Synthesis,evaluation and CoMFA/CoMSIA study of nitrofuranyl methyl N-heterocycles as novel antitubercular agents

A series of novel nitrofuranyl methyl N-heterocycles based on the structure of IIIM-MCD-211 were designed and synthesized. Compounds 6d, 8b and 12a show excellent activity against MTB H37Rv strain (MIC: 0.031–0.062?μg/mL) roughly comparable to INH and IIIM-MCD-211. In addition, a three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on the above mentioned chemical series employing comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques. The developed CoMFA and CoMSIA models display high external predictability (r²_pred of 0.954 and 0.935, respectively) and good statistical robustness. More importantly, the newly designed compounds 16a and 16b (MIC: <0.016?μg/mL) based on the two models, as expected, were found to be more active than 12a and IIIM-MCD-21. Design and synthesis of more potent nitrofuranyl methyl N-heterocycles as anti-TB agents are currently in progress.     

Characteristic gut microbiota and metabolic changes in patients with pulmonary tuberculosis

Intestinal flora provides an important contribution to the development of pulmonary tuberculosis (PTB). We performed a cross-sectional study in 52 healthy controls (HCs) and 83 patients with untreated active PTB to assess the differences in their microbiomic and metabolic profiles in faeces via V3-V4 16S rRNA gene sequencing and gas chromatography–mass spectrometry. Patients with PTB had considerable reductions in phylogenetic alpha diversity and the production of short-chain fatty acids, dysbiosis of the intestinal flora and alterations in the faecal metabolomics composition compared with HCs. Significant alterations in faecal metabolites were associated with changes in the relative abundance of specific genera. Our study describes the imbalance of the gut microbiota and altered faecal metabolomics profiles in patients with PTB; the results indicate that the gut microbiota and faecal metabolomic profiles can be used as potential preventive and therapeutic targets for PTB.     

Development of SSR markers and identification of major quantitative trait loci controlling shelling percentage in cultivated peanut (<Emphasis Type="Italic">Arachis hypogaea</Emphasis> L.)

Key message

A total of 204,439 SSR markers were developed in diploid genomes, and 25 QTLs for shelling percentage were identified in a RIL population across 4 years including five consistent QTLs.

Abstract

Cultivated peanut (Arachis hypogaea L.) is an important grain legume providing edible oil and protein for human nutrition. Genome sequences of its diploid ancestors, Arachis duranensis and A. ipaensis, were reported, but their SSRs have not been well exploited and utilized hitherto. Shelling percentage is an important economic trait and its improvement has been one of the major objectives in peanut breeding programs. In this study, the genome sequences of A. duranensis and A. ipaensis were used to develop SSR markers, and a mapping population (Yuanza 9102 × Xuzhou 68-4) with 195 recombinant inbred lines was used to map QTLs controlling shelling percentage. The numbers of newly developed SSR markers were 84,383 and 120,056 in the A. duranensis and A. ipaensis genomes, respectively. Genotyping of the mapping population was conducted with both newly developed and previously reported markers. QTL analysis using the phenotyping data generated in Wuhan across four consecutive years and genotyping data of 830 mapped loci identified 25 QTLs with 4.46–17.01% of phenotypic variance explained in the four environments. Meta-analysis revealed five consistent QTLs that could be detected in at least two environments. Notably, the consistent QTL cqSPA09 was detected in all four environments and explained 10.47–17.01% of the phenotypic variance. The segregation in the progeny of a residual heterozygous line confirmed that the cpSPA09 locus had additive effect in increasing shelling percentage. These consistent and major QTL regions provide opportunity not only for further gene discovery, but also for the development of functional markers for breeding.

     

The role of microvesicles and its active molecules in regulating cellular biology

Cell‐derived microvesicles are membrane vesicles produced by the outward budding of the plasma membrane and released by almost all types of cells. These have been considered as another mechanism of intercellular communication, because they carry active molecules, such as proteins, lipids and nucleic acids. Furthermore, these are present in circulating fluids, such as blood and urine, and are closely correlated to the progression of pathophysiological conditions in many diseases. Recent studies have revealed that microvesicles have a dual effect of damage and protection of receptor cells. However, the nature of the active molecules involved in this effect remains unclear. The present study mainly emphasized the mechanism of microvesicles and the active molecules mediating the different biological effects of receptor cells by affecting autophagy, apoptosis and inflammation pathways. The effective ways of blocking microvesicles and its active molecules in mediating cell damage when microvesicles exert harmful effects were also discussed.     

Association between polymorphisms in the promoter region of interleukin-10 and susceptibility to inflammatory bowel disease

The aim of this study was to assess the association of polymorphisms in the promoter region of the IL-10 gene with the risk of inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). Fifteen studies (3,693 cases and 4,574 controls) were included in a meta-analysis of association between IL-10 ?1082G/A, ?819C/T and ?592C/A polymorphisms, and IBD, CD and UC using allele contrast and the recessive, dominant, and additive models. Hardy–Weinberg equilibrium was confirmed for each study. Heterogeneity and study quality were investigated using stratification analyses and sensitivity analyses. Polymorphism ?1082G/A showed significant association with CD, with odds ratios (ORs) for the GG + GA genotype and GG versus AA genotype of 1.278 (1.004–1.627) and 1.238 (1.027–1.492) in all subjects. Significant associations were found in the Caucasian subgroup using the allele contrast, dominant, and additive models. C-allele carriers of the ?819C/T polymorphism were at increased risk of IBD (OR 1.093, 95 % CI 1.004–1.190). Association with the ?819C/T polymorphism was also found in Caucasians with CD (C vs. T: OR 1.104, 95 % CI 1.010–1.206; CC + CT vs. TT: OR 1.328, 95 % CI 1.006–1.754; CC vs. TT: OR 1.339, 95 % CI 1.008–1.778), and with UC (CC vs. CT + TT: OR 1.188, 95 % CI 1.019–1.385). No significant association was found between the ?592C/A polymorphism and IBD, CD or UC. In conclusion, the meta-analysis demonstrated clear association between the IL-10 polymorphisms ?1082G/A and ?819C/T and the risk of IBD.     

Activation of STAT3 stimulates AHSP expression in K562 cells

Studies on the chaperone proteinα-hemoglobin stabilizing protein(AHSP)reveal that abundant AHSP in erythroid cells enhance the cells’tolerance to oxidative stress imposed by excessα-hemoglobin in pathological conditions.However,the potential intracellular modulation of AHSP expression itself in response to oxidative stress is still unknown.The present study examined the effect and molecular mechanism of STAT3,an oxidative regulator,on the expression of AHSP.AHSP expression increased in K562 cells upon cytokine IL-6-induced STAT3 activation and decreased in STAT3 knock-down K562 cells.Regulation of AHSP in oxidative circumstance was then examined inα-globin-overloaded K562 cells,and real-time PCR showed strengthened expression of both AHSP and STAT3.ChIP analysis showed binding of STAT3 to AHSP promoter and binding was significantly augmented with IL6 stimulation and uponα-globin overexpression.Dual luciferase reporter assays of the wildtype and mutated SB3 element,an IL-6RE site,in the AHSP promoter in K562 cells highlighted the direct regulatory effect of STAT3 on AHSP gene.Finally,direct binding of STAT3 to SB3 site of AHSP promoter was confirmed with EMSA assays.Our work reveals an adaptive AHSP regulation mediated by the redox-sensitive STAT3 signaling pathway,and provides clues to the therapeutic strategy for AHSP enhancement.     

Associations of plasma high-sensitivity C-reactive protein concentrations with all-cause and cause-specific mortality among middle-aged and elderly individuals

Background

The plasma level of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is a strong predictor of disease development and premature mortality in the general population. Unhealthy lifestyle habits such as smoking or unhealthy eating is known to elevate the suPAR level. We aimed to investigate whether change in lifestyle habits impact on the suPAR level, and whether the resultant levels are associated with mortality.

Results

Paired suPAR measurements from baseline- and the 5-year visit of the population-based Inter99 study were compared with the habits of diet, smoking, alcohol consumption, and physical activity. Paired suPAR measurements for 3225 individuals were analyzed by linear regression, adjusted for demographics and lifestyle habits. Compared to individuals with a healthy lifestyle, an unhealthy diet, low physical activity, and daily smoking were associated with a 5.9, 12.8, and 17.6% higher 5-year suPAR, respectively. During 6.1 years of follow-up after the 5-year visit, 1.6% of those with a low suPAR (mean 2.93 ng/ml) died compared with 3.8% of individuals with a high suPAR (mean 4.73 ng/ml), P <  0.001. In Cox regression analysis, adjusted for demographics and lifestyle, the hazard ratio for mortality per 5-year suPAR doubling was 2.03 (95% CI: 1.22–3.37).

Conclusion

Lifestyle has a considerable impact on suPAR levels; the combination of unhealthy habits was associated with 44% higher 5-year suPAR values and the 5-year suPAR was a strong predictor of mortality. We propose suPAR as a candidate biomarker for lifestyle changes as well as the subsequent risk of mortality.

     

Probing the role of microenvironment for microencapsulated Sacchromyces cerevisiae under osmotic stress

Cell encapsulation opens a new avenue to the oral delivery of genetically engineered microorganism for therapeutic purpose. Osmotic stress is one of the universal chemical stress factors in the application of microencapsulation technology. In order to understand the effect and mechanism of the encapsulated microenvironment on protecting cells from hyper-osmotic stress, yeast cells of Saccharomyces cerevisiae Y800 were encapsulated in calcium alginate micro-gel beads (MB), alginate-chitosan-alginate (ACA) solid core microcapsules (SCM), and ACA liquid core microcapsules (LCM), respectively. The stress-induced intracellular components and enzyme activity including trehalose, glycerol and super oxide dismutase (SOD) were measured. Free cell culture was used as control. The survival of encapsulated cells and the cells released from MB, SCM and LCM after osmotic shock induced by NaCl solution (1, 2 and 3M) was evaluated. An analysis method was established to probe the effect of encapsulated microenvironment on the cell tolerance to osmotic stress. The results showed that LCM gave rise to the highest level of intracellular trehalose and glycerol, and SOD activity, as well as the highest survival rate of encapsulated cells or cells released from microcapsule. It was demonstrated that LCM was able to induce the highest stress response and stress tolerance of cells, which was adapted during culture, while SCM failed. The theoretical analysis revealed that it was the liquid alginate matrix in microcapsule that played a central role in domesticating the cells to adapt to hyper-osmotic stress. This finding provides a very useful guideline to cell encapsulation.