Aberrant DNA methylation in cervical carcinogenesis

Persistent infection wit h high-risk types of human papillomavirus(HPV) is known to cause cervical cancer;however,additional genetic and epigenetic alterations are required for progression from precancerous disease to invasive cancer.DNA methylation is an early and frequent molecular alteration in cervical carcinogenesis.In this review,we summarize DNA methylation within the HPV genome and human genome and identify its clinical implications.Methylation of the HPV long control region(LCR) and L1 gene is common during cervical carcinogenesis and increases with the severity of the cervical neoplasm.The L1 gene of HPV16 and HPV18 is consistently hypermethylated in invasive cervical cancers and can potentially be used as a clinical marker of cancer progression.Moreover,promoters of tumor suppressor genes(TSGs) involved in many cellular pathways are methylated in cervical precursors and invasive cancers.Some are associated with squamous cell carcinomas,and others are associated with adenocarcinomas.Identification of methylated TSGs in Pap smear could be an adjuvant test in cervical cancer screening for triage of women with high-risk HPV,atypical squamous cells of undetermined significance,or low grade squamous intraepithelial lesion(LSIL).However,consistent panels must be validated for this approach to be translated to the clinic.Furthermore,reversion of methylated TSGs using demethylating drugs may be an alternative anticancer treatment,but demethylating drugs without toxic carcinogenic and mutagenic properties must be identified and validated.

Berberine protects diabetic nephropathy rats by inhibiting endoplasmic reticulum stress

Objective:The aim of this study was to investigate the effects of Berberine(BBR)on Endoplasmic Reticulum Stress(ERS)in renal tissue of Diabetic Nephropathy(DN).Methods:The DN RAT model was induced by high glucose and high fat diet combined with intraperitoneal injection of Streptozocin.The experiment was divided into 3 groups:normal group(NC group),model group(DN group)and berberine intervention group(DN+BBR group)(n=6).DN+BBR group was treated with 200 mg/kg/d on the basis of the model of DN.NC group and DN group were treated with the same dose of sodium carboxymethyl cellulose.After 6 weeks treatment measured various indicators(include body weight,renal index(KI=kidney weight/body weight),fasting blood glucose(FBG),blood creatinine(SCR),urea nitrogen(BUN)and 24h urine protein(24h Pro)).The pathological changes of kidney were observed by HE,PAS and Masson staining.The changes of glomerulus and renal interstitium were observed by transmission electron microscope.The expression of PERK,IRE1,ATF6,CHOP and Caspase3 were detected by immunohistochemical staining.Results:(1)SCR,Bun,FBG and 24hUpro in DN group were significantly higher than those in NC group and the renal function of DN group severely impaired.Compare with DN group the renal function of DN+BBR group was significant improved.There were significant differences in SCR,Bun,FBG and 24hUpro in each group(p<0.01).(2)The results of HE,PAS and Masson staining showed that the glomerulus in DN group was more irregular and larger than that in NC group;the lumen of glomerulus became narrowed,diffuse mesangial matrix was increased and renal tubule was edematous.The glycogen deposits and collagen fibers in the renal interstitium were increased and inflammatory cells were infiltrated.After the berberine rescued,the glomerular condition of DN+BBR group was obviously improved;the edema of renal tubules was alleviated;the deposition of glycogen was decreased and the collagenous fibers accumulation is relatively reduced.(3)The results of transmission electron microscope showed that the podocytes of DN Group were irregular and a large number of podocytes fused and broken.The basement membrane was inhomogeneous and thickened.Whereas,the morphological function of podocyte of DN+BBR Group was improved.And the basement membrane was slightly thickened.(4)Immunohistochemistry shows that the expression of Chop,PERK,IRE1,ATF6 and Caspase3 in DN group was significantly increased and the DN+BBR group was contrarily.The difference of protein expression was statistically significant(p<0.05).Conclusion:These findings provide insights into the BBR can significantly improve the structure and function of kidney in DN rats.The hypothesis is that BBR can suppress endoplasmic reticulum stress and reduce the apoptosis of kidney cells,thus prevent the progress of DN and protect the kidney tissue.

Fluorescence detection of hydroxyl radical generated from oxygen reduction on Fe/N/C catalyst

Pyrolyzed Fe/N/C catalyst has been considered as the most promising candidate to replace Pt for oxygen reduction reaction(ORR) in fuel cells.However,poor stability of Fe/N/C catalyst,mainly attributed to the oxidation corrosion by aggressive ·OH radical,severely hampers its applications.However,the exact mechanism for generation of ·OH is unclear yet.Herein,we developed a fluorescent method to effectively detect ·OH generated from ORR on Fe/N/C catalyst by using coumarin as a fluorescent probe.A great difference in potential dependence between ·OH and H2O2 generated from the ORR was observed,which suggests that ·OH is not generated from the decomposition of H2O2 as traditional viewpoint.

Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth

Epithelial ovarian cancer(EOC) exhibits strong dependency on the tricarboxylic acid(TCA) cycle and oxidative phosphorylation to fuel anabolic process.Here,we show that malate dehydrogenase 2(MDH2),a key enzyme of the TCA cycle,is palmitoylated at cysteine 138(C138) residue,resulting in increased activity of MDH2.We next identify that ZDHHC18 acts as a palmitoyltransferase of MDH2.Glutamine deprivation enhances MDH2 palmitoylation by increasing the binding between ZDHHC18 and MDH2.MDH2 silencing represses mitochondrial respiration as well as ovarian cancer cell proliferation both in vitro and in vivo.Intriguingly,re-expression of wild-type MDH2,but not its palmitoylation-deficient C138 S mutant,sustains mitochondrial respiration and restores the growth as well as clonogenic capability of ovarian cancer cells.Notably,MDH2 palmitoylation level is elevated in clinical cancer samples from patients with high-grade serous ovarian cancer.These observations suggest that MDH2 palmitoylation catalyzed by ZDHHC18 sustains mitochondrial respiration and promotes the malignancy of ovarian cancer,yielding possibilities of targeting ZDHHC18-mediated MDH2 palmitoylation in the treatment of EOC.