Therapeutic mechanism of Toujie Quwen granules in COVID-19 based on network pharmacology.

BACKGROUND: Chinese medicine Toujie Quwen granule (TJQW) has proven to be effective in the treatment of mild coronavirus disease 2019 (COVID-19) cases by relieving symptoms, slowing the progression of the disease, and boosting the recovery of patients. But the bioactive compounds and potential mechanisms of TJQW for COVID-19 prevention and treatment are unclear. This study aimed to explore the potential therapeutic mechanism of TJQW in coronavirus disease 2019 (COVID-19) based on an integrated network pharmacology approach. METHODS: TCMSP were used to search and screen the active ingredients in TJQW. The Swiss TargetPrediction was used to predict the potential targets of active ingredients. Genes co-expressed with ACE2 were considered potential therapeutic targets on COVID-19. Venn diagram was created to show correlative targets of TJQW against COVID-19. Cytoscape was used to construct a "drug-active ingredient-potential target" network, STRING were used to construct protein-protein interaction network, and cytoHubba performed network topology analysis. Enrichment of biological functions and signaling pathways of core targets was performed by using the clusterProfiler package in R software and ClueGO with CluePedia plugins in Cytoscape. RESULTS: A total of 156 active ingredients were obtained through oral bioavailability and drug-likeness screenings. Two hundred twenty-seven potential targets of TJQW were related to COVID-19. The top ten core targets are EGFR, CASP3, STAT3, ESR1, FPR2, F2, BCL2L1, BDKRB2, MPO, and ACE. Based on that, we obtained 19 key active ingredients: umbelliprenin, quercetin, kaempferol, luteolin, praeruptorin E, stigmasterol, and oroxylin A. And the enrichment analysis obtained multiple related gene ontology functions and signaling pathways. Lastly, we constructed a key network of "drug-component-target-biological process-signaling pathway". Our findings suggested that TJQW treatment for COVID-19 was associated with elevation of immunity and suppression of inflammatory stress, including regulation of inflammatory response, viral process, neutrophil mediated immunity, PI3K-Akt signaling pathway, MAPK signaling pathway, Jak-STAT signaling pathway, Complement and coagulation cascades, and HIF-1 signaling pathway. CONCLUSIONS: Our study uncovered the pharmacological mechanism underlying TJQW treatment for COVID-19. These results should benefit efforts for people around the world to gain more knowledge about Chinese medicine TJQW in the treatment of this vicious epidemic COVID-19, and help to address this pressing problem currently facing the world.

The BET bromodomain inhibitor apabetalone induces apoptosis of latent HIV-1 reservoir cells following viral reactivation.

The persistence of latent HIV-1 reservoirs throughout combination antiretroviral therapy (cART) is a major barrier on the path to achieving a cure for AIDS. It has been shown that bromodomain and extra-terminal (BET) inhibitors could reactivate HIV-1 latency, but restrained from clinical application due to their toxicity and side effects. Thus, identifying a new type of BET inhibitor with high degrees of selectivity and safety is urgently needed. Apabetalone is a small-molecule selective BET inhibitor specific for second bromodomains, and has been evaluated in phase III clinical trials that enrolled patients with high-risk cardiovascular disorders, dyslipidemia, and low HDL cholesterol. In the current study, we examined the impact of apabetalone on HIV-1 latency. We showed that apabetalone (10-50 µmol/L) dose-dependently reactivated latent HIV-1 in 4 types of HIV-1 latency cells in vitro and in primary human CD4+ T cells ex vivo. In ACH2 cells, we further demonstrated that apabetalone activated latent HIV-1 through Tat-dependent P-TEFB pathway, i.e., dissociating bromodomain 4 (BDR4) from the HIV-1 promoter and recruiting Tat for stimulating HIV-1 elongation. Furthermore, we showed that apabetalone (10-30 µmol/L) caused dose-dependent cell cycle arrest at the G1/G0 phase in ACH2 cells, and thereby induced the preferential apoptosis of HIV-1 latent cells to promote the death of reactivated reservoir cells. Notably, cardiovascular diseases and low HDL cholesterol are known as the major side effects of cART, which should be prevented by apabetalone. In conclusion, apabetalone should be an ideal bifunctional latency-reversing agent for advancing HIV-1 eradication and reducing the side effects of BET inhibitors.

[Multi-centered, randomized controlled clinical study on Chinese medicine formula particles for hyperlipidaemia associated with highly active antiretroviral therapy].

OBJECTIVE: To observe the effect and safety of Xiaozhi particles, integrated taohong Siwu tang and Erchen tang and Xuezhikang capsule in treating hyperlipidaemia (HLP) associated with highly active antiretroviral therapy (HAART). METHOD: In the multi-centered, randomized controlled clinical study, 180 hyperlipidaemia associated with highly active antiretroviral therapy cases were divided into the treatment group treated by Xiaozhi particles, integrated Taohong Siwu tang and Erchen tang, and the control group treated by Xuezhikang capsule. The treatment course was 12 weeks. The total cholesterol (Tch), triglyceride (TG), low density lipoprotein (LDL) and high-density lipoprotein(HDL) were observed. RESULT: After 12 weeks, compared with Xuezhikang capsule, the change difference of Tch, LDL, HDL in the Chinese traditional medicine formula groups of patients is significant (P < 0.05), the change of the TG has no significant difference. The effect of Tch, LDL in Xuezhikang capsule groups is better than in traditional Chinese medicine formula group,but the effect of HDL in traditional Chinese medicine formula group is better than in Xuezhikang capsule groups. CONCLUSION: Integrated Taohong Siwu tang and Erchen tang, Xiaozhi particles and Xuezhikang capsule can be used to control the hyperlipidaemia associated with highly active antiretroviral therapy as one of the main Chinese native medicine preparation.

[Randomized controlled study of integrated treatment of traditional Chinese medicine and western medicine on AIDS with pulmonary inflammation patients].

OBJECTIVE: To compare effects of integrated treatment traditional Chinese medicine and Western medicine (TCM-WM) and simple western medicine on TCM clincal symptoms in the patient of AIDS with pulmonary inflammation. METHOD: A multicenter randomized controlled trials of 164 subjects evaluated the effects of clinical symptoms of AIDS with pulmonary inflammation of TWO regimens: the TCM-WM group (n = 111) and western medicine treatment group (n = 53), while incidence of TCM symptoms in different time points in two groups were analyzed. RESULT: Twenty eight days after treatment, the cured and markedly effective rate of TCM symptoms in the TCM-WM group significantly exceeding that in the western medicine treatment group (cured and markedly effective rate significant efficiency 44.55% vs 20.00%), while the incidence rate for the TCM symptoms of fever and headache in the TCM-WM group was significantly lower than that in western medicine group. CONCLUSION: The integrated treatment of traditional Chinese medicine and Western medicine helps to alleviate the TCM clinical symptoms of AIDS with pulmonary inflammation.

[Study of traditional Chinese medicine syndrome features of AIDS-related chronic diarrhea].

OBJECTIVE: To study the AIDS-related chronic diarrhea in traditional Chinese medicine (TCM) clinical manifestations and syndrome factors, explore the characteristics of syndrome. METHOD: A multicenter, prospective collection of 311 cases of AIDS patients with chronic diarrhea, study the characteristics of TCM syndrome by using the method of descriptive statistics and exploratory factor analysis. RESULT: The common clinical manifestation of TCM: fatigue (229 cases, 73.63%), bowel (229 cases, 68.81%), diarrhea (194 cases, 62.38%), thin fur (201 cases, 64.63%), pink tongue (166 cases, 53.38%), greasy fur, thready pulse (126 cases, 40.51%), sink vein (64 cases, 20.58%), slippery pulse. 17 common factors were extracted, common disease syndrome factor as the spleen, stomach, liver, gallbladder and colon syndrome factors of disease, Qi, Yang deficiency, Qi stagnation, dampness and heat evil. CONCLUSION: AIDS-related chronic diarrhea symptoms involving multiple organs, the disease belongs to deficiency and excess.

[Study on quality of life of asymptomatic HIV infected persons with traditional Chinese medicine].

OBJECTIVE: Study on quality of life of asymptomatic HIV infected persons with traditional Chinese medical, which can provide the clinical basis for improving the quality of life. METHOD: This study applied a randomized, double-blind, and placeb-parallel control designed method to select 1 200 persons in the asymptomatic period of HIV infection as the subjects. The subjects were randomly divided into the treatment group and the control group at the ratio of about 2:1. According to the results of monthly differential diagnosis of TCM, the test group and the control group were given homologue Chinese drugs preparations and model Chinese drugs. The total study period was 18 months. Using PRO scale and the world health organization AIDS determination of quality of life short scale form (WHOQOL-HIV-BREF) to investigate asymptomatic HIV infected persons, according to different times, we calculated the total score and each domain score of quality of life of the treatment group and control group, we did statistical analysis. RESULT: Form the PRO scale,we can see that the treatment group showed a trend of stability, compared with the control group with significant statistical difference (P < 0.05) after 6 months; from the WHOQOL-HIV scale analysis, we can see that compared with before treatment, the quality of life of the treatment group was increased, the difference was significant (P < 0.05), but the quality of life of the control quality of life was decreased, the differences was significant (P < 0.05). CONCLUSION: Dialectical therapy of Chinese medicine can significantly improve the patient's quality of life, which can provide the basis for the prevention and control policy formulation and implementation with asymptomatic HIV infected persons.

[Therapeutic effects of Fuzhenghuayu decoction in a CCl4-induced liver cirrhosis rat model and on hepatic stellate cell activation].

OBJECTIVE: To evaluate the influence of Fuzhenghuayu decoction on fibrotic liver tissue and activated hepatic stellate cells (HSCs) using a carbon tetrachloride (CCl4)-induced liver cirrhosis rat model system. METHODS: Sixty-four Sprague-Dawley rats were randomly divided into the following groups: normal (non-model, non-drug intervention), CCl4 liver fibrosis model, and CCl4 liver fibrosis model Fuzhenghuayu drug intervention at low dose (0.75 g/kg/d) and high dose (1.5 g/kg/d). The drug intervention was administered via oral-gastric irrigation once daily for 6 times per week over a 6-week period. Four rats from each group were sacrificed at the end of week 2, 4, and 6 for serum and liver tissue collection. Liver fibrosis was evaluated by histology, and expression of a-smooth muscle actin (a-SMA) was determined by immunohistochemistry. Liver function was assessed by measuring levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil). Between-group comparisons were made by completely random design and ANOVA with Bonferroni correction. RESULTS: At the end of weeks 2, 4 and 6, all four groups showed significantly different levels of ALT, AST, and TBil; in addition, the model group and drug intervention groups had significantly higher levels of ALT, AST, and TBil than the control group, the drug intervention groups showed significantly lower levels of ALT, AST, and TBil than the model group (P less than 0.01 or less than 0.05), and the differences between the low dose and high dose groups reached statistical significance (P less than 0.01 or less than 0.05). At the end of weeks 2, 4 and 6, the model group and drug intervention groups had significantly higher area ratio of liver fibrosis than the normal group (F = model: 18.68, low dose: 49.95, high dose: 82.44, P less than 0.01), but the two drug intervention groups had significantly less area ratio of liver fibrosis than the model group (P less than 0.05) and the high dose group showed the most robust decrease. In addition, the model group and drug intervention groups showed higher expression of a-SMA than the normal group (F = model: 18.68, low dose: 49.95, high dose: 82.44, P less than 0.01), but two drug intervention groups had significantly less a-SMA than the model group (F = model: 46.32, low dose: 40.30, high dose: 58.42, P less than 0.05) and the high dose group showed the most robust decrease. CONCLUSION: The Fuzhenghuayu decoction reduces the numbers of activated HSCs, thereby leading to down-regulated a-SMA expression and reduced degree of liver fibrosis; these effects may represent the mechanism by which this drug suppresses hepatic fibrosis.

[Efficacy controlled observation on acupuncture and western medicine for gastrointestinal dysmotility in liver cirrhosis].

OBJECTIVE: To observe the therapeutic effect of acupuncture on gastrointestinal dysmotility in liver cirrhosis. METHODS: Forty cases of gastrointestinal dysmotility in liver cirrhosis were randomized into an acupuncture group and a motilium group, 20 cases in each one. In the acupuncture group, on the basis of the conventional treatment, electroacupuncture was applied at Zusanli (ST 36), Sanyinjiao (SP 6) and Taichong (LR 3) for 30 min, once a day. In the motilium group, on the basis of the conventional treatment, motilium was taken orally 30 min before meals, 10 mg each time, three times a day. The treatment was required for 2 weeks in both groups. The changes in the digestive tract symptom score and liver function Child-Pugh score were observed and the efficacy was assessed. RESULTS: The total effective rate of digestive tract symptoms was 85.0% (17/20) in the acupuncture group and 70.0% (14/20) in the motilium group. The score improvements in abdominal distention, belching and vomiting in the acupuncture group were superior to those in the motilium group (all P < 0.05). In the acupuncture group, the liver function Child-Pugh total score was 8.40 +/- 0.22 before treatment and reduced to 5.36 +/- 0.17 after treatment, in which the scores for ascites, serum bilirubin and albumin were all reduced (all P < 0.05) and the reducing range was increased in tendency with the improvements in digestive tract symptoms. In the motilium group, Child-Pugh score was not changed obviously as compared with that before treatment. CONCLUSION Acupuncture effectively alleviates digestive tract symptoms and improves liver function for the patients of liver cirrhosis, its efficacy on gastrointestinal dysmotility in liver cirrhosis is superior to motilium.

[Preliminary study on features of syndrome distribution and cluster analysis for AIDS patients with pulmonary infection].

OBJECTIVE: To investigate Chinese medical features of acquired immunodeficiency syndrome (AIDS) patients with pulmonary infection. METHODS: Using cluster analysis method, Chinese medical syndromes of 196 AIDS patients with pulmonary infection were analyzed. The distribution features of each syndrome type were analyzed according to the severity and CD4+ numerical analysis. RESULTS: Basic Chinese medical syndrome types could be summed up as three kinds: exterior invasion of wind heat and phlegm heat obstructing Fei syndrome (61 cases, 31.1%), Fei-Pi deficiency and Fei stagnation of phlegm syndrome (64 cases, 32.7%), Fei-Shen deficiency and yin deficiency induced inner heat syndrome (71 cases, 36.2%). There was statistical difference in the severity degree and the distribution of CD4 among the three syndrome types (P < 0.05). CONCLUSIONS: AIDS patients with pulmonary infection involve Fei, Shen, and Pi. The pathogenic factors were related to "wind", "heat", "phlegm", and "xu". The Chinese medical syndrome distribution was closely correlated with patients' immunity.

[Inhibitory effect of anluohuaxianwan on experimental hepatic fibrosis in rats].

OBJECTIVE: To investigate the effects of anluohuaqianwan on experimental hepatic fibrosis induced by dimethyl nitrosamine (DMN) in rats. METHODS: 36 male SD rats were randomly dividied into three groups: model group, normal group, anluohuaqianwan group. The rats in the three groups were treated with DMN daily for 4 weeks. The liver function was detected using auto biochemistry analyzer, the serum HA, LN, IV-C, PIIIP were detected by immunoradiometry, the histopathology was observed in the left liver lobe after HE staining, the expression of matrix metalloproteinase-2 (MMP-2) in liver tissue were detected by immunohistochemistry. RESULTS: The serum levels of ALT, AST, ALP, TP, ALB and the contents of HA, LN, IV-C in model group were significantly increased compared to these in the normal group (P less than 0.01). The serum levels of ALT, AST and the contents of HA in anluohuaqianwan group were significantly lower than those in the model group (P less than 0.01). The liver MMP-2 in the model group was significantly increased compared to that in the normal group (P less than 0.05). The expression of MMP-2 in liver tissue of model group was lower than that in the anluohuaqianwan group (P less than 0.05). CONCLUSION: Anluohuaqianwan can inhibit liver fibrosis in rats induced by DMN.