Reversal of doxorubicin resistance in lung cancer cells by neferine is explained by nuclear factor erythroid-derived 2-like 2 mediated lung resistance protein down regulation

Aim:Development of multi drug resistance and dose limiting cardiotoxicity are hindering the use of Doxorubicin(Dox)in clinical settings.Augmented dox efflux induced by lung resistance protein(LRP)over expression has been related to multi drug resistance phenotype in various cancers.An alkaloid from lotus,Neferine(Nef)shows both anticancer and cardioprotective effects.Here,we have investigated the interconnection between nuclear factor erythroid-derived 2-like 2(NRF2)and LRP in Dox resistance and how Nef can overcome Dox resistance in lung cancer cells by altering this signaling.Methods:Anti-proliferative and apoptotic-inducing effects of Nef and Dox combination in Parental and Dox resistant lung cancer cells were determined in monolayers and 3D spheroids.Intracellular Dox was analyzed using flow cytometry,siRNA knockdown and western blot analysis were used to elucidate NRF2-LRP crosstalk mechanism.

原子因素的角色(导出 erythroid 2 ) 在新陈代谢的动态平衡和胰岛素行动喜欢 2 : 为糖尿病处理的一个新奇机会？

Redox balance is fundamentally important for physiological homeostasis. Pathological factors that disturb this dedicated balance may result in oxidative stress, leading to the development or aggravation of a variety of diseases, including diabetes mellitus, cardiovascular diseases, metabolic syndrome as well as in? ammation, aging and cancer. Thus, the capacity of endogenous free radical clearance can be of patho-physiological importance; in this regard, the major reactive oxy- gen species defense machinery, the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) system needs to beprecisely modulated in response to pathological alterations. While oxidative stress is among the early events that lead to the development of insulin resistance, the activation of Nrf2 scavenging capacity leads to insulin sensitization. Furthermore, Nrf2 is evidently involved in regulating lipid metabolism. Here we summarize recent findings that link the Nrf2 system to metabolic homeostasis and insulin action and present our view that Nrf2 may serve as a novel drug target for diabetes and its complications.

Sulforaphane enhances Nrf2-mediated antioxidant responses of skeletal muscle induced by exhaustive exercise in HIIT mice

Nuclear factor erythroid-derived 2-like 2(Nrf2)is the master regulator of antioxidant defenses.High-intensity interval training(HIIT)has been proposed as a time-efficient training program and has become a substantial component of modern training program In the present study,we evaluated the effects of sulforaphane(SFN),a dietary isothiocyanate derived from cruciferous vegetables and a potent Nrf2 activator,on Nrf2-mediated antioxidant defense responses of skeletal muscle induced by exhaustive exercise in HIIT mice.Male C57 BL/6 J mice were randomly allocated into control group,HIIT group,and HIIT pretreated with SFN(HIIT+SFN)group.On the third day after completion of a 6-weeks HIIT protocol,an exhaustive treadmill test was conducted in all mice.Mice were intraperitoneally injected with SFN(HIIT+SFN group)or PBS(HIIT and control mice)4 times in 3 days prior to the exhaustive treadmill test.The results indicated that the 6-weeks HIIT protocol did not increase the antioxidative capacity of skeletal muscle during exhaustive exercise.Importantly,SFN treatment improved anti oxidative capacity of skeletal muscle in response to the acute exhaustive exercise by increasing mRNA and nucleoprotein expression of Nrf2 and these genes involved in antioxidant generation and decreasing blood creatine kinase(CK)and 4-hydroxy-2-nonenal(4-HNE)-modified protein levels in the HIIT mice.

CRISPR-Cas9-based genome-wide screening identified novel targets for treating sorafenib-resistant hepatocellular carcinoma:a cross-talk between FGF21 and the NRF2 pathway

The treatment of hepatocellular carcinoma(HCC)has been dominated by multikinase inhibitors for more than a decade.However,drug resistance can severely restrict the efficacy of these drugs.Using CRISPR/CAS9 genome library screening,we evaluated Kelch-like ECH-associated protein 1(KEAP1)as a key regulator of sorafenib’s susceptibility in HCC.We also investigated whether KEAP1’s knockdown can stabilize nuclear factor(erythroid-derived 2)-like 2(NRF2)protein levels that led to sorafenib’s resistance,including an NRF2 inhibitor that can synergize with sorafenib to abolish HCC’s growth in vitro and in vivo.Furthermore,we clarified that fibroblast growth factor 21(FGF21)is an important downstream regulator of NRF2 in HCC.Intriguingly,we observed that FGF21 bound to NRF2 through the C-terminus of FGF21,thereby stabilizing NRF2 by reducing its ubiquitination and generating a positive feedback loop in sorafenib-resistant HCC.These findings,therefore,propose that targeting FGF21 is a promising strategy to combat HCC sorafenib’s resistance.

Prostate cancer and chemoprevention by natural dietary phytochemicals

Prostate cancer is the second leading cancer among men in the United States. Several studies have correlated the development of prostate cancer with diet and life-style. Therefore, a balanced diet and improved life style might inhibit prostate cancer progression. Cancer chemoprevention has emerged as an important factor in controlling cancer development through natural or synthetic compounds. Oxidative stress is among the factors contributing to prostate cancer development. The transcription factor nuclear factor(erythroid-derived 2)-like 2(Nrf2) controls detoxifying antioxidant enzymes expression by binding to the antioxidant response element(ARE) in the promoter of these genes to activate their expression. Many natural products can fight oxidative stress and protects cells from DNA damage by activating the Nrf2/ARE pathway. High consumption of fruits and vegetables can reduce disease incidence and invasive tumors. In this review, the roles of important fruit and vegetable phytochemicals in regulating prostate cancer progression and tumor growth are discussed.

Priming of intestinal cytoprotective genes and antioxidant capacity by dietary phytogenic inclusion in broilers

The potential of a phytogenic premix(PP)based on ginger,lemon balm,oregano and thyme to stimulate the expression of cytoprotective genes at the broiler gut level was evaluated in this study.In particular,the effects of PP inclusion levels on a selection of genes related to host protection against oxidation(catalase[GAT],superoxide dismutase 1[SOD1],glutathione peroxidase 2[GPX2],heme oxygenase 1[HMOX1],NAD(P)H quinone dehydrogenase 1[NQO1],nuclear factor(erythroid-derived 2)-like 2[Nrf2]and kelch like ECH associated protein 1[Keap1]),stress(heat shock 70 kDa protein 2[HSP70]and heat shock protein 90 alpha family class A member 1[HSP90])and inflammation(nuclear factor kappa B subunit 1[NF-κB1],Toll-like receptor 2 family member B(TLR2 B)and Toll-like receptor 4[TLR4])were profiled along the broiler intestine.In addition,broiler intestinal segments were assayed for their total antioxidant capacity(TAC).Depending on PP inclusion level(i.e.0,750,1,000 and 2,000 mg/kg diet)in the basal diets,1-d-old Cobb broiler chickens(n=500)were assigned into the following 4 treatments:CON,PP-750,PP-1000 and PP-2000.Each treatment had 5 replicates of 25 chickens with ad libitum access to feed and water.Data were analyzed by ANOVA and means compared using Tukey’s honest significant difference(HSD)test.Polynomial contrasts tested the linear and quadratic effect of PP inclusion levels.Inclusion of PP increased(P≤0.05)the expression of cytoprotective genes against oxidation,except CAT.In particular,the cytoprotective against oxidation genes were up-regulated primarily in the duodenum and the ceca and secondarily in the jejunum.Most of the genes were upregulated in a quadratic manner with increasing PP inclusion level with the highest expression levels noted in treatments PP-750 and PP-1000 compared to CON.Similarly,intestinal TAC was higher in PP-1000 in the duodenum(P=0.011)and the ceca(P=0.050)compared to CON.Finally,increasing PP inclusion level resulted in linearly reduced(P<0.05)expression of NF-κB1,TLR4 and HSP70,the former in the duodenum and the latter 2 in the ceca.Overall,PP inclusion consistently up-regulated cytoprotective genes and down-regulated stress and inflammation related ones.The effect is dependent on PP inclusion level and the intestinal site.The potential of PP to beneficially prime bird cytoprotective responses merit further investigation under stress-challenge conditions.