Explore the vast range of titles available.

To the Editor: Shaw and colleagues (March 27 issue) 1 report that ceritinib can overcome crizotinib resistance in patients with non–small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene ( ALK ) rearrangement. ROS1 is a paralog of ALK in humans, and crizotinib is an efficient ROS1 inhibitor. 2 , 3 A study by Awad and colleagues, published in the Journal in 2013, reported an acquired mutation (G2032R) in the gene encoding CD74–ROS1 kinase that conferred marked resistance to crizotinib. 4 Thus, we thought it would be interesting to explore the potential of ceritinib to overcome the resistance to the mutation exhibited by . . .

Curcumin, the major active component of turmeric (Curcuma longa), is widely used as a spice and food-coloring agent, and also exhibits multiple biological activities. However, as curcumin has poor systemic bioavailability its pharmacology remains to be elucidated. Owing to the high concentration of curcumin in the gastrointestinal tract after oral administration, we hypothesize that it may exert regulative effects on the gut microbiota. We investigated the regulative effects of oral curcumin administration on the gut microbiota of C57BL/6 mice and found that curcumin significantly affected the abundance of several representative families in gut microbial communities, including Prevotellaceae, Bacteroidaceae, and Rikenellaceae. Considering the pathogenic associations between gut microbiota and many diseases, the present findings may help us to interpret the therapeutic benefits of curcumin.

Alzheimer’s disease (AD) is a neurodegenerative disease with increasing prevalence worldwide, while there are no effective drugs at present. Curcumin, a natural polyphenolic substance isolated from turmeric, is a promising natural compound to combat AD, but its pharmacology remains to be fully understood for its poor in vivo bioavalibility. Inspired by the recently reported associations between gut microbiota and AD development, the present study investigated the interactions of curcumin with gut microbiota of APP/PS1 double transgenic mice from two directions: (i) curcumin influences gut microbiota, and (ii) gut microbiota biotransform curcumin. It was found that curcumin administration tended to improve the spatial learning and memory abilities and reduce the amyloid plaque burden in the hippocampus of APP/PS1 mice. On the one hand, curcumin administration altered significantly the relative abundances of bacterial taxa such as Bacteroidaceae, Prevotellaceae, Lactobacillaceae, and Rikenellaceae at family level, and Prevotella, Bacteroides, and Parabacteroides at genus level, several of which have been reported to be key bacterial species associated with AD development. On the other hand, a total of 8 metabolites of curcumin biotransformed by gut microbiota of AD mice through reduction, demethoxylation, demethylation and hydroxylation were identified by HPLC-Q-TOF/MS, and many of these metabolites have been reported to exhibit neuroprotective ability. The findings provided useful clues to understand the pharmacology of curcumin and microbiome-targeting therapies for AD.

The newly reported associations between Alzheimer’s disease (AD) and gut microbiota indicate the potential of gut microbiota regulation–based therapeutic intervention for AD. Silymarin and its main active component, silibinin, are promising natural agents against AD, while their acting mechanisms remain to be explored. The present study investigated the effects of silibinin and silymarin administration on behavioral and histological manifestations, and regulation on the gut microbiota of transgenic APP/PS1 mice. First, silibinin and silymarin administration could alleviate memory deficits and reduce the amyloid plaque burden in the brain of APP/PS1 mice in comparison with controls. Second, silibinin and silymarin administration tended to decrease the microbiota diversity and exhibited regulative effect in abundances on several key bacterial species associated with AD development. This implied that gut microbiota regulation by silibinin and silymarin might be involved in their effects against AD. Further studies are warranted to fully elucidate the molecular mechanisms.

Silymarin has been used for improving hepatic damage and lipid disorders, but its action mechanism remains to be clarified. Here, we investigate the contributions of the gut microbiota to the improvement of liver lipid metabolism by silymarin. We find i) strong and significant microbial shifts upon silymarin but not silibinin treatment; ii) over 60% variations of liver fat are explained by silymarin-induced bacterial B12 production in male rats but not in male germ-free mice; iii) fecal microbiota transplantation confirms their protective roles against liver fat accumulation; iv) upregulation of one-carbon metabolism and fatty acid degradation pathways are observed based on the liver transcriptome analyses; and v) in humans the delta changes of serum B12 associate negatively with the fluctuations of serum triglycerides. Overall, we reveal a mechanism of action underpinning the lipid-lowering effect of silymarin via the gut microbiota and its vitamin B12 producing capabilities. Silymarin has been used for improving hepatic damage and lipid disorders, but its action mechanism remains to be clarified. Here, the authors reveal a mechanism of action underpinning the lipid-lowering effect of silymarin via the gut microbiota and its vitamin B12 producing capabilities.

Background In recent years, the associations between vitamin D status and Alzheimer’s disease (AD) and dementia have gained increasing interests. The present meta-analysis was designed to estimate the association between vitamin D deficiency and risk of developing AD and dementia. Methods A literature search conducted until February 2015 identified 10 study populations, which were included in the meta-analysis. Pooled risk ratios (RRs) and 95 % confidence interval (CI) were calculated with a random-effect model using Stata software package. Results Results of our meta-analysis showed that subjects with deficient vitamin D status (25(OH)D level < 50 nmol/L) were at increased risk of developing AD by 21 % compared with those possessing 25(OH)D level > 50 nmol/L. Similar analysis also found a significantly increased dementia risk in vitamin D deficient subjects. There is no evidence for significant heterogeneity among the included studies. Conclusion Available data indicates that lower vitamin D status may be associated with increased risk of developing AD and dementia. More studies are needed to further confirm the associations and to evaluate the beneficial effects of vitamin D supplementation in preventing AD and dementia.

Natural products have often been the sole means to treat diseases and injuries. in fact, it has only been during the past decades that natural products have taken a secondary role in drug discovery and drug development, after the advent of molecular biology and combinatorial chemistry made possible the rational design of chemical compounds to target specific molecules. The past few years, however, have seen a renewed interest in the use of natural compounds and, more importantly, their role as a basis for drug development.

Identifying modifiable risk factors for Parkinson’s disease (PD) to help prevent this disease has attracted increasing interest in recent years for the limited effective drugs at present. Despite many studies indicated that infection acts as a risk factor for PD, there is no quantitative assessment of the impact of viral and bacterial infections on the risk of developing PD. The present study performed a meta-analysis on the basis of 38 datasets from 13 studies covering 287,773 PD cases and 7,102,901 controls to ascertain the association between PD and infection and the differences in the strength of the viral and bacterial infections. The overall meta-analytic results indicated that individuals with infection had a 20% increased risk of PD compared with controls (OR 1.20, 95%CI 1.07–1.32). The subgroup analysis according to the type of infection found that bacterial infection had a significant impact on increased risk of PD (OR 1.40, 95%CI 1.32–1.48). The present analysis indicated that infection could increase the risk of developing PD, and physician should be aware of the risk of developing PD in subjects with infection.

ABSTRACT Owing to the significant pathogenic role played by oxidative stress in diabetes mellitus, the associations between antioxidants and the incidence of diabetes mellitus have garnered much interest, while the findings are conflicting. The present study aimed to investigate the bidirectional causal connections underlying the relationship between circulating levels of eight endogenous and five exogenous antioxidants and the risks of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), as well as three complications: diabetic ketoacidosis, diabetic nephropathy, and diabetic retinopathy, by means of Mendelian randomization analyses. The analyses indicate that albumin and bilirubin may causally contribute to protection against the development of T1DM and T2DM, respectively. The exogenous β‐carotene is likely to act as a protective factor against the development of T2DM. Bilirubin may have a causally protective role in preventing the development of diabetic ketoacidosis. For the reverse analysis of diseases predicting antioxidant levels, T1DM, T2DM, and their complications were likely to be associated with varied levels of several antioxidants, but the effects are weak overall. Our analyses may provide useful clues that inform the use of antioxidants for preventing or predicting both diabetes mellitus and its complications. The bidirectional causal associations between levels of a series of endogenous and exogenous antioxidants and risks of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), as well as three complications, diabetic ketoacidosis, diabetic nephropathy, and diabetic retinopathy, were investigated by Mendelian randomization analyses.

Background Despite accumulating epidemiological studies support that diabetes increases the risk of Alzheimer’s disease (AD), the causal associations between diabetes and AD remain inconclusive. The present study aimed to explore: i) whether diabetes is causally related to the increased risk of AD; ii) and if so, which diabetes-related physiological parameter is associated with AD; iii) why diabetes drugs can be used as candidates for the treatment of AD. Two-sample Mendelian randomization (2SMR) was employed to perform the analysis. Results Firstly, the 2SMR analysis provided a suggestive association between genetically predicted type 1 diabetes (T1D) and a slightly increased AD risk (OR = 1.04, 95% CI = [1.01, 1.06]), and type 2 diabetes (T2D) showed a much stronger association with AD risk (OR = 1.34, 95% CI = [1.05, 1.70]). Secondly, further 2SMR analysis revealed that diabetes-related physiological parameters like fasting blood glucose and total cholesterol levels might have a detrimental role in the development of AD. Thirdly, we obtained 74 antidiabetic drugs and identified SNPs to proxy the targets of antidiabetic drugs. 2SMR analysis indicated the expression of three target genes, ETFDH, GANC, and MGAM, were associated with the increased risk of AD, while CPE could be a protective factor for AD. Besides, further PPI network found that GANC interacted with MGAM, and further interacted with CD33, a strong genetic locus related to AD. Conclusions In conclusion, the present study provides evidence of a causal association between diabetes and increased risk of AD, and also useful genetic clues for drug development.