Identification of active compounds of traditional chinese medicine derived from maxing shigan decoction for COVID-19 treatment: a meta-analysis and in silico study.

BACKGROUND: Coronavirus 2019 (COVID-19) poses a serious threat to human health. In China, traditional Chinese medicine (TCM), mainly based on the Maxing Shigan decoction (MXSGD), is used in conjunction with western medicine to treat COVID-19. RESEARCH DESIGN AND METHODS: We conducted a network meta-analysis to investigate whether MXSGD-related TCM combined with western medicine is more effective in treating COVID-19 compared to western medicine alone. Additionally, using network pharmacology, cross-docking, and molecular dynamics (MD) simulation to explore the potential active compounds and possible targets underlying the therapeutic effects of MXSGD-related TCM. RESULTS: MXSGD-related TCM combined with western medicine was better for treating COVID-19 compared to western medicine alone. Network pharmacological analysis identified 43 shared ingredients in the MXSGD-related TCM prescriptions and 599 common target genes. Cross-docking of the 43 compounds with 154 proteins that matched these genes led to the identification of 60 proteins. Pathway profiling revealed that the active ingredients participated in multiple signaling pathways that contribute to their efficacy. Molecular docking and MD simulation demonstrated that MOL007214, the most promising molecule, could stably bind to the active site of SARS-CoV-2 3CLpro. CONCLUSION: This study demonstrates the important role of MXSGD-related TCM in the treatment of COVID-19.

Combination of Type I and II tyrosine kinase inhibitors-avapritinib and sunitinib-in refractory gastrointestinal stromal tumor after failure to multi-line therapy: a case report.

Background: Tyrosine kinase inhibitors (TKIs) are currently the main treatment choice for gastrointestinal stromal tumors (GISTs). However, the long-term use of TKIs can lead to drug resistance. There is no study or clinical report of combination therapies of TKIs that have been approved for marketing. Combination pharmacotherapy is a new approach for patients who do not respond to monotherapy. This case provides a reference value for selective combination of TKIs in treating advanced GIST. Case Description: In this article, we report the case of a 55-year-old female who was diagnosed with duodenal GIST in April 2018 and underwent R0 resection. KIT exon 9 mutation was detected. The patient had disease recurrence with multiple abdominal metastases during imatinib adjuvant therapy after 27 months, and failure to 2nd-line sunitinib treatment after 6 months. She underwent a cytoreductive surgery (R1), and the postoperative mutation analysis suggested KIT exon 9 mutation, with newly found secondary KIT_exon16_p. L783V mutation and other mutations on TP53, POT1, and SETD2, etc. The patient experienced short-term tumor control of standard 3rd-line therapy of regorafenib and the rapid progression of the 4th-line of ripretinib afterwards. Different TKI combination therapies (i.e., ripretinib plus sunitinib, ripretinib plus avapritinib and avapritinib plus sunitinib) were administered to the patient sequentially. Ripretinib plus sunitinib led to stable disease but was discontinued due to intolerable adverse effects. Finally, the patient received a combination regimen of avapritinib plus sunitinib. The patient's tumor showed continuous shrinking in 2 consecutive computed tomography scan evaluations within 4 months with acceptable side effects. Conclusions: Combined type I and type II TKIs of avapritinib combined with sunitinib therapy achieved tumor regression for a heavily multi-line treated patient. Our case provides a reference for a savage treatment choice in refractory GISTs after failure to all standard treatment.

Unraveling the Mechanism of Zhibaidihuang Decoction against IgA Nephropathy Using Network Pharmacology and Molecular Docking Analyses.

Zhibaidihuang Decoction (ZBDHD) is a traditional Chinese medicine with immense potential to treat IgA nephropathy. However, its core ingredients and representative mechanism remain unclear. In this study, we uncovered the key component and underlying mechanisms of ZBDHD for IgA nephropathy by applying network pharmacology and molecular docking approaches. This was done by first identifying the active ingredients and, subsequently, their corresponding gene targets in ZBDHD with the help of the Traditional Chinese Medicine Systems Pharmacology and analysis platform (TCMSP) database, thereby constructing the drug-compound-target network. The IgA nephropathy-associated genes were then identified using GeneCards, Drugbank, and OMIM databases. The overlapped targets were later obtained to establish Protein-Protein Interaction (PPI) networks, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Finally, we performed molecular docking among active compounds and hub genes, and thereby verified the key compound of ZBDHD. The drug-compound-gene network consisted of 289 nodes and 1,113 edges. The top four active ingredients were beta-sitosterol, kaempferol, quercetin and stigmasterol. The top five hub genes in the PPI network were AKT1, ILB1, IL-6, TNF, and TP53. Molecular docking results could demonstrate that there was high affinity among active compounds and the core targets, while quercetin may possibly be the key compound of ZBDHD. We first identified the positive compound and the candidate molecular mechanisms of ZBDHD in an IgA nephropathy treatment and discovered that quercetin might be the core compound of ZBDHD in the treatment of IgA nephropathy.

A Novel Perineal Nerve Block Approach for Transperineal Prostate Biopsy: An Anatomical Analysis-based Randomized Single-blind Controlled Trial.

OBJECTIVE: To develop and validate a novel perineal nerve block approach for transperineal prostate biopsy. PATIENTS AND METHODS: Five adult male cadavers were dissected to delineate the superficial and deep branches of the perineal nerve. Afterwards, 90 out of 115 patients were selected and randomly assigned to receive periprostatic, periapical triangle, or branches of perineal nerve (BPN) block. The primary outcome was the maximal pain intensity associated with transperineal prostate biopsy, which was assessed by the 10-point visual analog scale. The secondary outcomes included the number of biopsy with visual analog scale of ≥4 in each biopsy procedure, and the incidences of complications. RESULTS: On the horizontal line of the upper anal border, the locations of the superficial branch of perineal nerve on the left and right sides were 1.87 ± 0.05 cm and 1.86 ± 0.06 cm, respectively; and the deep branch were 2.15 ± 0.07 cm and 2.16 ± 0.06 cm, respectively, from the midline, and lied between the deep layer of superficial fascia and prostate capsule. The number of cases finally enrolled in data analysis in periprostatic block, periapical triangle block, and BPN block groups were 26, 27, and 30, respectively. The maximal pain intensities were 3.4 (3.1-3.7), 3.3 (3.0-3.6), and 1.8 (1.5-2.2) in the 3 groups, respectively, and the numbers of biopsy with the pain intensity of ≥4 were 4.0 (3.2-4.9), 4.2 (3.3-5.2), and 0.7 (0.1-1.2), respectively. There were 4, 3 and 4 cases developing hematuria, and 1, 1 and 2 burdened with urine retention after biopsy in the 3 groups, respectively. CONCLUSION: Collectively, BPN block is a safe, effective and repeatable local anesthesia approach for transperineal prostate biopsy.

Thamnolia vermicularis extract improves learning ability in APP/PS1 transgenic mice by ameliorating both Aß and Tau pathologies.

Considering the complicated pathogenesis of Alzheimer's disease (AD), multi-targets have become a focus in the discovery of drugs for treatment of this disease. In the current work, we established a multi-target strategy for discovering active reagents capable of suppressing both Aß level and Tau hyperphosphorylation from natural products, and found that the ethanol extract of Thamnolia vermicularis (THA) was able to improve learning ability in APP/PS1 transgenic mice by inhibiting both Aß levels and Tau hyperphosphorylation. SH-SY5Y and CHO-APP/BACE1 cells and primary astrocytes were used in cell-based assays. APP/PS1 transgenic mice [B6C3-Tg(APPswe, PS1dE9)] were administered THA (300 mg·kg-1·d-1, ig) for 100 d. After the administration was completed, the learning ability of the mice was detected using a Morris water maze (MWM) assay; immunofluorescence staining, Congo red staining and Thioflavine S staining were used to detect the senile plaques in the brains of the mice. ELISA was used to evaluate Aß and sAPPß contents, and Western blotting and RT-PCR were used to investigate the relevant signaling pathway regulation in response to THA treatment. In SH-SY5Y cells, THΑ (1, 10, 20 µg/mL) significantly stimulated PI3K/AKT/mTOR and AMPK/raptor/mTOR signaling-mediated autophagy in the promotion of Aß clearance as both a PI3K inhibitor and an AMPK indirect activator, and restrained Aß production as a suppressor against PERK/eIF2α-mediated BACE1 expression. Additionally, THA functioned as a GSK3ß inhibitor with an IC50 of 1.32±0.85 µg/mL, repressing Tau hyperphosphorylation. Similar effects on Aß accumulation and Tau hyperphosphorylation were observed in APP/PS1 transgenic mice treated with THA. Furthermore, administration of THA effectively improved the learning ability of APP/PS1 transgenic mice, and markedly reduced the number of senile plaques in their hippocampus and cortex. The results highlight the potential of the natural product THA for the treatment of AD.