Total Synthesis of Mannopeptimycin ß via ß-Hydroxyenduracididine Ligation.

Nonribosomal peptide synthesis in bacteria has endowed cyclic peptides with fascinating structural complexity via incorporating nonproteinogenic amino acids. These bioactive cyclic peptides provide interesting structural motifs for exploring total synthesis and medicinal chemistry studies. Cyclic glycopeptide mannopeptimycins exhibit antibacterial activity against antibiotic-resistant Gram-positive pathogens and act as the lipid II binder to stop bacterial cell wall biosynthesis. Here, we report a strategy streamlining solution phase-solid phase synthesis and chemical ligation-mediated peptide cyclization for the total synthesis of mannopeptimycin ß.

Structure-activity relationship of daptomycin analogues with substitution at (2S, 3R) 3-methyl glutamic acid position.

Daptomycin is a highly effective lipopeptide antibiotic against Gram-positive pathogens. The presence of (2S, 3R) 3-methyl glutamic acid (mGlu) in daptomycin has been found to be important to the antibacterial activity. However the role of (2S, 3R) mGlu is yet to be revealed. Herein, we reported the syntheses of three daptomycin analogues with (2S, 3R) mGlu substituted by (2S, 3R) methyl glutamine (mGln), dimethyl glutamic acid and (2S, 3R) ethyl glutamic acid (eGlu), respectively, and their antibacterial activities. The detailed synthesis of dimethyl glutamic acid was also reported.

TIMP3 regulates osteosarcoma cell migration, invasion, and chemotherapeutic resistances.

Tissue inhibitors of metalloproteinases (TIMPs) inhibit matrix metalloproteinases (MMPs) to limit degradation of the extracellular matrix. Low levels of TIMP3 have been demonstrated in cancer tissues at advanced clinical stages, with positive distant metastasis and chemotherapeutic resistance. We examined the role of TIMP3 in osteosarcoma (OS) cell invasiveness and chemoresistance. TIMP3 was overexpressed or knocked down in the human OS cell lines Saos2 and MG63. Cell migration and invasion capacities were then evaluated using Transwell assays, and resistance to cisplatin was assessed by CCK-8 assay and flow cytometry. Real-time PCR and western blotting were used to investigate activation of signaling pathways downstream of TIMP3. Overexpression of TIMP3 inhibited the migration and invasion of Saos2 and MG63 cells, while knockdown of TIMP3 had the opposite effect. Cell survival after exposure to cisplatin was inhibited by TIMP3 overexpression in both Saos2 and MG63 cells. Consistently, downregulation of TIMP3 gene expression significantly decreased the sensitivity of OS cells to cisplatin treatment. MMP1, MMP2, Bcl-2, and Akt1 were all downregulated following TIMP3 overexpression, while Bax and cleaved caspase-3 were upregulated. TIMP3 knockdown had opposite effects on the regulation of these genes. Taken together, our findings suggest TIMP3 as a new target for inhibition of OS progression and chemotherapeutic resistance.

Trametinib, a novel MEK kinase inhibitor, suppresses lipopolysaccharide-induced tumor necrosis factor (TNF)-α production and endotoxin shock.

Lipopolysaccharide (LPS), one of the most prominent pathogen-associated molecular patterns (PAMPs), activates macrophages, causing release of toxic cytokines (i.e. tumor necrosis factor (TNF)-α) that may provoke inflammation and endotoxin shock. Here, we tested the potential role of trametinib, a novel and highly potent MAPK/ERK kinase (MEK) inhibitor, against LPS-induced TNF-α response in monocytes, and analyzed the underlying mechanisms. We showed that trametinib, at nM concentrations, dramatically inhibited LPS-induced TNF-α mRNA expression and protein secretion in transformed (RAW 264.7 cells) and primary murine macrophages. In ex-vivo cultured human peripheral blood mononuclear cells (PBMCs), this MEK inhibitor similarly suppressed TNF-α production by LPS. For the mechanism study, we found that trametinib blocked LPS-induced MEK-ERK activation in above monocytes, which accounted for the defective TNF-α response. Macrophages or PBMCs treated with a traditional MEK inhibitor PD98059 or infected with MEK1/2-shRNA lentivirus exhibited a similar defect as trametinib, and nullified the activity of trametinib. On the other hand, introducing a constitutively-active (CA) ERK1 restored TNF-α production by LPS in the presence of trametinib. In vivo, mice administrated with trametinib produced low levels of TNF-α after LPS stimulation, and these mice were protected from LPS-induced endotoxin shock. Together, these results show that trametinib inhibits LPS-induced TNF-α expression and endotoxin shock probably through blocking MEK-ERK signaling.

Epidemiological investigation of the first locally acquired case of COVID-19 identified by influenza surveillance-Taiwan, February 2020.

BACKGROUND: COVID-19 and influenza have similar clinical presentations that can range from mild to severe disease. The World Health Organization recommends that countries use existing influenza surveillance to monitor COVID-19 transmission in communities. We aim to describe the surveillance and investigation of COVID-19 at the early stage of the pandemic in Taiwan. METHODS: In February 2020, the Taiwan Centers for Disease Control enhanced COVID-19 surveillance through its existing influenza surveillance. We retrospectively tested patients for SARS-CoV-2 who had symptoms of severe complicated influenza but were negative in influenza testing. We conducted an epidemiological investigation and contact tracing for the index patient and secondary cases to prevent virus transmission. RESULTS: We identified the first COVID-19 patient on February 15 through enhanced COVID-19 surveillance. He had no history of traveling abroad and an unclear history of contact with COVID-19 cases. He presented with influenza-like illness on January 27 and was hospitalized from February 3 to 15. We identified 39 close contacts of the index patient, including 11 family members and 28 healthcare workers. In total, four close family contacts of the index patient tested positive for SARS-CoV-2. An additional 84 close contacts of the four secondary cases were identified and traced; none was diagnosed with COVID-19. CONCLUSIONS: We recommend enhancing COVID-19 surveillance by testing patients with influenza-like illness. To prevent the spread of COVID-19, we recommend using appropriate personal protective equipment when in close contact with patients who present with influenza-like illness or when caring for patients with pneumonia of unknown etiology.

Docosahexaenoic acid induces apoptosis in colorectal carcinoma cells by modulating the PI3 kinase and p38 MAPK pathways.

Numerous studies have shown that long-chain polyunsaturated fatty acids can kill cancer cells in vitro as well as in vivo, while normal cells remain unaffected. Unfortunately, the cellular and molecular mechanisms responsible for this phenomenon are still poorly understood. The aim of this study was to investigate the potential chemopreventative/antiproliferative potential of docosahexaenoic acid (DHA) in an adenocarcinoma cell line (CaCo2 cells) and to evaluate the signalling pathways modulated by it. DHA (5-50 microM) significantly inhibited cell viability in a dose-dependent manner in CaCo2 cells, while the viability of normal colon cells (NCM460 cells) was not compromised. DHA also induced apoptosis in CaCo2 cells, as indicated by increases in caspase-3 activation and poly-ADP-ribose polymerase cleavage. Signalling proteins, which include extracellular signal-regulated kinase, p38 mitogen-activated protein kinase (MAPK), Akt and p53 were analysed by Western blotting using phosphospecific and total antibodies. The protein inhibitors wortmannin (phosphoinositide 3 kinase inhibitor), PD 98059 (MEK inhibitor) and SB 203580 (p38 inhibitor) as well as silencing RNA [small interfering RNA (siRNA)] of the p38 MAPK protein, were used to investigate cross-talk between signalling pathways. DHA supplementation significantly suppressed Akt phosphorylation, which also correlated with decreased cell viability and increased apoptosis in CaCo2 cells. Furthermore, siRNA experiments suggested a possible role for p38 MAPK in the phosphorylation of p53 at Ser15, a site which is associated with DNA damage. DHA might thus exert its beneficial effects by means of increased apoptosis and suppression of the important survival-related kinase, Akt.

Differential induction of apoptosis and inhibition of the PI3-kinase pathway by saturated, monounsaturated and polyunsaturated fatty acids in a colon cancer cell model.

Although numerous studies have shown that certain long chain fatty acids can induce apoptosis in cancer cells, the molecular mechanisms for this phenomenon are still poorly elucidated. The phosphoinositide 3-kinase (PI3-kinase) signaling pathway plays a pivotal role in the regulation of cell growth and can also contribute to tumorigenesis and cancer progression. The aims of the present study were three fold: (i) to investigate the potential chemopreventative/antiproliferative effect of various fatty acids in colon cancer cells (CaCo-2 cells) and normal colon epithelium cells (NCM460 cells); (ii) to investigate the mechanisms by which incubation with various fatty acids influences the PI3-kinase pathway in CaCo-2 cells; and (iii) to evaluate apoptosis in our cell model. Although all the fatty acids increased the viability of normal (NCM460) cells, only docosahexaenoic acid (DHA) significantly reduced cell viability and induced apoptosis in the cancer (CaCo-2) cells. Our results indicate that DHA is an effective chemotherapeutic agent to induce apoptosis in cancer cells and that this effect is mediated by the PI3-kinase signaling pathway.

Total synthesis of teixobactin.

To cope with the global bacterial multidrug resistance, scientific communities have devoted significant efforts to develop novel antibiotics, particularly those with new modes of actions. Teixobactin, recently isolated from uncultured bacteria, is considered as a promising first-in-class drug candidate for clinical development. Herein, we report its total synthesis by a highly convergent Ser ligation approach and this strategy allows us to prepare several analogues of the natural product.

Increased intake of vegetables, but not fruits, may be associated with reduced risk of hip fracture: A meta-analysis.

Association between dietary intake of vegetables and fruits and risk of hip fracture has been reported for many years. However, the findings remain inconclusive. We conducted a meta-analysis to evaluate the relationship between intake of vegetables and fruits, and risk of hip fracture. Literature search for relevant studies was performed on PubMed and Embase databases. Five observational studies were included in the meta-analysis. Summary hazard ratio (HR) with corresponding 95% confidence interval (CI) was calculated from pooled data using the random-effects model irrespective of heterogeneity. Sensitivity and subgroup analysis were performed to explore possible reasons for heterogeneity. The summary HR for hip fracture in relation to high intake vs. low intake of only vegetables, only fruits, and combined intake of fruits and vegetables, was 0.75 (95% CI, 0.61-0.92), 0.87 (95% CI, 0.74-1.04), and 0.79 (95% CI, 0.61-1.03), respectively. Subgroup analyses based on study design, geographical location, number of cases, and gender showed similar results. Increased intake of vegetables, but not fruits, was found to be associated with a lower risk of hip fracture. Large prospective clinical trials with robust methodology are required to confirm our findings.

[Surveillance and risk assessment system of schistosomiasis in Jiangsu Province â ¢ Risk of schistosomiasis transmission in the area along the Yangtze River in Yangzhou City].

OBJECTIVE: To evaluate the potential risk of schistosomiasis transmission in the area along the Yangtze River in Yangzhou City, so as to provide evidences for establishing a post-transmission surveillance system for schistosomiasis in marshland regions. METHODS: The water infectivity, floating boatmen and fishermen infection, reservoir host infection and wild feces contamination were investigated in five districts/counties along the Yangtze River in Yangzhou City, including Guangling, Hanjiang, Jiangdu, Yizheng and Development Zone, and the transmission factors and risky characteristics were assessed after interruption of schistosomiasis transmission in marshland regions. RESULTS: A total of 15 key water regions were identified in the area along the Yangtze River in Yangzhou City in 2015. A total of 1 500 sentinel mice were placed, after breeding, their overall survival rate was 99.33%; 1 490 were dissected, with no schistosome infection. Of the 5 576 floating boatmen and fishermen examined, no schistosome infection was observed, and among the 3 566 domestic animals (including 171 cattle, 1 895 sheep and 1 500 pigs), no infections were detected. During the period between January and March, 2016, there were 3 200 mouse traps placed on 8 marshlands, and 62 wild mice were captured from 6 marshlands, with a capture rate of 1.94%, and no schistosomeinfected wild mice were seen. In addition, there were 35 pieces of fresh wild feces captured from 7 marshlands, including 11 pieces of bovine feces (31.43%), 17 pieces of sheep feces (48.57%), 2 pieces of dog feces (5.71%) and 5 pieces of other feces (14.29%), and no infections were detected. CONCLUSIONS: There is a low risk of schistosomiasis transmission in the area along the Yangtze River in Yangzhou City. However, the contamination of feces from bovine and sheep that are freely pastured on marshlands is a big threat to schistosomiasis control.

Association between cadmium exposure and renal cancer risk: a meta-analysis of observational studies.

Cadmium (Cd) is a widespread environmental pollutant and has been a recognized carcinogen for several decades. Many observational studies reported Cd exposure might be one cause of renal cancer. However, these findings are inconsistent. We conducted a meta-analysis to evaluate the relationship between cadmium exposure and renal cancer risk. A comprehensive PubMed and Embase search was conducted to retrieve observational studies meeting our meta-analysis criteria. A combined odds ratio (OR) and corresponding 95% confidence interval (CI) were applied to assess the association between Cd exposure and renal cancer risk. The meta-analysis showed that a high Cd exposure significantly increased renal cancer 1.47 times (OR = 1.47; 95% CI = 1.27 to 1.71, for highest versus lowest category of cadmium categories). The significant association remained consistent when stratified by geographic region and gender, however mixed results were produced when stratified by sample size, study design, NOS score, adjustment for covariates, effects measure, and exposure type. Our results indicated that a high Cd exposure was associated with increased renal cancer risk and the association was higher for occupational exposure compared with non-occupational exposure. This meta-analysis suggests that a high Cd exposure may be a risk factor for renal cancer in occupational population.

Exposure to fluoride in drinking water and hip fracture risk: a meta-analysis of observational studies.

BACKGROUND: Many observational studies have shown that exposure to fluoride in drinking water is associated with hip fracture risk. However, the findings are varied or even contradictory. In this work, we performed a meta-analysis to assess the relationship between fluoride exposure and hip fracture risk. METHODS: PubMed and EMBASE databases were searched to identify relevant observational studies from the time of inception until March 2014 without restrictions. Data from the included studies were extracted and analyzed by two authors. Summary relative risks (RRs) with corresponding 95% confidence intervals (CIs) were pooled using random- or fixed-effects models as appropriate. Sensitivity analyses and meta-regression were conducted to explore possible explanations for heterogeneity. Finally, publication bias was assessed. RESULTS: Fourteen observational studies involving thirteen cohort studies and one case-control study were included in the meta-analysis. Exposure to fluoride in drinking water does not significantly increase the incidence of hip fracture (RRs, 1.05; 95% CIs, 0.96-1.15). Sensitivity analyses based on adjustment for covariates, effect measure, country, sex, sample size, quality of Newcastle-Ottawa Scale scores, and follow-up period validated the strength of the results. Meta-regression showed that country, gender, quality of Newcastle-Ottawa Scale scores, adjustment for covariates and sample size were not sources of heterogeneity. Little evidence of publication bias was observed. CONCLUSION: The present meta-analysis suggests that chronic fluoride exposure from drinking water does not significantly increase the risk of hip fracture. Given the potential confounding factors and exposure misclassification, further large-scale, high-quality studies are needed to evaluate the association between exposure to fluoride in drinking water and hip fracture risk.

Identification of phenanthroindolizines and phenanthroquinolizidines as novel potent anti-coronaviral agents for porcine enteropathogenic coronavirus transmissible gastroenteritis virus and human severe acute respiratory syndrome coronavirus.

The discovery and development of new, highly potent anti-coronavirus agents and effective approaches for controlling the potential emergence of epidemic coronaviruses still remains an important mission. Here, we identified tylophorine compounds, including naturally occurring and synthetic phenanthroindolizidines and phenanthroquinolizidines, as potent in vitro inhibitors of enteropathogenic coronavirus transmissible gastroenteritis virus (TGEV). The potent compounds showed 50% maximal effective concentration (EC50) values ranging from 8 to 1468 nM as determined by immunofluorescent assay of the expression of TGEV N and S proteins and by real time-quantitative PCR analysis of viral yields. Furthermore, the potent tylophorine compounds exerted profound anti-TGEV replication activity and thereby blocked the TGEV-induced apoptosis and subsequent cytopathic effect in ST cells. Analysis of the structure-activity relations indicated that the most active tylophorine analogues were compounds with a hydroxyl group at the C14 position of the indolizidine moiety or at the C3 position of the phenanthrene moiety and that the quinolizidine counterparts were more potent than indolizidines. In addition, tylophorine compounds strongly reduced cytopathic effect in Vero 76 cells induced by human severe acute respiratory syndrome coronavirus (SARS CoV), with EC50 values ranging from less than 5 to 340 nM. Moreover, a pharmacokinetic study demonstrated high and comparable oral bioavailabilities of 7-methoxycryptopleurine (52.7%) and the naturally occurring tylophorine (65.7%) in rats. Thus, our results suggest that tylophorine compounds are novel and potent anti-coronavirus agents that may be developed into therapeutic agents for treating TGEV or SARS CoV infection.

Birth weight and lung function in a cohort of Chinese school children.

OBJECTIVE: Evidence on the association between birth weight and lung function is conflicting. We evaluated the children's lung function in relation to their birth weight in China. METHODS: A prospective cohort study was conducted in 1,599 school children. Baseline data on birth weight and other potential confounding variables were obtained from self-administered questionnaires. Pulmonary function tests were performed with a standard procedure and repeated 6 months later. RESULTS: There were no significant differences in the standard deviation score (SDS) of forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) between children with low birth weight (LBW) and those with normal birth weight (NBW). The growth rates in lung function between children with LBW and NBW were also insignificant. CONCLUSIONS: No association between birth weight and lung function was found among Chinese school children.