Network pharmacology explores the mechanisms of Eucommia ulmoides cortex against postmenopausal osteoporosis

Postmenopausal osteoporosis (PMOP) has become one of most frequent chronic disease worldwide with aging population. Eucommia ulmoides cortex (EU), a traditional Chinese medicine, has long since been used to treat PMOP. The aim of this study is to explore pharmacological mechanisms of EU against PMOP through using network pharmacology approach.The active ingredients of EU were obtained from Traditional Chinese Medicine System Pharmacology database, and target fishing was performed on these ingredients in UniProt database for identification of their relative targets. Then, we screened the targets of PMOP using GeneCards database and DisGeNET database. The overlapping genes between PMOP and EU were obtained to performed protein–protein interaction, Gene Ontology analysis, Kyoto encyclopedia of genes, and genomes analysis.Twenty-eight active ingredients were identified in EU, and corresponded to 207 targets. Also, 292 targets were closely associated with PMOP, and 50 of them matched with the targets of EU were considered as therapeutically relevant. Gene ontology enrichment analysis suggested that EU exerted anti-PMOP effects via modulating multiple biological processes including cell proliferation, angiogenesis, and inflammatory response. Kyoto encyclopedia of genes and genomes enrichment analysis revealed several pathways, such as PI3K-AKT pathway, mitogen-activated protein kinase pathway, hypoxia-inducible factors-1 pathway, tumor necrosis factor pathway, and interleukin-17 pathway that might be involved in regulating the above biological processes.Through the method of network pharmacology, we systematically investigated the mechanisms of EU against PMOP. The multi-targets and multi-pathways identified here could provide new insights for further determination of more exact mechanisms of EU.     

Clinical course and outcomes of COVID-19 patients with chronic obstructive pulmonary disease: A retrospective observational study in Wuhan,China

Information about coronavirus disease 2019 (COVID-19) patients with pre-existing chronic obstructive pulmonary disease (COPD) is still lacking. The aim of this study is to describe the clinical course and the outcome of COVID-19 patients with comorbid COPD.This retrospective study was performed at Wuhan Huoshenshan Hospital in China. Patients with a clear diagnosis of COVID-19 who had comorbid COPD (N = 78) were identified. COVID-19 patients without COPD were randomly selected and matched by age and sex to those with COPD. Clinical data were analyzed and compared between the two groups. The composite outcome was the onset of intensive care unit admission, use of mechanical ventilation, or death during hospitalization. Multivariable Cox regression analyses controlling for comorbidities were performed to explore the relationship between comorbid COPD and clinical outcome of COVID-19.Compared to age- and sex-matched COVID-19 patients without pre-existing COPD, patients with pre-existing COPD were more likely to present with dyspnea, necessitate expectorants, sedatives, and mechanical ventilation, suggesting the existence of acute exacerbations of COPD (AECOPD). Greater proportions of patients with COPD developed respiratory failure and yielded poor clinical outcomes. However, laboratory tests did not show severer infection, over-activated inflammatory responses, and multi-organ injury in patients with COPD. Kaplan–Meier analyses showed patients with COPD exhibited longer viral clearance time in the respiratory tract. Multifactor regression analysis showed COPD was independently correlated with poor clinical outcomes.COVID-19 patients with pre-existing COPD are more vulnerable to AECOPD and subsequent respiratory failure, which is the main culprit for unfavorable clinical outcomes. However, COPD pathophysiology itself is not associated with over-activated inflammation status seen in severe COVID-19.     

Melatonin inhibits EMT and PD‐L1 expression through the ERK1/2/FOSL1 pathway and regulates anti‐tumor immunity in HNSCC

Melatonin is an endogenous hormone with various biological functions and possesses anti‐tumor properties in multiple malignancies. Immune evasion is one of the most important hallmarks of head and neck squamous cell carcinoma (HNSCC) and is closely related to tumor progression. However, as an immune modulator under physiological conditions, the roles of melatonin in tumor immunity in HNSCC remains unclear. In this study, we found that the endogenous melatonin levels in patients with HNSCC were lower than those in patients with benign tumors in head and neck. Importantly, lower melatonin levels were related to lymph node metastasis among patients with HNSCC. Moreover, melatonin significantly suppressed programmed death‐ligand 1 (PD‐L1) expression and inhibited epithelial–mesenchymal transition (EMT) of HNSCC through the ERK1/2/FOSL1 pathway in vitro and in vivo. In SCC7/C3H syngeneic mouse models, anti‐programmed death‐1 (PD‐1) antibody combined with melatonin significantly inhibited tumor growth and modulated anti‐tumor immunity by increasing CD8⁺ T cell infiltration and decreasing the regulatory T cell (Treg) proportion in the tumor microenvironment. Taken together, melatonin inhibited EMT and downregulated PD‐L1 expression in HNSCC through the ERK1/2/FOSL1 pathway and exerted synergistic effects with anti‐PD‐1 antibody in vivo, which could provide promising strategies for HNSCC treatment.     

IL-1 receptor-associated kinase 1 participates in the modulation of the NLRP3 inflammasome by tumor-associated macrophages in hepatocellular carcinoma

BackgroundHepatocellular carcinomas (HCCs) occur frequently in the digestive system and are associated with high mortality. This current study examined the regulatory relationship between interleukin (IL)-1 receptor-associated kinase 1 (IRAK1), NLR family pyrin domain-containing 3 (NLRP3) inflammasomes, and tumor-associated macrophages (TAMs) in the growth and metastasis of HCC.MethodsThe expression of IRAK1 and NLRP3 was assessed in tissues and cells via quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. Immunohistology was performed to detect the macrophage markers CD68, CD163, and CD168 in tumor tissues. Small interfering (si)RNA targeting IRAK1 (si-IRAK1) was designed to silence IRAK1 expression. Following si-IRAK1 transfection and/or co-culture with TAMs, HCC cell viability, proliferation, migration, and invasion, as well as the expression of NLRP3 and pro-inflammatory cytokines IL-1 β, IL-18, and monocyte chemotactic protein 1 (MCP-1) were assessed.ResultsHCC tissues showed elevated expression of IRAK1 and NLRP3, as well as increased expression of the macrophage markers CD68, CD163, and CD168, compared to adjacent healthy tissues. Silencing of IRAK1 expression in HepG2 and Huh7 cells resulted in suppression of cell proliferation, migration, and invasion, and also reduced expression of NLRP3 and the pro-inflammatory cytokines IL-1β, IL-18, and MCP-1. Moreover, TAMs promoted HepG2 and Huh7 cell proliferation, migration, and invasion, and elevated the expression of NLRP3, IL-1β, IL-18, and MCP-1. Furthermore, IRAK1 silencing reversed the effects of TAMs on HepG2 and Huh7 cells.ConclusionsThe expression of IRAK1 was associated with HCC growth and metastasis, as well as NLRP3 inflammasome activation. The ability of TAMs to promote HCC growth and metastasis may be activated by NLRP3 inflammasomes and regulated by IRAK1.     

Displaced proximal humerus fractures treated with ORIF via the deltoid interfascicular approach vs the deltopectoral approach: A prospective case-control study

Background:The purpose of this study was to evaluate the clinical outcomes and complications of displaced proximal humeral fractures treated with proximal humeral internal locking system (PHILOS) plate fixation via a deltoid interfascicular (DI) vs a deltopectoral (DP) approach.Methods:This prospective case-control study was conducted with patients admitted to our hospital from May 2015 to June 2018 who suffered from unilateral displaced proximal humerus fractures. Patients were treated with PHILOS plate fixation via a DI (DI group) or DP approach (DP group). The clinical outcomes and complication data were collected for comparison between the 2 groups. The patients were followed up at 3, 6, and 12 months; and every 6 months thereafter. The patients’ functional recoveries were evaluated according to the normalized Constant-Murley score, range of motion of the shoulder (flexion, abduction, external/internal rotation) and disabilities of the arm, shoulder and hand score.Results:A total of 77 patients, followed for an average of 15 ± 2.2months (range, 12–21), were enrolled (36 in DI group and 41 in DP group) for final analysis. No significant differences in age, sex, affected side, fracture type, injury mechanism or time from injury to operation were found between the 2 groups (all P > .05). The incision length, intra-operative blood loss, and duration of operation in the DI group were significantly less than those in the DP group, respectively (all P < .05). The functional outcomes assessed by the normalized Constant-Murley score and range of motion of flexion and internal rotation in the DI group were superior to those in the DP group at 3 and 6months after the operation (P < .05); however, no significant differences were observed at the 12-month and subsequent follow-ups (all P > .05). There was no significant difference in the range of shoulder external rotation and abduction during the postoperative follow-ups (P > .05). At the last follow-up, the mean disabilities of the arm, shoulder, and hand score was 14.0 (6.6) points in the DI group and 14.4 (6.9) points in the DP group (P = .793). Complications occurred in 1 patient in the DI group and 8 patients in the DP group (P = .049).Conclusion:The current study demonstrates that DI approach is a safe and effective alternative for the treatment displaced proximal humerus fractures. The DI approach rather than DP approach was recommended when lateral and posterior exposure of the proximal humerus is required, especially when fixed with PHILOS plate.     

Efficacy analysis of Cheng’s GIRAFFE reconstruction after proximal gastrectomy for adenocarcinoma of esophagogastric junction

ObjectiveReconstruction of the digestive tract for adenocarcinoma of esophagogastric junction (AEG) is in dispute. This study evaluated Cheng’s gastric tube interposition esophagogastrostomy with reconstruction of His angle and fundus (Cheng’s GIRAFFE anastomosis) in laparoscopic/open proximal gastrectomy for Siewert type II AEG, which was performed at Zhejiang Cancer Hospital and the First Affiliated Hospital of Zhejiang Chinese Medical University. Here, we discuss the preliminary results of gastric emptying and anti-reflux.MethodsFrom a retrospective database, 74 patients with advanced Siewert type II AEG underwent curative proximal gastrectomy with GIRAFFE anastomosis, and their gastric emptying and anti-reflux outcomes were evaluated by the Reflux Disease Questionnaire (RDQ) score, nuclide gastric emptying, 24-h impedance-pH monitoring and gastroscopy.ResultsSeventy-four patients successfully completed proximal partial gastrectomy with Cheng’s GIRAFFE esophagogastric anastomosis. RDQ score six months after the operation was 2.2±2.5. Results of nuclide gastric emptying examinations showed that the gastric half-emptying time was 67.0±21.5 min, the 1-h residual rate was (52.2±7.7)%, the 2-h residual rate was (36.4±5.1)%, and the 3-h residual rate was (28.8±3.6)%; 24-h impedance-pH monitoring revealed that the mean DeMeester score was 5.8±2.9. Reflux esophagitis was observed by gastroscopy in 7 patients six months after surgery.ConclusionsCheng’s GIRAFFE anastomosis is safe and feasible for Siewert type II AEG.     

Efficacy and safety of transcatheter arterial chemoembolization-lenvatinib sequential therapy for patients with unresectable hepatocellular carcinoma: a single-arm clinical study

BackgroundRepeated transcatheter arterial chemoembolization (TACE) could cause ischemia of the tumor tissue and increases production of angiogenic factors in patients with hepatocellular carcinoma (HCC). Lenvatinib can inhibit the expression of angiogenic factors induced by ischemia after TACE and reduce angiogenesis and tumor recurrence. TACE-lenvatinib sequential therapy may improve clinical outcomes. There have been few investigations of TACE-lenvatinib sequential therapy for the treatment of unresectable HCC. We aimed to evaluate the efficacy and safety of TACE-lenvatinib sequential therapy for unresectable HCC.MethodsFrom May 2018 to May 2021, 53 consecutive patients who underwent TACE-lenvatinib sequential therapy were retrospectively reviewed. Of these, 30 patients who met the inclusion criteria were selected. Lenvatinib treatment started within 1 or 2 weeks after TACE at a dose of 8 or 12 mg once daily. Treatment response was assessed using dynamic magnetic resonance imaging (MRI) according to the modified response evaluation criteria in solid tumor (mRECIST). Blood tests were also performed at every response evaluation. Patients with complete response (CR) or partial response (PR) and stable disease (SD) received continuous lenvatinib therapy, and patients with progressive disease (PD) received repeated TACE. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were calculated. Statistical analysis was performed using the Kaplan-Meier method.ResultsThe median age was 58.5±9.1 years, and 16.7% (5/30) of patients were female. A total of 12 patients were categorized as Barcelona Clinic Liver Cancer (BCLC) Stage B and 18 were BCLC Stage C. The mean follow-up time was 15.7 months. The ORR was 76.7% (23/30), and the DCR was 96.7% (29/30). The median PFS was 6.1 months, and the median OS was 20.7 months. The most common lenvatinib-related AE was rash, and the most common TACE-related AE was elevated aspartate aminotransferase (AST). No treatment-related mortality was observed.ConclusionsFrom our findings, TACE-lenvatinib sequential therapy may prolong OS and PFS in patients with unresectable HCC, and the side effects are acceptable. The efficacy and safety of the sequential therapy should be confirmed in multiple center randomized controlled trials (RCTs) with a large sample and sufficient follow-up period.     

The bevacizumab plus oxaliplatin-based chemotherapy regimen is more suitable for metastatic colorectal cancer patients with a history of schistosomiasis: a clinical retrospective analysis

BackgroundThe basic platelet counts of schistosomiasis patients are low. If it does not meet the requirements for chemotherapy, the patient’s treatment will not be carried out, which directly affects their prognosis. Therefore the impact of treatment on platelet counts is critically important. The effects of bevacizumab plus oxaliplatin-based chemotherapy and bevacizumab plus irinotecan-based chemotherapy regimens on platelets are different but have not been determined. In order to find a more suitable plan for metastatic colorectal cancer (mCRC) patients with a history of schistosomiasis, we conducted a retrospective analysis of mCRC patients and evaluated the impact of bevacizumab on their platelets.MethodsThe medical records of all mCRC patients with a history of schistosomiasis who received oxaliplatin-based chemotherapy or irinotecan-based chemotherapy as first-line treatment for no less than 4 cycles, with or without bevacizumab from September 1, 2017, to June 30, 2019, in Kunshan Hospital were reviewed. Six-month cumulative incidence rates of splenomegaly and thrombocytopenia of chemotherapy with and without bevacizumab groups, oxaliplatin-based chemotherapy with and without bevacizumab groups, irinotecan-based chemotherapy with and without bevacizumab groups were compared from the first cycle until the completion of chemotherapy using Kaplan-Meier analysis and Log-rank test.ResultsEvaluable splenic enlargement and thrombocytopenia results were obtained from 153 mCRC patients. The 6-month cumulative incidence rates of splenomegaly (23.3% vs. 55%; P=0.01) and that of thrombocytopenia (43.8% vs. 57.5%; P=0.40) were lower in the bevacizumab group than the non-bevacizumab group, however there were no statistical differences for the rates of thrombocytopenia. For patients treated with oxaliplatin, the rates of splenomegaly (19.5% vs. 66.7%; P=0.01) and thrombocytopenia (31.7% vs. 77.2%; P=0.02) were lower in the bevacizumab-treated cohort than that in the non-bevacizumab cohort. When stratified for irinotecan, there were no statistical differences in the frequency of splenomegaly between the two groups. However, the rates of thrombocytopenia were higher in the bevacizumab-treated cohort than that in the non-bevacizumab cohort (59.4% vs. 8.7%; P=0.01).ConclusionsThe bevacizumab plus oxaliplatin-based chemotherapy regimen is safer for mCRC patients with a history of schistosomiasis, especially for patients with a lower platelet count.     

自噬对糖皮质激素作用下MC3T3-E1成骨细胞增殖的影响

背景:目前,糖皮质激素(GCs)作用下成骨细胞自噬与其增殖能力的关系尚存争议.目的:探讨自噬对GCs作用下MC3T3-E1成骨细胞增殖能力的影响.方法:不同浓度(0、10-8 M、10-6 M、10-4 M)的地塞米松(DXMS)分别作用于MC3T3-E1成骨细胞,CCK-8检测不同时间(12 h、24 h、48 h)...