and liquid chromatography mass spectrometry. Immunofluorescence was used to observe VaD-induced microglia activation. The inflammatory cytokine levels were assessed by enzyme linked immunosorbent assay. Western blot was used to examine the TNFR1-mediated TNF pathway, which was screened out by network pharmacology analysis. Results: QZZD treatment alleviated pathological changes and neuronal damage in VaD rats and attenuated their cognitive impairment. In addition, QZZD increased CBF and the expression of acetylcholine and 5-hydroxytryptamine in the hippocampal region. Notably, QZZD inhibited microglial activation and the expression of IL-6 and TNF-α. Network pharmacology and western blot indicated that QZZD inhibited the levels of TNFR1, NF-κBp65, p-ERK, TNF-α, and IL-6, which are related to the TNFR1-mediated TNF signaling pathway. Conclusion: QZZD clearly improved learning and memory function, reduced brain pathological damage, elevated CBF and hippocampal neurotransmitter levels, and alleviated neuroinflammation of VaD rats partly by inhibiting the TNFR1-mediated TNF pathway, indicating its potential value in the clinical therapy of VaD.

With the rapid development of information technology, the society’s demand for innovative talents has become increasingly prominent. The purpose of this study is to optimize the teaching strategies of entrepreneurship education for college students, further cultivate college students’ entrepreneurial ideas, and promote the formation of entrepreneurial values. The problems existing in entrepreneurship education in colleges and universities are studied based on entrepreneurial psychology and attribution theory. A questionnaire survey is conducted on the problems with a high probability of entrepreneurial failure of college students. The heads of new ventures in Xi’an are selected. Then, 300 questionnaires are distributed, and 209 are returned. The survey results are analyzed using failure attribution and failure learning. Suggestions are provided for management strategies of new ventures. The results show that the Corrected Item-Total Correlation (CITC) value of R−1 is 0.65, and the CITC value of R−2 is 0.35. In addition, the Kaiser-Meyer-Olkin (KMO) values of entrepreneurial failure attribution and entrepreneurial failure mode are both greater than 0.7, which indicates that the scale of entrepreneurial failure attribution has good validity and can be used for factor analysis. However, the KMO values of entrepreneurial failure attribution and entrepreneurial failure learning model are both greater than 0.7, and the significance of Bartlett sphericity test is 0.00, which indicates that the survey has good validity. The research has practical application and reference value for the cultivation of college students’ innovative and entrepreneurial ability.

There is yet no effective drug for Alzheimer’s disease (AD) which is one of the world’s most common neurodegenerative diseases. The Qin-Zhi-Zhu-Dan Formula (QZZD) is derived from a widely used Chinese patent drug–Qing-Kai-Ling Injection. It consists of Radix Scutellariae, Fructus Gardeniae, and Pulvis Fellis Suis. Recent study showed that QZZD and its effective components played important roles in anti-inflammation, antioxidative stress and preventing brain injury. It was noted that QZZD had protective effects on the brain, but the mechanism remained unclear. This study aims to investigate the mechanism of QZZD in the treatment of AD combining network pharmacology approach with experimental validation. In the network pharmacology analysis, a total of 15 active compounds of QZZD and 135 putative targets against AD were first obtained. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were then applied to clarify the biological mechanism. The anti-inflammatory mechanism of QZZD was proved, and a synthetic pathway–TNFR1-ERK1/2-NF-κBp65 signaling pathway was obtained. On the basis of the above discoveries, we further validated the protective effects QZZD on neurons with an APP/PS1 double transgenic mouse model. Weight change of the mice was monitored to assess QZZD’s influence on the digestive system; water maze experiment was used for evaluating the effects on spatial learning and memory; Western blotting and immunohistochemistry analysis were used to detect the predicted key proteins in network pharmacology analysis, including Aβ, IL-6, NF-κBp65, TNFR1, p-ERK1/2, and ERK1/2. We proved that QZZD could improve neuroinflammation and attenuate neuronal death without influencing the digestive system in APP/PS1 double transgenic mice with dementia. Combining animal pharmacodynamic experiments with network pharmacology analysis, we confirmed the importance of inflammation in pathogenesis of AD, clarified the pharmacodynamic characteristics of QZZD in treating AD, and proved its neuroprotective effects through the regulation of TNFR1-ERK1/2-NF-κBp65 signaling pathway, which might provide reference for studies on treatment of AD in the future.

Calculus bovis (CB), a famous traditional Chinese medicine, is commonly used to treat various inflammatory diseases, including oral ulcers. However, the potential mechanisms of CB in the treatment of oral ulcers are still limited. The present study aimed to use a network pharmacology-based approach to understand the multi-compound, multi-target, multi-pathway effect of CB against oral ulcers. The network pharmacology included the following main parts: first, we screened bioactive compounds and predicted corresponding targets via multiple databases; second, we used R software to analyze related Gene Ontology (GO) and KEGG terms; third, we calculated the network proximity on the protein–protein interaction background and identified potential modules. Finally, a rat oral ulcer model was used to validate the therapeutic effect of CB against oral ulcers and test the expression of important targets. Through network pharmacology analysis, 12 bioactive compounds were initially screened out. The network proximity Z score was -4.37, indicating the potential therapeutic efficacy of CB against oral ulcers. Six potential modules were identified, while module 1 was related to the NOD-like receptor signaling pathway and module 6 was related to apoptosis. Experiments confirmed the therapeutic efficacy of CB against oral ulcers. Western blotting indicated that CB upregulated the anti-apoptosis protein Bcl-xl and downregulated the pro-apoptosis protein Bax and the nlrp3 signal. In conclusion, CB exerted a curative effect on oral ulcers by inhibiting apoptosis and nlrp3 activation.

Abstract Background Cerebral ischemia is the second-leading cause of death and the main cause of permanent adult disabilities worldwide. Qingkailing (QKL) injection, a patented Chinese medicine approved by the China Food and Drug Administration, has been widely used in clinical practice to treat cerebral ischemia in China. The NOD-like receptor pyrin 3 (NLRP3) inflammasome is activated in cerebral ischemia and thus, is an effective therapeutic target. AMP-activated protein kinase (AMPK) is an important regulator inhibiting NLRP3 inflammasome activation. Methods We investigated the potential of QKL injection to provide neuroprotection after cerebral ischemia in a rat model of middle cerebral artery occlusion (MCAO). Adult male Sprague-Dawley rats (210–230 g) were randomly divided into three groups which consist of sham, MCAO and 3 ml/kg QKL. Rats in the QKL group received intraperitoneal injections of 3 ml/kg QKL, while rats in other groups were given saline in the same volumes. After 90 min ischemia and 24 h reperfusion, neurological function, laser speckle imaging, brain infarction, brain water content and brain blood barrier permeability were examined and cell apoptosis at prefrontal cortex were evaluated 24 h after MCAO, and western blot and real-time quantitative polymerase chain reaction was also researched, respectively. Results Intraperitoneal administration of QKL alleviated neurological deficiencies, cerebral infarction, blood-brain barrier permeability, brain oedema and brain cell apoptosis after MCAO induction. QKL decreased pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β, and increased anti-inflammatory cytokines, IL-4 and IL-10. Furthermore, QKL activated phosphorylated AMPK, decreased oxidative stress and decreased NLRP3 inflammasome activation. Conclusions QKL relieved cerebral ischemia reperfusion injury and suppressed the inflammatory response by inhibiting AMPK-mediated activation of the NLRP3 inflammasome. These results suggest that QKL might have potential in treating brain inflammatory response and attenuating the cerebral ischemia-reperfusion injury.

Objective: To study the effects of social stress (CS) and social stress combined with high-fat diet on fat mobilization as a candidate mechanism for the induction or aggravation of non-alcoholic fatty liver disease (NAFLD). Methods: Thirty-two male Wistar rats (250 ± 10 g) were randomly allocated to a blank control group (BC), a high-fat diet group (HFD), a CS group, and a combined CS and high-fat diet group (CS + HFD). Rats were sacrificed and tissues were collected after 8 weeks. Liver and body mass were measured and used to calculate the liver index. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and free fatty acids (FFAs) were measured. Liver sections were examined microscopically after oil red O and hematoxylin and eosin staining. The relative mRNA expression of acetyl-CoA carboxylase (ACCase), hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase in liver, and hormone-sensitive lipase (HSL), and adipose triglyceride lipase (ATGL) in subcutaneous adipose tissue, were measured by real-time PCR. The liver concentrations of triglyceride, reactive oxygen species, and ACCase were measured by ELISA and HSL activity was determined using turbidimetry. Results: NAFLD developed in the CS, HFD, and CS + HFD groups, with the most severe NAFLD being in the CS + HFD group. Serum AST, ALT, and FFA, liver index, and hepatic triglyceride, FFA, and tumor necrosis factor-α were significantly higher in both the CS and CS + HFD groups. However, food intake and ACCase mRNA expression were lower. The mRNA expression of HSL and ATGL in adipose tissue was much higher, and HSL activity was higher in the CS group than in the BC group, and in the CS + HFD group than in the HFD group. Conclusion: We have successfully established two models of stress-induced NAFLD, suggesting stress can induce and aggravate NAFLD by promoting fat mobilization through upregulation of HSL and ATGL. Keywords: Non-alcoholic fatty liver disease, Chronic stress, Fat mobilization, Free fatty acid

Major depressive disorder (MDD), which is highly associated with non-alcoholic fatty liver disease (NAFLD), has complex pathogenic mechanisms. However, a limited number of studies have evaluated the mutual pathomechanisms involved in MDD and NAFLD development. Chronic stress-mediated elevations in glucocorticoid (GC) levels play an important role in the development of MDD-related NAFLD. Elevated GC levels can induce the release of inflammatory factors and changes in gut permeability. Elevated levels of inflammatory factors activate the hypothalamic–pituitary–adrenal (HPA) axis, which further increases the release of GC. At the same time, changes in gut permeability promote the release of inflammatory factors, which results in a vicious circle among the three, causing disease outbreaks. Even though the specific role of the thyroid hormone (TH) in this pathogenesis has not been fully established, it is highly correlated with MDD and NAFLD. Therefore, changing lifestyles and reducing psychological stress levels are necessary measures for preventing MDD-related NAFLD. Among them, GC inhibitors and receptor antagonists may be key in the alleviation of early and mid-term disease progression. However, combination medications may be important in late-stage diseases, but they are associated with various side effects. Traditional Chinese medicines have been shown to be potential therapeutic alternatives for such complex diseases.

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease in China. Sinisan (SNS) is a traditional Chinese medicine formula that has been widely used in treating chronic liver diseases, including NAFLD. However, its underlying biological mechanisms are still unclear. In this study, we employed a network pharmacology approach consisting of overlapped terms- (genes or pathway terms-) based analysis, protein-protein interaction (PPI) network-based analysis, and PPI clusters identification. Unlike the previous network pharmacology study, we used the shortest path length-based network proximity algorithm to evaluate the efficacy of SNS against NAFLD. And we also used random walk with restart (RWR) algorithm and Community Cluster (Glay) algorithm to identify important targets and clusters. The screening results showed that the mean shortest path length between genes of SNS and NAFLD was significantly smaller than degree-matched random ones. Six PPI clusters were identified and ten hub targets were obtained, including STAT3, CTNNB1, MAPK1, MAPK3, AGT, NQO1, TOP2A, FDFT1, ALDH4A1, and KCNH2. The experimental study indicated that SNS reduced hyperlipidemia, liver steatosis, and inflammation. Most importantly, JAK2/STAT3 signal was inhibited by SNS treatment and was recognized as the most important signal considering the network pharmacology part. This study provides a systems perspective to study the relationship between Chinese medicines and diseases and helps to discover potential mechanisms by which SNS ameliorates NAFLD.

Stroke is the second leading cause of death after heart disease globally and cerebral ischemic stroke accounts for approximately 70% of all incident stroke cases. We selected four main compounds from a patent Chinese medicine, Qingkailing (QKL) injection, including baicalin from Scutellaria baicalensis Georgi (Huang Qin), geniposide from Gardenia jasminoides J. Ellis (Zhizi), and cholic acid and hyodeoxycholic acid from Bovis Calculus (Niuhuang) with a ratio of 4.4:0.4:3:2.6 m/m, to develop a more efficacious and safer modern Chinese medicine injection against ischemic stroke, refined QKL (RQKL). In this study, we investigated multiple targets, levels, and pathways of RQKL by using an integrative pharm\acology combining experimental validation approach. In silica study showed that RQKL may regulate PI3K-Akt, estrogen, neurotrophin, HIF-1, MAPK, Hippo, FoxO, TGF-beta, NOD-like receptor, apoptosis, NF-kappa B, Wnt, chemokine, TNF, Toll-like receptor signaling pathways against ischemic stroke. The experimental results showed that RQKL improved neurological function and prevented infract volume and blood-brain-barrier damage. RQKL inhibited microgliosis and astrogliosis, and protected neurons from ischemic/reperfusion injury. RQKL also inhibited cell apoptosis and affecting the ratio of the anti-apoptosis protein B-cell lymphoma-2 (Bcl2) and pro-apoptosis protein Bcl2-associated X protein (Bax). Western blot analysis showed that RQKL activated AKT/PI3K signaling pathway and antibody array showed RQKL inhibited inflammatory response and decreased proinflammatory factor Tnf, Il6, and Il1b, and chemokines Ccl2, Cxcl2, and Cxcl3, and increased anti-inflammatory cytokine Il10. In conclusion, RQKL protected tissue against ischemic stroke through multiple-target, multiple signals, and modulating multiple cell-types in brain. This study not only promoted our understanding of the role of RQKL against ischemic stroke, but also provided a pattern for the study of Chinese medicine combining pharmaceutical Informatics and system biology methods.

Abstract Background Nonalcoholic fatty liver disease (NAFLD) represents one of the most common forms of liver disease worldwide, and it is always regarded as a consequence of a sedentary, food-abundant lifestyle, sitting for an extended time, and a low physical activity level, which often coincide with chronic and long-lasting psychological stress. A Chinese medicine Sinisan (SNS) may be a potential formula for treating this kind of disease. Methods In this study, a long-term chronic restraint stress protocol was used to investigate the mechanism underlying stress-induced NALFD. To investigate the effect of SNS treatment on stress-induced NAFLD, we measured the liver and serum values of total cholesterol (TC), triglyceride (TG), liver free fatty acids (FFA), low-density lipoprotein, superoxide dismutase, tumor necrosis factor-α, malondialdehyde, interleukin (IL)-6, and serum values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase. Results are shown as a mean ± standard deviation. Significant differences between the groups were evaluated using the Student t-test. For multiple comparisons, one-way analysis of variance (ANOVA) was used. If the results of ANOVA indicated significant differences, post hoc analysis was performed with the Tukey test or Dunnett test, and p

Post-stroke depression (PSD) is one of the most frequent complications of stroke. The Yi-nao-jie-yu prescription (YNJYP) is an herbal prescription widely used as a therapeutic agent against PSD in traditional Chinese medicine. Disruption of adult neurogenesis has attracted attention as a potential cause of cognitive pathophysiology in neurological and psychiatric disorders. The Notch signaling pathway plays an important role in neurogenesis. This study investigated the effects of YNJYP on adult neurogenesis and explored its underlying molecular mechanism in a rat model of PSD that is established by middle cerebral artery occlusion and accompanied by chronic immobilization stress for 1 week. At 2, 4, and 8 weeks, depression-like behavior was evaluated by a forced swim test (FST) and sucrose consumption test (SCT). Neurogenesis was observed by double immunofluorescence staining. Notch signals were detected by real-time polymerase chain reaction. The results show that, at 4 weeks, the immobility time in the FST for rats in the PSD group increased and the sucrose preference in the SCT decreased compared with that in the stroke group. Therefore, YNJYP decreased the immobility time and increased the sucrose preference of the PSD rats. Further, PSD interfered with neurogenesis and decreased the differentiation toward neurons of newly born cells in the hippocampal dentate gyrus, and increased the differentiation toward astrocytes, effects that were reversed by YNJYP, particularly at 4 weeks. At 2 weeks, compared with the stroke group, expression of target gene Hes5 mRNA transcripts in the PSD group decreased, but increased after treatment with YNJYP. At 4 weeks, compared with the stroke group, the expression of Notch receptor Notch1 mRNA transcripts in the PSD group decreased, but also increased after treatment with YNJYP. Overall, this study indicated that disturbed nerve regeneration, including the increased numbers of astrocytes and decrease numbers of neurons, is a mechanism of PSD, and Notch signaling genes dynamically regulate neurogenesis. Moreover, YNJYP can relieve depressive behavior in PSD rats, and exerts a positive effect on neurogenesis by dynamically regulating the expression of Notch signaling genes.

During the past decade, accumulating evidence from both clinical and experimental studies has indicated that erythropoietin may have antidepressant effects. In addition to the kidney and liver, many organs have been identified as secretory tissues for erythropoietin, including the brain. Its receptor is expressed in cerebral and spinal cord neurons, the hypothalamus, hippocampus, neocortex, dorsal root ganglia, nerve axons, and Schwann cells. These findings may highlight new functions for erythropoietin, which was originally considered to play a crucial role in the progress of erythroid differentiation. Erythropoietin and its receptor signaling through JAK2 activate multiple downstream signaling pathways including STAT5, PI3K/Akt, NF-κB, and MAPK. These factors may play an important role in inflammation and neuroprogression in the nervous system. This is particularly true for the hippocampus, which is possibly related to learning, memory, neurocognitive deficits and mood alterations. Thus, the influence of erythropoietin on the downstream pathways known to be involved in the treatment of depression makes the erythropoietin-related pathway an attractive target for the development of new therapeutic approaches. Focusing on erythropoietin may help us understand the pathogenic mechanisms of depression and the molecular basis of its treatment.