Dimethyl fumarate induces necroptosis in colon cancer cells through GSH depletion/ROS increase/MAPKs activation pathway

Background and Purpose

Dimethyl fumarate (DMF) is a newly approved drug for the treatment of relapsing forms of multiple sclerosis and relapsing-remitting multiple sclerosis. Here, we investigated the effects of DMF and its metabolites mono-methylfumarate (MMF and methanol) on different gastrointestinal cancer cell lines and the underlying molecular mechanisms involved.

Experimental Approach

Cell viability was measured by the MTT or CCK8 assay. Protein expressions were measured by Western blot analysis. LDH release, live- and dead-cell staining, intracellular GSH levels, and mitochondrial membrane potential were examined by using commercial kits.

Key Results

DMF but not MMF induced cell necroptosis, as demonstrated by the pharmacological tool necrostatin-1, transmission electron microscopy, LDH and HMGB1 release in CT26 cells. The DMF-induced decrease in cellular GSH levels as well as cell viability and increase in reactive oxygen species (ROS) were inhibited by co-treatment with GSH and N-acetylcysteine (NAC) in CT26 cells. DMF activated JNK, p38 and ERK MAPKs in CT26 cells and JNK, p38 and ERK inhibitors partially reversed the DMF-induced decrease in cell viability. GSH or NAC treatment inhibited DMF-induced JNK, p38, and ERK activation in CT26 cells. DMF but not MMF increased autophagy responses in SGC-7901, HCT116, HT29 and CT26 cancer cells, but autophagy inhibition did not prevent the DMF-induced decrease in cell viability.

Conclusion and Implications

DMF but not its metabolite MMF induced necroptosis in colon cancer cells through a mechanism involving the depletion of GSH, an increase in ROS and activation of MAPKs.     

Do the fragments from decomposed ZIF-8 greatly affect some of the intramolecular proton-transfer of thymine? A quantum chemical study

The intramolecular proton-transfer processes of thymine were investigated by the density functional theory method. It is shown that the mutation from keto (T) to enol (T′) form is affected by zeolitic imidazolate framework-8 (ZIF-8) fragments such as single 2-methylimidazole neutral crystals (M), and negatively charged 2-methylimidazole ligands (M⁻). Results show that with the number (n) of water (w) molecules that assist proton-transfer increasing from 1 to 4, the order of the tautomeric energy barriers (in kcal mol⁻¹) is T-2w (16.3) < T-1w (17.6) < T-3w (17.8) < T-4w (20.5). In the presence of M, the order of energy barrier is MT-2w (16.6) < MT-1w (17.7) < MT-3w (18.9) < MT-4w (20.8). M⁻ has a catalysis effect on the energy barrier and the order is M⁻T-2w (14.4) < M⁻T-3w (15.2) < M⁻T-1w (16.3) < M⁻T-4w (16.8). The attachment of the M⁻ fragment slightly promotes the proton-transfer processes in some instances. The characterization of the proton-transfer processes is helpful to understand the genotoxicity of ZIF-8 during drug delivery applications.

Investigations on whether fragments from decomposed ZIF-8 would affect the intramolecular proton-transfer of thymine by DFT modeling.     

藤草煎治疗脑出血卒中后抑郁39例临床观察

目的探讨藤草煎治疗脑出血后抑郁的疗效。方法选取脑出血合并抑郁患者72例,随机分为对照组和治疗组,对照组给予氟哌噻吨美利曲辛治疗,治疗组给予藤草煎汤剂口服,分别于入选时、治疗3个月时采用神经功能缺损评分(NIHSS)和汉密尔顿抑郁量表(HAMD)进行评价。结果治疗3个月时2组患者NIHSS评分和HAMD评分与治疗前比较均明显降低(P<0.05);治疗组NIHSS评分优于对照组,差异有统计学意义(P<0.05),HAMD评分与对照组比较差异无统计学意义(P>0.05)。结论藤草煎治疗脑出血后抑郁具有明显的临床疗效。     

Protective effect of Ruellia tuberosa L. extracts against abnormal expression of hepatic detoxification enzymes in diabetic rats

Ruellia tuberosa L. (RTL) has been used as a folk medicine for curing diabetes mellitus in East Asia decades. This study investigated the effect of RTL on hepatic detoxification enzyme expression in diabetic rats. Male Wistar rats were fed a high fat diet (HFD) and intraperitoneally injected with streptozotocin (STZ) to induce diabetes. Subsequently, rats received oral administrations of 100 or 400 mg kg⁻¹ body weight RTL extract, in either water (RTLW) or ethanol (RTLE), once a day for 4 weeks. The real-time PCR analyses showed that abnormality of hepatic phase I and II detoxification enzyme expression was observed in diabetic rats. However, both RTLW and RTLE significantly normalized the expression of hepatic phase I detoxification enzymes such as CYP 2E1, and expression of phase II detoxification enzymes such as UGT 1A7 and GST M1 in diabetic rats. Furthermore, we found that fasting serum glucose, hemoglobin A1C (HbA1C) and the area under the curve of oral glucose tolerance test (AUC_OGTT) levels were significantly reduced in both RTLW and RTLE treated diabetic rats. Moreover, both RTLW and RTLE significantly increased the activity of hepatic anti-oxidative enzymes such as superoxide dismutase (SOD) in diabetic rats. The present study suggests that RTL may ameliorate abnormal hepatic detoxification function via alleviating hyperglycemia and enhancing hepatic antioxidant capacity in HFD/STZ-induced diabetic rats.

Ruellia tuberosa L. (RTL) has been used as a folk medicine for curing diabetes mellitus in East Asia decades.     

Analysis of oxidation degree of graphite oxide and chemical structure of corresponding reduced graphite oxide by selecting different-sized original graphite

The thermal exfoliation and reduction of graphite oxide (GO) is the most commonly used strategy for large-scale preparation of graphene, and the oxidation degree of GO would influence the chemical structure of prepared graphene, thereby affecting its final physical and chemical properties. In addition to serving as the precursor for synthesizing graphene, GO also possesses great potential for various important applications owing to its abundant oxygen-containing groups and hybrid electronic structure. Therefore, systematically studying the influencing factors on the oxidation degree of GO and clarifying the effect of oxidation degree on the corresponding graphene is particularly important. Herein, we have studied the effect of the lateral size of the original graphite on the oxidation degree of GO in order to control the oxidation degree of GO. GOs with different degrees of oxidation were synthesized using a modified Hummers method. The results of X-ray diffraction (XRD), X-ray photoelectron spectra (XPS) and Raman spectroscopy revealed that decreased lateral size of the original graphite would lead to increased oxidation degree of GO. Furthermore, the interlayer spacing of the GO samples achieved 0.9–1.0 nm, which indicated that the modified Hummers method could make well oxidized graphite. The corresponding reduced graphite oxide (rGO) was also prepared by low-temperature exfoliation of GO at 140 °C under ambient atmosphere. It was found that a larger lateral size of GO resulted in rGO with fewer oxygen-containing functional groups, but a smaller lateral size of graphite possessed a higher exfoliation degree with a larger specific surface area. More importantly, the relationship between binding energy (E_B) of photoelectron of C atom in oxygen-containing groups and the number of oxygen-containing groups in GO and rGO samples was analyzed theoretically.

The thermal reduction of GO is the most commonly used strategy for preparation of rGO, and the oxidation degree of GO would influence the chemical structure of prepared rGO, thereby affecting its physical and chemical properties.     

Correction: Tunnel injection from WS2 quantum dots to InGaN/GaN quantum wells

Correction for ‘Tunnel injection from WS₂ quantum dots to InGaN/GaN quantum wells’ by Svette Reina Merden Santiago et al., RSC Adv., 2018, 8, 15399–15404.

Eqn (4) in the published paper was incorrect; the correct version is shown below:4The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Associations between Vitamin D Status,Supplementation, Outdoor Work and Risk of Parkinson’s Disease: A Meta-Analysis Assessment

The present study aimed to quantitatively assess the associations between vitamin D and Parkinson’s Disease (PD) risks, which include: (i) risk of PD in subjects with deficient and insufficient vitamin D levels; (ii) association between vitamin D supplementation and risk of PD; and (iii) association between outdoor work and PD risk, through meta-analyzing available data. An electronic literature search supplemented by hand searching up to March 2015 identified seven eligible studies comprising 5690 PD patients and 21251 matched controls. Odds ratio (OR) and 95% confidence interval (CI) of PD risk were assessed through pooling the collected data from eligible studies using Stata software. Pooled data showed that subjects with deficient and insufficient vitamin D levels had increased PD risks compared with matched-controls according to the corresponding OR: 2.08, 95% CI: 1.63 to 2.65, and 1.29, 95% CI: 1.10 to 1.51. Vitamin D supplementation was associated with significantly reduced risk of PD (OR: 0.62, 95% CI: 0.35 to 0.90). Outdoor work was also related to reduced risk of PD (OR: 0.72, 95% CI: 0.63 to 0.81). The findings may stimulate larger, well-designed studies to further verify the associations between vitamin D and PD risk.