Traditional Chinese medication for oral submucous fibrosis: A systematic review and network meta-analysis of randomized controlled trials.

OBJECTIVE: The purpose of this study was to investigate the effectiveness of various drug therapy methods for treating oral submucous fibrosis (OSF) in terms of increasing mouth opening, reducing VAS score, decreasing lesion area, minimizing side effects, and determining effective proportion. METHOD: A database search was conducted. Only randomized clinical trials were included, and Cochrane checklist was used for assessing the risk of bias. Stata.17 software was employed and effective treatment ranking was used. RESULTS: Thirty-one RCT studies, with a total of 2986 patients, were included in the period of 2010-2022. The combination of oral Chinese herbal medicine formulas (OC) and intralesional Salvia miltiorrhiza (ISM) was found to be the most effective treatment in improving mouth opening. For reducing the burning pain, the combination of intralesional steroids (IS) and oral Salvia miltiorrhiza (OSM) was found to be more effective than the others. In terms of lesion area, IS combined with OC was more effective than the others. IS combined with ISM had the highest effective proportion while having the lowest incidence of side effects which mentioned the incidence of side effects. CONCLUSION: This study indicates that OC and SM can be employed by clinicians for treating OSF effectively.

New ingenane and ingol diterpenoids from Euphorbia royleana.

Phytochemical investigation on the 95% EtOH extract of the Traditional Chinese Medicine (TCM) Euphorbia royleana (Ba-wang-bian in Chinese) led to the isolation of 11 diterpenoids (1-11) and two triterpenoids (12 and 13). Among them, compounds 1 and 2 were new ingenane and ingol diterpenoids, respectively. Their structures were elucidated by a combination of spectroscopic analyses (1 D and 2 D NMR, HRMS, ECD, UV, and IR data) and chemical methods. Compounds 12 and 13 exhibited moderate cytotoxicities in vitro against human lung cancer cell line A549 with IC50 values of 14.84 ± 0.56 and 27.11 ± 1.65 µM, respectively.

Exploration of the Potential Mechanisms of Lingqihuangban Granule for Treating Diabetic Retinopathy Based on Network Pharmacology.

BACKGROUND: The Lingqihuangban Granule (LQHBG), a remarkable Chinese herbal compound, has been used for decades to treat diabetic retinopathy (DR) in the Department of Ophthalmology, Shanghai General Hospital (National Clinical Research Center for Eye Diseases) with obvious effects. Through the method of network pharmacology, the present study constructed bioactive component-relative targets and protein-protein interaction network of the LQHBG and implemented gene function analysis and pathway enrichment of targets, discussing the mechanisms of traditional Chinese medicine LQHBG in treating DR. MATERIALS AND METHODS: The bioactive ingredients of LQHBG were screened and obtained using TCMSP and ETCM databases, while the potential targets of bioactive ingredients were predicted by SwissTargetPrediction and ETCM databases. Compared with the disease target databases of TTD, Drugbank, OMIM and DisGeNET, the therapeutic targets of LQHBG for DR were extracted. Based on the DAVID platform, GO annotation and KEGG pathway analyses of key targets were explored, combined with the screening of core pathways on the Omicshare database and pathway annotation on the Reactome database. RESULTS: A total of 357 bioactive components were screened from LQHBG, involving 86 possible targets of LQHBG treating DR. In the PPI network, INS and ALB were identified as key genes. The effective targets were enriched in multiple signaling pathways, such as PI3K/Akt and MAPK pathways. CONCLUSION: This study revealed the possible targets and pathways of LQHBG treating DR, reflecting the characteristics of multicomponent, multitarget and multipathway treatment of a Chinese herbal compound, and provided new ideas for further discussion.

Schisandrin B targets cannabinoid 2 receptor in Kupffer cell to ameliorate CCl4-induced liver fibrosis by suppressing NF-κB and p38 MAPK pathway.

BACKGROUND: Lignans, the major bioactive components of Schisandra chinensis, displays an anti-liver fibrosis effect. However, which one is the most effective lignan and what is its molecular mechanisms are still unclear. PURPOSE: This research aimed to screen the most effective components of lignans, identify and verify its pharmacological target, and investigate its molecular mechanism against liver fibrosis. METHODS: First, the most effective lignans were screened by a comprehensive RAW264.7/CMC system and LPS-induced RAW264.7. Second, the potential targets were predicted by a liver fibrosis domain-specific chemo-genomics knowledgebase and further verified by competition binding assay. Third, the effect of anti-liver fibrosis was evaluated by employing RAW264.7, co-cultured hepatic stellate cells (HSC) and CCl4-induced liver fibrosis CB2-/- mice. The qPCR, ELISAs, western blot analyses, and immunofluorescence were used to evaluate the expression of main inflammatory factors and key proteins in NF-κB and p38 MAPK pathway. RESULTS: Schisandrin B was identified as the most effective component for attenuating liver fibrosis, and CB2 was proven to be a potential target for anti-liver fibrosis. The in vitro and in vivo assays indicated that schisandrin B ameliorated CCl4-induced liver fibrosis through suppressing NF-κB and p38 MAPK pathway in Kupffer cells by targeting CB2 receptor CONCLUSION: Schisandrin B targets CB2 receptor to inhibit Kupffer cell polarization by downregulating the NF-κB and p38 MAPK signaling pathways for ameliorating liver fibrosis.

Discovery of 8,9-seco-ent-Kaurane Diterpenoids as Potential Leads for the Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a lethal malignancy without safe and effective therapeutic drugs. In this study, the anti-TNBC bioassay-guided isolation of the medicinal plant Croton kongensis followed by the structural modification led to the construction of a small ent-kaurane diterpenoid library (1-25). With subsequent biological screening, 20 highly potent compounds (IC50s < 3 µM) were identified. Among them, 8,9-seco-ent-kaurane 6 displayed comparable activity (IC50s ∼ 80 nM) to doxorubicin but with better selectivity. The analysis of structure-activity relationships suggested that the cleavage of the C8-C9 bond and the presence of α,ß-unsaturated ketone moiety were essential for the activity. The mechanistic study revealed that 6 induced apoptosis, autophagy, and metastasis suppression in TNBC cells via inhibition of Akt. In vivo, 6 significantly suppressed the TNBC tumor growth without causing side effects. All these results suggested that 6 may serve as a promising lead for the development of novel anti-TNBC agents in the future.

Effects of different acupuncture treatment methods on post-stroke cognitive impairment: study protocol for a multicenter randomized controlled trial.

BACKGROUND: Cognitive impairment is a common dysfunction after stroke that seriously affects the overall recovery of patients. Cognitive rehabilitation training is currently the main treatment to improve cognitive function, but its curative effect is limited. Acupuncture is a core component of traditional Chinese medicine (TCM), and some previous clinical studies have shown that it might be effective in treating post-stroke cognitive impairment (PSCI), but further evidence from large-sample studies is needed. The overall objective of this trial is to obtain further data to develop an optimized acupuncture treatment for PSCI by comparing the effects of different acupuncture treatment methods on cognitive function in PSCI patients. METHODS/DESIGN: In this multicenter, prospective, randomized controlled trial, 206 eligible stroke inpatients who meet the trial criteria will be randomly assigned to 2 groups: an electroacupuncture (EA) plus needle retention (NR) group and an EA group. Both groups of patients will undergo the same routine cognitive rehabilitation treatments. All treatments will be given 5 times per week for 8 weeks. The primary outcomes will be assessed using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment scale (MOCA). The secondary outcome will be measured by the Barthel Index (BI). All outcomes will be evaluated at baseline, week 4, week 8, and the third and sixth month after the end of treatment. DISCUSSION: Our aim is to evaluate the effects of two different acupuncture treatment methods for treating PSCI patients. This study is expected to provide data to be used in developing an optimized acupuncture treatment method for PSCI treatment. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900027849. Registered on 30 November 2019, http://www.chictr.org.cn/showproj.aspx?proj=46316.

Mannose-Modified Liposome Co-Delivery of Human Papillomavirus Type 16 E7 Peptide and CpG Oligodeoxynucleotide Adjuvant Enhances Antitumor Activity Against Established Large TC-1 Grafted Tumors in Mice.

BACKGROUND: Previously, we demonstrated the therapeutic efficacy of a human papillomavirus (HPV) vaccine, including HPV16 E7 peptide and CpG oligodeoxynucleotides (CpG ODN), against small TC-1 grafted tumors. Here, we developed an HPV16 E7 peptide and CpG ODN vaccine delivered using liposomes modified with DC-targeting mannose, Lip E7/CpG, and determined its anti-tumor effects and influence on systemic immune responses and the tumor microenvironment (TME) in a mouse large TC-1 grafted tumor model. METHODS: L-alpha-phosphatidyl choline (SPC), cholesterol (CHOL), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol-2000)] (DSPE-PEG-2000), 1,2-dioleoyl-3-trimethylammonium-propane chloride salt (DOTAP) and Mannose-PEG-DSPE, loaded with HPV16 E7 peptide and CpG ODN, were used to construct the Lip E7/CpG vaccine. The anti-tumor effects and potential mechanism of Lip E7/CpG were assessed by assays of tumor growth inhibition, immune cells, in vivo cytotoxic T lymphocyte (CTL) responses and cytokines, chemokines, CD31, Ki67 and p53 expression in the TME. In addition, toxicity of Lip E7/CpG to major organs was evaluated. RESULTS: Lip E7/CpG had a diameter of 122.21±8.37 nm and remained stable at 4°C for 7 days. Co-delivery of HPV16 E7 peptide and CpG ODN by liposomes exerted potent anti-tumor effects in large (tumor volume ≥200mm3) TC-1 grafted tumor-bearing mice with inhibition rates of 80% and 78% relative to the control and Free E7/CpG groups, respectively. Vaccination significantly increased numbers of CD4+ and CD8+ T cells, and IFN-γ-producing cells in spleens and tumors and enhanced HPV-specific CTL responses, while reducing numbers of inhibitory cells including myeloid-derived suppressor cells and macrophages. Expression of cytokines and chemokines was altered and formation of tumor blood vessels was reduced in the Lip E7/CpG group, indicating possible modulation of the immunosuppressive TME to promote anti-tumor responses. Lip E7/CpG did not cause morphological changes in major organs. CONCLUSION: Lip E7/CpG induced anti-tumor effects by enhancing cellular immunity and improving tumor-associated immunosuppression. Mannose-modified liposomes are the promising vaccine delivery strategy for cancer immunotherapy.

The comparative effectiveness of traditional Chinese medicine exercise therapies in elderly people with mild cognitive impairment: A protocol for a network meta-analysis.

BACKGROUND: Mild cognitive impairment (MCI) in the elderly is a health problem worldwide. Several clinical trials indicated that traditional Chinese medicine (TCM) exercise therapies can effectively improve MCI, such as Tai Ji, Baduan jin exercise, Liuzi jue, and finger exercise. However, there is still controversy over which therapy is the best for elderly MCI patients. In this study, we aimed to systematically evaluate and compare the effectiveness and safety of these 4 TCM exercise therapies in elderly patients with MCI. METHODS: The Web of Science, PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Clinical Trials, China National Knowledge Infrastructure, Wangfang database, and Chinese Biomedical Medicine will be comprehensively searched to collect all randomized controlled trials which included elderly participants with MCI receiving TCM exercise therapies through July 2020. Two reviewers will independently screen and evaluate each included study and extract the outcome indexes. ADDIS 1.16.8 software will be used for the network meta-analysis and STATA 14 software will be used for drawing network evidence plots and funnel plots. RESULTS: We will use the Bayesian statistical model to conduct a network meta-analysis to rank the effectiveness and safety of these 4 interventions, and use the GRADE approach to interpret the results. CONCLUSION: This network meta-analysis will find out the optimal treatment plan for MCI and provide evidence-based bias for clinical treatments decision-making. PROTOCOL REGISTRATION NUMBER: INPLASY202070006.

Revealing active ingredients, potential targets, and action mechanism of Ermiao fang for treating endometritis based on network pharmacology strategy.

ETHNOPHARMACOLOGICAL RELEVANCE: Ermiao fang (EMF) is a traditional Chinese medicinal herbal formula from ancient times and recorded in the pharmacopeia of the People's Republic of China. It is composed of two typical Chinese herbal medicines, Cortex Phellodendri (Huangbai), the bark of Phellodendron chinensis Schneid. (Rutaceae), and Rhizoma Atractylodis (Cangzhu), the rhizome of Atractylodes lancea (Thunb.) DC. (Compositae). EMF has been clinically used for the treatment of endometritis for many years in China. AIM OF THE STUDY: This study was aimed to identify the active ingredients, potential targets, and mechanism of action of EMF for the treatment of endometritis. MATERIALS AND METHODS: In this research, the pharmacological effects of EMF on endometritis were first evaluated by establishing a rat model of endometritis. A network pharmacology-based analytical strategy was then used to predict its targets and signaling pathways. An endometritis-related protein target and compound database was built for EMF. The compounds in EMF and those absorbed into the blood were identified by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS). High-throughput virtual screening and molecule docking methods were used to predict the protein targets of EMF. The surface plasmon resonance analysis (SPR) method was used to validate the affinity between the compound and proteins. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was used to predict the related pathways. Western blotting analysis was used to evaluate the expression of key proteins in the related pathways. RESULTS: The animal study showed that EMF could reduce uterine inflammation in rats with endometritis. Then, an ingredient database including 187 compounds and a protein target database including 836 proteins were constructed. Twenty-four compounds in EMF were identified by UHPLC-Q-TOF/MS, among which eight compounds were present in rat plasma after an oral administration of EMF. Afterward, 39 potential target proteins were predicted by the high-throughput screening method, and 20 of them were selected after further screening using molecular docking. Subsequently, an ingredient-target network was constructed, and the target proteins were classified into the NF-κB and MAPK signal pathways by KEGG pathway enrichment analysis. Finally, the affinity between the active ingredients and the target proteins was verified by SPR. The Western blotting analysis showed that EMF significantly inhibited the elevated NF-κB and MAPK pathway proteins in rats with endometritis. CONCLUSIONS: EMF exhibited a significant pharmacological effect on rats with endometritis. Network pharmacology analysis revealed that eight compounds were absorbed into the blood after oral administration and interacted with 20 targets. Western blotting analysis indicated that EMF exerted anti-inflammatory effects by inhibiting the NF-κB and MAPK signaling pathway proteins in the treatment of endometritis.

[Study on transformation rules of terrestrosin D in course of Tribuli Fructus stir-frying based on simulated processing technology].

The contents of terrestrosin D and hecogenin from Tribuli Fructus were determined before and after stir-frying. The results showed that the content of terrestrosin D was decreased significantly,and the content of hecogenin was increased significantly after such processing. In order to verify the inference that terrestrosin D was converted to hecogenin by stir-frying,the quantitative variation rules of terrestrosin D and hecogenin were studied by simulated processing technology,and the simulated processing product of terrestrosin D was qualitatively characterized by ultra performance liquid chromatography/time of flight mass spectrometry( UPLC-TOF/MS) to clarify its transformation process during stir-frying. The results showed that the content of terrestrosin D was decreased significantly at first and then a platform stage appeared with the prolongation of processing time at a certain temperature. Raising the stir-frying temperature could further decrease the content of terrestrosin D and delay the time that the platform stage appeared. When the processing was simulated at higher temperatures( 220 ℃ and 240 ℃),the content of hecogenin was increased gradually with the increase of processing temperature and the prolongation of processing time. In the process of stir-frying,the deglycosylation reaction of terrestrosin D to hecogenin was not completed in one step. The deglycosylation reaction occurred first at the end of the sugar chain,and then other glycosyl units in the sugar chain were sequentially removed from the outside to the inside to finally form the hecogenin. This study provides a basis for further revealing the detoxification mechanism of stir-fried Tribuli Fructus.

Lignans and triterpenoids from Vitex negundo var. heterophylla and their biological evaluation.

Three new phenylnaphthalene-type lignans, vitexnegheteroins E-G (1-3), and a new polyoxygenated ursane-type triterpene, vitexnegheteroin H (9), were isolated from the seeds of Vitex negundo var. heterophylla, together with ten known compounds. Their structures were established on the basis of extensive 1D and 2D NMR experiments, as well as their mass spectroscopic data. The absolute configurations of compounds 1 and 2 were determined by comparing their experimental ECD spectra with that calculated by the time-dependent density functional theory (TDDFT) method. The isolates were evaluated for their cytotoxicities against three human cancer cell lines, inhibitory activities on lipopolysaccharide-induced NO production in murine microglial BV-2 cells, and antioxidant activities for ABTS radical scavenging.

Correlation Between Brain Activation Changes and Cognitive Improvement Following Cognitive Remediation Therapy in Schizophrenia: An Activation Likelihood Estimation Meta-analysis.

BACKGROUND: Several studies using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) have indicated that cognitive remediation therapy (CRT) might improve cognitive function by changing brain activations in patients with schizophrenia. However, the results were not consistent in these changed brain areas in different studies. The present activation likelihood estimation (ALE) meta-analysis was conducted to investigate whether cognitive function change was accompanied by the brain activation changes, and where the main areas most related to these changes were in schizophrenia patients after CRT. Analyses of whole-brain studies and whole-brain + region of interest (ROI) studies were compared to explore the effect of the different methodologies on the results. METHODS: A computerized systematic search was conducted to collect fMRI and PET studies on brain activation changes in schizophrenia patients from pre- to post-CRT. Nine studies using fMRI techniques were included in the meta-analysis. Ginger ALE 2.3.1 was used to perform meta-analysis across these imaging studies. RESULTS: The main areas with increased brain activation were in frontal and parietal lobe, including left medial frontal gyrus, left inferior frontal gyrus, right middle frontal gyrus, right postcentral gyrus, and inferior parietal lobule in patients after CRT, yet no decreased brain activation was found. Although similar increased activation brain areas were identified in ALE with or without ROI studies, analysis including ROI studies had a higher ALE value. CONCLUSIONS: The current findings suggest that CRT might improve the cognition of schizophrenia patients by increasing activations of the frontal and parietal lobe. In addition, it might provide more evidence to confirm results by including ROI studies in ALE meta-analysis.

Immunomodulatory Activities on RAW 264.7 Macrophages of a Polysaccharide from Veiled Lady Mushroom, Dictyophora indusiata (Higher Basidiomycetes).

A water-soluble polysaccharide named DI was extracted from the fruiting bodies of gastroid mushroom Dictyophora indusiata with boiling water. The chemical and physical characteristics of DI were investigated by a combination of chemical and instrumental analysis methods. The immunomodulatory activities on RAW 264.7 macrophage of DI in vitro were also studied. The results showed that DI is a ß-(1→3)-glucan with side branches of ß-(1→6)-glucosyl units, and it has triple-helical structure. DI has no toxic effect on cells, but can promote macrophage multiplication. DI significantly affects the immune function by promoting the production of nitric oxide and cytokines, such as tumor necrosis factor-α, interleukin-1, -6, and -12, showing an obvious dose-effect relationship. This work extends the application scope of the polysaccharide from D. indusiata in the biomedical field.

Nuclear orphan receptor NR4A2 confers chemoresistance and predicts unfavorable prognosis of colorectal carcinoma patients who received postoperative chemotherapy.

BACKGROUND: NR4A2, an orphan nuclear receptor essential in neuron generation, has been recently linked to inflammatory and metabolic pathways of colorectal carcinoma (CRC). However, the effects of NR4A2 on chemo-resistance and postoperative prognosis of CRC remain unknown. METHODS: NR4A2 was transfected into CRC cells to investigate its effects on chemo-resistance to 5-fluorouracil and oxaliplatin and chemotherapeutics-induced apoptosis. We also investigated prostaglandin E2 (PGE2)-induced NR4A2 expression and its effect on chemo-resistance. Tissue microarrays including 51 adenoma, 14 familial adenomatous polyposis with CRC, 17 stage IV CRC with adjacent mucosa and 682 stage I-III CRC specimens were examined immunohistochemically for NR4A2 expression. Median follow-up time for stage I-III CRC patients was 53 months. RESULTS: Ectopic expression of NR4A2 increased the chemo-resistance, and attenuated the chemotherapeutics-induced apoptosis. Transient treatment of PGE2 significantly up-regulated NR4A2 expression via protein kinase A pathway and increased the chemo-resistance. NR4A2 expression in epithelials consecutively increased from adenoma, adjacent mucosa to CRC (P(trend)<0.001). In multivariate Cox regression analyses, high NR4A2 expression in cancer nuclei (immunoreactive score ≥ 4) significantly predicted a shorter disease-specific survival (DSS) of CRC patients (hazard ratio [HR]=1.88, P=0.024). High NR4A2 expression specifically predicted a shorter DSS of colon cancer patients (dichotomisation, HR=2.55, log-rank test P=0.011), especially for those who received postoperative 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX) chemotherapy (3-score range, HR=1.86, log-rank test P=0.020). CONCLUSION: High expression of NR4A2 in CRC cells confers chemo-resistance, attenuates chemotherapeutics-induced apoptosis, and predicts unfavorable prognosis of colon cancer patients, especially for those who received postoperative chemotherapy. NR4A2 may be prognostic and predictive for colon cancer.

Risk factor for clear cell renal cell carcinoma in Chinese population: a case-control study.

BACKGROUND: Risk factors for clear cell renal cell carcinoma (ccRCC) differ among populations and remain controversial. We carried out a hospital-based case-control study to examine the effects of health status, lifestyle, and some genetic polymorphisms on ccRCC risk in Chinese subjects. METHODS: Between 2007 and 2009, 250 newly diagnosed, histologically confirmed ccRCC cases and 299 sex-, age-matched healthy controls provided complete information including consumption of tea and alcohol, smoking, occupational exposure, body mass index (BMI), hypertension, diabetes, and urolithiasis by face-to-face interview in Shanghai. Genetic polymorphisms of cytochrome P450 mono-oxygenase (CYP1A1: 6235T>C, 4889A>G, and 4887C>A), glutathione S-transferase (GSTP1: 342A>G), and N-acetyltransferase (NAT2: 481C>T, 590G>A, and 857G>A) were identified by PCR-RFLP and DNA sequencing. Adjusted odds ratio (AOR) and 95% confidence interval (CI) were derived through multivariate logistic regression. RESULTS: Green tea intake (≥500 ml/d) was inversely associated with ccRCC risk, with an AOR of 0.34 (95% CI 0.21-0.55). BMI (≥25 kg/m(2)), hypertension, and urolithiasis were independently associated with an increased risk of ccRCC, with AOR (95% CI) of 2.10 (1.32-3.34), 2.49 (1.57-3.93), and 3.33 (1.12-9.89), respectively. No association was observed between smoking, alcohol consumption, or occupational exposure with ccRCC risk. The polymorphisms and their interactions with the environmental exposures were mostly not associated with ccRCC risk. CONCLUSION: BMI (≥25 kg/m(2)), hypertension, and urolithiasis are independently associated with an increased risk, whereas green tea intake (≥500 ml/d) is independently associated with a decreased risk of ccRCC. The polymorphisms of the xenobiotic-metabolizing enzymes are weakly associated with ccRCC risk in Chinese subjects.