Aldehyde Dehydrogenase 1 making molecular inroads into the differential vulnerability of nigrostriatal dopaminergic neuron subtypes in Parkinson’s disease

A preferential dysfunction/loss of dopaminergic(DA)neurons in the substantia nigra pars compacta(SNpc)accounts for the main motor symptoms of Parkinson’s disease(PD),the most common degenerative movement disorder.However,the neuronal loss is not stochastic,but rather displays regionally selectivity,indicating the existence of different DA subpopulations in the SNpc.To identify the underlying molecular determinants is thereby instrumental in understanding the pathophysiological mechanisms of PD-related neuron dysfunction/loss and offering new therapeutic targets.Recently,we have demonstrated that aldehyde dehydrogenase 1(ALDH1A1)is one such molecular determinant that defines and protects an SNpc DA neuron subpopulation preferentially affected in PD.In this review,we provide further analysis and discussion on the roles of ALDH1A1 in the function and survival of SNpc DA neurons in both rodent and human brains.We also explore the feasibility of ALDH1A1 as a potential biomarker and therapeutic target for PD.

Limonin inhibits the stemness of cancer stem-like cells derived from colorectal carcinoma cells potentially via blocking STAT3 signaling

BACKGROUND Limonin is one of the most abundant active ingredients of Tetradium ruticarpum.It exerts antitumor effects on several kinds of cancer cells.However,whether limonin exerts antitumor effects on colorectal cancer(CRC)cells and cancer stem-like cells(CSCs),a subpopulation responsible for a poor prognosis,is unclear.AIM To evaluate the effects of limonin on CSCs derived from CRC cells.METHODS CSCs were collected by culturing CRC cells in serum-free medium.The cytotoxicity of limonin against CSCs and parental cells(PCs)was determined by cholecystokinin octapeptide-8 assay.The effects of limonin on stemness were detected by measuring stemness hallmarks and sphere formation ability.RESULTS As expected,limonin exerted inhibitory effects on CRC cell behaviors,including cell proliferation,migration,invasion,colony formation and tumor formation in soft agar.A relatively low concentration of limonin decreased the expression stemness hallmarks,including Nanog andβ-catenin,the proportion of aldehyde dehydrogenase 1-positive CSCs,and the sphere formation rate,indicating that limonin inhibits stemness without presenting cytotoxicity.Additionally,limonin treatment inhibited invasion and tumor formation in soft agar and in nude mice.Moreover,limonin treatment significantly inhibited the phosphorylation of STAT3 at Y705 but not S727 and did not affect total STAT3 expression.Inhibition of Nanog andβ-catenin expression and sphere formation by limonin was obviously reversed by pretreatment with 2μmol/L colievlin.CONCLUSION Taken together,these results indicate that limonin is a promising compound that targets CSCs and could be used to combat CRC recurrence and metastasis.

How to conjugate the stemness marker ALDH1A1 with tumor angiogenesis,progression,and drug resistance

Cancer is the second leading cause of death worldwide.The survival of cancer patients depends on the efficacy of therapies and the development of resistance.There are many mechanisms involved in the acquisition of drug resistance by cancer cells,including the acquisition of stem-like features.Cancer stem cells(CSCs)represent a major source of tumor progression and treatment resistance.CSCs are a subpopulation of cancer cells having the abilities to self-renew and form spheres in vitro.Aldehyde dehydrogenase 1A1(ALDH1A1)is a cytosolic enzyme involved in the detoxification of cells from toxic aldehydes and belongs to the ALDH family.High ALDH1A1 activity is closely related to stemness phenotype of several tumors,possibly contributing to cancer progression and diffusion in the body.We have documented the contribution of ALDH1A1 in tumor angiogenesis in breast cancer cells by the activation of hypoxia inducible factor-1αand vascular endothelial growth factor signaling.This review discusses the involvement of ALDH1A1 in the development of different hallmarks of cancer to propose it as a novel putative target for cancer treatment to achieve better outcome.Here,we analyze the involvement of ALDH1A1 in the acquisition of stemness phenotype in tumor cells,the regulation of tumor angiogenesis and metastases,and the acquisition of anticancer drug resistance and immune evasion.