[Role of NLRP3 inflammasome in diabetic neuropathy and prevention and treatment with traditional Chinese medicine].

As one of the most frequent complications of diabetes, diabetic neuropathy often involves peripheral and central nervous systems. Neuroinflammation is the key pathogenic factor of secondary nerve injury in diabetes. NOD-like receptor pyrin domain-containing 3(NLRP3) inflammasome is a group of subcellular multiprotein complexes, including NLRP3, apoptosis associated speck-like protein(ASC), and pro-cysteinyl aspartate specific proteinase 1(pro-caspase-1). NLRP3 inflammasome is an inducer of innate immune responses. Its activation stimulates the inflammatory cascade reaction, promotes the release of inflammatory mediators, triggers cell death and uncontrolled autophagy, activates glial cells, facilitates peripheral immune cell infiltration, and initiates amyoid ß(Aß)-tau cascade reactions. As a result, it contributes to the central nerve, somatic nerve, autonomic nerve, and retinal nerve cell damage secondary to diabetes. Therefore, due to its key role in the neuroinflammation responses of the body, NLRP3 inflammasome may provide new targets for the treatment of diabetic neuropathy. With multi-target and low-toxicity advantages, traditional Chinese medicine plays a vital role in the treatment of diabetic neuropathy. Accumulating evidence has shown that traditional Chinese medicine exerts curative effects on diabetic neuropathy possibly through regulating NLRP3 inflammasome. Although the role of NLRP3 inflammasome in diabetes and related complications has been investigated in the literature, systematical studies on drugs and mechanism analysis for secondary neuropathy are still lacking. In this article, the role of NLRP3 inflammasome in diabetic neuropathy was explored, and the research progress on traditional Chinese medicine in the treatment of diabetic neuropathy through NLRP3 inflammasome was reviewed.

Potential effect of tropical fruits Phyllanthus emblica L. for the prevention and management of type 2 diabetic complications: a systematic review of recent advances.

Phyllanthus emblica is a fruit widely consumed in subtropical areas, which is rich in polyphenols and other nutrients. There are increasing evidences that as a daily and nutritious fruit, it may have a positive role in controlling diabetic complications. According to the new study, its mechanisms include enhancing the functioning of insulin, reducing insulin resistance, activating the insulin-signaling pathway, protecting ß-cells, scavenging free radicals, alleviating inflammatory reactions, and reducing the accumulation of advanced glycation end products. Owing to its few side effects, and low price, it should be easily accepted by patients and has potential for preventing diabetes. Taken together, Phyllanthus emblica may be an ideal fruit for controlling diabetic complications. This review highlights the latest findings of the role of Phyllanthus emblica in anti-diabetes and its complications, especially clarifies the molecular mechanism of the chemical components related to this effect, and prospects some existing problems and future research directions.

Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease.

BACKGROUND: Patients with mild or moderate chronic obstructive pulmonary disease (COPD) rarely receive medications, because they have few symptoms. We hypothesized that long-term use of tiotropium would improve lung function and ameliorate the decline in lung function in patients with mild or moderate COPD. METHODS: In a multicenter, randomized, double-blind, placebo-controlled trial that was conducted in China, we randomly assigned 841 patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (mild) or 2 (moderate) severity to receive a once-daily inhaled dose (18 µg) of tiotropium (419 patients) or matching placebo (422) for 2 years. The primary end point was the between-group difference in the change from baseline to 24 months in the forced expiratory volume in 1 second (FEV1) before bronchodilator use. Secondary end points included the between-group difference in the change from baseline to 24 months in the FEV1 after bronchodilator use and the between-group difference in the annual decline in the FEV1 before and after bronchodilator use from day 30 to month 24. RESULTS: Of 841 patients who underwent randomization, 388 patients in the tiotropium group and 383 in the placebo group were included in the full analysis set. The FEV1 in patients who received tiotropium was higher than in those who received placebo throughout the trial (ranges of mean differences, 127 to 169 ml before bronchodilator use and 71 to 133 ml after bronchodilator use; P<0.001 for all comparisons). There was no significant amelioration of the mean (±SE) annual decline in the FEV1 before bronchodilator use: the decline was 38±6 ml per year in the tiotropium group and 53±6 ml per year in the placebo group (difference, 15 ml per year; 95% confidence interval [CI], -1 to 31; P=0.06). In contrast, the annual decline in the FEV1 after bronchodilator use was significantly less in the tiotropium group than in the placebo group (29±5 ml per year vs. 51±6 ml per year; difference, 22 ml per year [95% CI, 6 to 37]; P=0.006). The incidence of adverse events was generally similar in the two groups. CONCLUSIONS: Tiotropium resulted in a higher FEV1 than placebo at 24 months and ameliorated the annual decline in the FEV1 after bronchodilator use in patients with COPD of GOLD stage 1 or 2. (Funded by Boehringer Ingelheim and others; Tie-COPD ClinicalTrials.gov number, NCT01455129 .).

Image Inpainting Using Two-Stage Loss Function and Global and Local Markovian Discriminators.

Image inpainting networks can produce visually reasonable results in the damaged regions. However, existing inpainting networks may fail to reconstruct the proper structures or tend to generate the results with color discrepancy. To solve this issue, this paper proposes an image inpainting approach using the proposed two-stage loss function. The loss function consists of different Gaussian kernels, which are utilized in different stages of network. The use of our two-stage loss function in coarse network helps to focus on the image structure, while the use of it in refinement network is helpful to restore the image details. Moreover, we proposed a global and local PatchGANs (GAN means generative adversarial network), named GL-PatchGANs, in which the global and local markovian discriminators were used to control the final results. This is beneficial to focus on the regions of interest (ROI) on different scales and tends to produce more realistic structural and textural details. We trained our network on three popular datasets on image inpainting separately, both Peak Signal to Noise ratio (PSNR) and Structural Similarity (SSIM) between our results, and ground truths on test images show that our network can achieve better performance compared with the recent works in most cases. Besides, the visual results on three datasets also show that our network can produce visual plausible results compared with the recent works.

Phase III study of dulanermin (recombinant human tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand) combined with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer.

Background Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 30 mg/m2 on days 2 to 4) for up to six cycles plus dulanermin (75 µg/kg on days 1 to 14) or placebo every three weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was progression-free survival (PFS), and the secondary end points included objective response rate (ORR), overall survival (OS), and safety evaluation. Results Between October 2009 and June 2012, 452 untreated patients with stage IIIB to IV NSCLC were randomly assigned to receive dulanermin plus NP (n = 342) and placebo plus NP (n = 110). Median PFS was 6.4 months in the dulanermin arm versus 3.5 months in the placebo arm (hazard ratio (HR), 0.4034; 95% CI, 0.3181 to 0.5117, p < 0.0001). ORR was 46.78% in the dulanermin arm versus 30.00% in the placebo arm (p = 0.0019). Median OS was 14.6 months in the dulanermin arm versus 13.9 months in the placebo arm (HR, 0.94; 95% CI, 0.74 to 1.21, p = 0.64). The most common grade ≥ 3 adverse events (AEs) were oligochromemia, leukopenia, neutropenia, and oligocythemia. Overall incidence of AEs, grade ≥ 3 AEs, and serious AEs were similar across the two arms. Conclusion Addition of dulanermin to the NP regimen significantly improved PFS and ORR. However, our results showed that the combination of dulanermin with chemotherapy had a synergic activity and favorable toxic profile in the treatment of patients with advanced NSCLC.

Rapid, microwave-accelerated synthesis and anti-osteoporosis activities evaluation of Morusin scaffolds and Morusignin L scaffolds.

Described herein is a facile and efficient methodology toward the synthesis of Morusin scaffolds and Morusignin L scaffolds 4-9 and 12via a novel three-step approach (Michael addition or prenylation, cyclization and cyclization) and use a rapid, microwave-accelerated cyclization as the key step. Furthermore, their biological activities have been preliminarily demonstrated by in vitro evaluation for anti-osteoporosis activity. These Morusin, Morusignin L and newly synthesized compounds 5b, 6a, 8e, 8f greatly exhibited the highest potency, especially at the 10-5mol/L (P<0.01), and had good in vitro anti-osteoporosis activities using the commercially available standard drug Ipriflavone as a positive control. The mechanisms associated with anti-osteoporosis effects of these compounds may be through the inhibition of TRAP enzyme activity and bone resorption in osteoclasts, and promotion effect of osteoblast proliferation in vitro. The results indicated that Morusin scaffolds and Morusignin L scaffolds may be useful leads for further anti-osteoporosis activity screenings.

Corilagin attenuates aerosol bleomycin-induced experimental lung injury.

Idiopathic pulmonary fibrosis (IPF) is a progressing lethal disease with few clinically effective therapies. Corilagin is a tannin derivative which shows anti-inflammatory and antifibrotics properties and is potentiated in treating IPF. Here, we investigated the effect of corilagin on lung injury following bleomycin exposure in an animal model of pulmonary fibrosis. Corilagin abrogated bleomycin-induced lung fibrosis as assessed by H&E; Masson's trichrome staining and lung hydroxyproline content in lung tissue. Corilagin reduced the number of apoptotic lung cells and prevented lung epithelial cells from membrane breakdown, effluence of lamellar bodies and thickening of the respiratory membrane. Bleomycin exposure induced expression of MDA, IKKα, phosphorylated IKKα (p-IKKα), NF-κB P65, TNF-α and IL-1ß, and reduced I-κB expression in mice lung tissue or in BALF. These changes were reversed by high-dose corilagin (100 mg/kg i.p) more dramatically than by low dose (10 mg/kg i.p). Last, corilagin inhibits TGF-ß1 production and α-SMA expression in lung tissue samples. Taken together, these findings confirmed that corilagin attenuates bleomycin-induced epithelial injury and fibrosis via inactivation of oxidative stress, proinflammatory cytokine release and NF-κB and TGF-ß1 signaling. Corilagin may serve as a promising therapeutic agent for pulmonary fibrosis.

Protective Effect and Possible Mechanisms of Artemisinin and Its Derivatives for Diabetic Nephropathy: A Systematic Review and Meta-Analysis in Animal Models.

Background: Artemisinin and its derivatives have potential antidiabetic effects. There is no evaluation of reported studies in the literature on the treatment of diabetic nephropathy (DN), one of the commonest diabetic microangiopathies, with artemisinins. Here, we aimed to evaluate preclinical evidence for the efficacy and possible mechanisms of artemisinins in reducing diabetic renal injury. Methods: We conducted an electronic literature search in fourteen databases from their inception to November 2021. All animal studies assessing the efficacy and safety of artemisinins in DN were included, regardless of publication or language. Overall, 178 articles were screened according to predefined inclusion and exclusion criteria. Finally, 18 eligible articles were included in this systematic review. The SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool was used to assess the risk of bias in the included studies. The primary outcomes were kidney function, proteinuria, and renal pathology. Secondary endpoints included changes in fasting plasma glucose (FPG) levels, body weight, and relevant mechanisms. Results: Of the 18 included articles involving 418 animal models of DN, 1, 2, 6, and 9 used dihydroartemisinin, artemether, artesunate, and artemisinin, respectively. Overall, artemisinins reduced indicators of renal function, including blood urea nitrogen (P < 0.00001), serum creatinine (P < 0.00001), and kidney index (P = 0.0001) compared with control group treatment. Measurements of proteinuria (P < 0.00001), microalbuminuria (P < 0.05), and protein excretion (P = 0.0002) suggested that treatment with artemisinins reduced protein loss in animals with DN. Artemisinins may lower blood glucose levels (P = 0.01), but there is a risk of weight gain (P < 0.00001). Possible mechanisms of action of artemisinins include delaying renal fibrosis, reducing oxidative stress, and exerting antiapoptotic and anti-inflammatory effects. Conclusion: Available evidence suggests that artemisinins may be protective against renal injury secondary to diabetes in preclinical studies; however, high-quality and long-term trials are needed to reliably determine the balance of benefits and harms.

Development and validation of prognostic m6A-related lncRNA and mRNA model in thyroid cancer.

Although N6-methyladenosine (m6A) regulators and lncRNAs influence the carcinogenesis of thyroid cancer (THCA), the association between m6A-related lncRNAs and THCA remains unexplored. Therefore, we have developed and validated a prognostic model based on m6A-related lncRNAs and mRNAs in THCA. Data from the Cancer Genome Atlas were used to analyze the expression and prognostic characteristics of m6A-related lncRNAs and mRNAs in THCA. Univariate Cox regression analysis was used to screen out independent prognostic factors, while Lasso Cox regression was performed to construct m6A-related lncRNA and mRNA models. The correlation between the prognostic models and gene mutation, immune cell infiltration, tumor microenvironment score, tumor mutational burden, and microsatellite instability were assessed. The prognostic models showed excellent accuracy in predicting the prognosis of patients with THCA. Our study established an m6A-related nomogram capable of predicting the prognosis of patients with THCA. In addition, the hub lncRNAs and mRNAs provide insight into improving the prognosis of THCA. These findings can improve our understanding of m6A modifications in THCA and the prognosis and treatment strategies of THCA.

Challenges and strategies to research ethics in conducting COVID-19 research.

The number of research involving human subjects on coronavirus disease 2019 (COVID-19) is surging, bringing challenges to the ethical review committee (ERC) in terms of reviewing speed and special ethical considerations under the pandemic. However, the existing ethical review system and regulations have their limitations to meet the demand for a prompt and efficient epidemic control. Since the research under the public health emergency is different from that carried out in familiar situations to design and implementation, the strategy for a satisfactory ERC response should balance the duty of protecting individual participants as well as the special public needs derived from the disease control. It is suggested that the ethical review-related regulations need to be updated, and a unified supervision system to the overall ERC is required. ERC collaboration, capacity-improving and efficiency-improving measures need to be taken. With respect to the reviewing guidelines, it is suggested that the international norms should be explained with more consideration of the local condition and the exceptional circumstances in this public health emergency. A joint effort needs to be taken for better research conduction.

[Familial idiopathic pulmonary fibrosis: case report and review of literature].

OBJECTIVE: To investigate the clinical features of familial idiopathic pulmonary fibrosis (FIPF) and therefore to improve the recognition of the disease. METHODS: Clinical data of 5 patients with idiopathic pulmonary fibrosis belonging to 2 families were analyzed retrospectively. RESULTS: There were 3 patients in one family and 2 in another family. The average age at first diagnosis of the 5 patients with FIPF were (55 +/- 12) years. The most common initial symptoms were cough and progressive dyspnea, bibasilar end-inspiratory Velcro and clubbed fingers. HRCT revealed reticular opacities and diffuse honeycombing. Pulmonary ventilatory function was normal, but the diffusing capacity for carbon monoxide was reduced. One case was confirmed to have usual interstitial pneumonia by surgical lung biopsy. CONCLUSIONS: The clinical features of FIPF are similar to those of nonfamilial IPF. Asymptomatic FIPF can be identified early by lung HRCT.

[Cell apoptosis and the associated signal expression in epithelial cells from patients with idiopathic pulmonary fibrosis].

OBJECTIVE: To investigate the changes and significance of cell apoptosis, Fas/FasL and P53 protein in epithelial cells from patients with idiopathic pulmonary fibrosis (IPF). METHODS: Cell apoptosis and the expressions of Fas/FasL and P53 protein in lung tissues from 12 patients with IPF (IPF group) and 10 normal controls (control group) were detected by terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) and immunohistochemistry. RESULTS: Compared with the control group (0/10), the percentage of apoptosis in alveolar epithelial cells and bronchial cells of the IPF group (12/12) was higher. The percentage of Fas, FasL and P53 protein expressions (12/12, 12/12, 11/12) in alveolar epithelial cells of the IPF group were higher than those of the control group (5/10, 2/10, 0/10); and the percentage of Fas, FasL and P53 protein expressions (12/12, 12/12, 11/12) in bronchial cells of the IPF group were also higher than those of the control group (6/10, 3/10, 0/10). There was a significant correlation between the percentage of apoptosis and Fas/FasL and P53 protein expression (r=0.625-0.839, all P<0.01). The correlation of the Fas/FasL and P53 protein expression was also significant (r=0.571-0.760, all P<0.01). CONCLUSION: The apoptosis percentage of epithelial cells and the expression of Fas/FasL and P53 protein are up-regulated in lung tissues of IPF, which may play an important role in the development of the disease.

Clinical significance of DAPK promoter hypermethylation in lung cancer: a meta-analysis.

Death-associated protein kinase 1 (DAPK) is an important serine/threonine kinase involved in various cellular processes, including apoptosis, autophagy, and inflammation. DAPK expression and activity are deregulated in a variety of diseases including cancer. Methylation of the DAPK gene is common in many types of cancer and can lead to loss of DAPK expression. However, the association between DAPK promoter hypermethylation and the clinicopathological significance of lung cancer remains unclear. In this study, we searched the MEDLINE, PubMed, Web of Science, and Scopus databases, systematically investigated the studies of DAPK promoter hypermethylation in lung cancer and quantified the association between DAPK promoter hypermethylation and its clinicopathological significance by meta-analysis. We observed that the frequency of DAPK methylation was significantly higher in lung cancer than in non-malignant lung tissues (odds ratio 6.02, 95% confidence interval 3.17-11.42, P<0.00001). The pooled results also showed the presence of a prognostic impact of DAPK gene methylation in lung cancer patients (odds ratio 3.63, 95% confidence interval 1.09-12.06, P=0.04). In addition, we summarized these findings and discuss tumor suppressor function, clinicopathological significance, and potential drug targeting of DAPK in lung cancer.

ß-Lactamases in amoxicillin-clavulanate-resistant Escherichia coli strains isolated from a Chinese tertiary hospital.

A total of 52 strains were resistant to amoxicillin-clavulanate by disk diffusion method in a Chinese tertiary hospital from July 2011 to December 2011. Among these isolates, 2 isolates possessed a phenotype consistent with production of inhibitor-resistant temoniera (TEM) (IRT) ß-lactamase, and the TEM-type gene was cloned into strains of Escherichia coli JM109 cells. Both had no blaTEM mutations and were identified as TEM-1 ß-lactamase producers. As a result, no IRT ß-lactamase was detected. Multiplex PCR detected most of these strains produced TEM-1 enzymes, and plasmid-mediated AmpC ß-lactamase and oxacillinase-1 ß-lactamases are important mechanisms of resistance as well.

N-cadherin expression is associated with acquisition of EMT phenotype and with enhanced invasion in erlotinib-resistant lung cancer cell lines.

BACKGROUND: The epidermal growth-factor receptor tyrosine kinase inhibitors have been effective in non-small cell lung cancer patients. However, acquired resistance eventually develops in most patients despite an initial positive response. Emerging evidence suggests that there is a molecular connection between acquired resistance and the epithelial-mesenchymal transition (EMT). N-cadherin is involved in the EMT and in the metastasis of cancer cells. Here, we analyzed N-cadherin expression and function in erlotinib-resistant lung cancer cell lines. METHODS: H1650 cell lines were used to establish the subline resistant to erlotinib(H1650ER). Then, induction of the EMT was analyzed using immunostaining and western blots in H1650ER cells. N-cadherin expression in the resistant cells was examined using FACS and western blot. In addition, an invasion assay was performed to characterize the resistant cells. The effects of N-cadherin on cell proliferation and invasion were analyzed. The association of N-cadherin expression with the EMT phenotype was investigated using immunohistochemical analysis of 13 archived, lung adenocarcinoma tissues, before and after treatment with erlotinib. RESULTS: In H1650ER cells, N-cadherin expression was upregulated, paralleled by the reduced expression of E-cadherin. The marked histological change and the development of a spindle-like morphology suggest that H1650ER cells underwent an EMT, accompanied by a decrease in E-cadherin and an increase in vimentin. A change in the EMT status between pre-and post-treatment was observed in 11 out of 13 cases (79%). In biopsies of resistant cancers, N-cadherin expression was increased in 10 out of 13 cases. Induction of the EMT was consistent with aggressive characteristics. Inhibition of N-cadherin expression by siRNA was tested to reduce proliferation and invasion of H1650ER cells in vitro. CONCLUSIONS: Our data provide evidence that induction of the EMT contributes to the acquired resistance to EGFR-TKIs in lung cancer. It suggests that N-cadherin is a potential molecular target in the treatment of NSCLC.