Role of autophagy in cholangiocarcinoma:An autophagy-based treatment strategy

Cholangiocarcinomas(CCAs)are diverse biliary epithelial tumours involving the intrahepatic,perihilar and distal parts of the biliary tree.The three entirely variable entities have distinct epidemiology,molecular characteristics,prognosis and strategy for clinical management.However,many cholangiocarcinoma tu-mor-cells appear to be resistant to current chemotherapeutic agents.The role of autophagy and the therapeutic value of autophagy-based therapy are largely unknown in CCA.The multistep nature of autophagy offers a plethora of re-gulation points,which are prone to be deregulated and cause different human diseases,including cancer.However,it offers multiple targetable points for designing novel therapeutic strategies.Tumor cells have evolved to use auto-phagy as an adaptive mechanism for survival under stressful conditions such as energy imbalance and hypoxic region of tumors within the tumor microenvir-onment,but also to increase invasiveness and resistance to chemotherapy.The purpose of this review is to summarize the current knowledge regarding the interplay between autophagy and cholangiocarcinogenesis,together with some preclinical studies with agents that modulate autophagy in order to induce tumor cell death.Altogether,a combinatorial strategy,which comprises the current anti-cancer agents and autophagy modulators,would represent a positive CCA patient approach.

Modulation of autophagy for neuroprotection and functional recovery in traumatic spinal cord injury

Spinal cord injury(SCI) is a serious central nervous system trauma that leads to loss of motor and sensory functions in the SCI patients. One of the cell death mechanisms is autophagy, which is ‘self-eating' of the damaged and misfolded proteins and nucleic acids, damaged mitochondria, and other impaired organelles for recycling of cellular building blocks. Autophagy is different from all other cell death mechanisms in one important aspect that it gives the cells an opportunity to survive or demise depending on the circumstances. Autophagy is a therapeutic target for alleviation of pathogenesis in traumatic SCI. However, functions of autophagy in traumatic SCI remain controversial. Spatial and temporal patterns of activation of autophagy after traumatic SCI have been reported to be contradictory. Formation of autophagosomes following therapeutic activation or inhibition of autophagy flux is ambiguous in traumatic SCI studies. Both beneficial and harmful outcomes due to enhancement autophagy have been reported in traumatic SCI studies in preclinical models. Only further studies will make it clear whether therapeutic activation or inhibition of autophagy is beneficial in overall outcomes in preclinical models of traumatic SCI. Therapeutic enhancement of autophagy flux may digest the damaged components of the central nervous system cells for recycling and thereby facilitating functional recovery. Many studies demonstrated activation of autophagy flux and inhibition of apoptosis for neuroprotective effects in traumatic SCI. Therapeutic induction of autophagy in traumatic SCI promotes axonal regeneration, supporting another beneficial role of autophagy in traumatic SCI. In contrast, some other studies demonstrated that disruption of autophagy flux in traumatic SCI strongly correlated with neuronal death at remote location and impaired functional recovery. This article describes our current understanding of roles of autophagy in acute and chronic traumatic SCI, crosstalk between autophagy and apoptosis, therapeutic activation or inhibition of autophagy for promoting functional recovery, and future of autophagy in traumatic SCI.

Pharmacological modulation of autophagy for Alzheimer's disease therapy:Opportunities and obstacles

Alzheimer's disease(AD)is a prevalent and deleterious neurodegenerative disorder characterized by an irreversible and progressive impairment of cognitive abilities as well as the formation of amyloidβ(Aβ)plaques and neurofibrillary tangles(NFTs)in the brain.By far,the precise mechanisms of AD are not fully understood and no interventions are available to effectively slow down progression of the disease.Autophagy is a conserved degradation pathway that is crucial to maintain cellular homeostasis by targeting damaged organelles,pathogens,and disease-prone protein aggregates to lysosome for degradation.Emerging evidence suggests dysfunctional autophagy clearance pathway as a potential cellular mechanism underlying the pathogenesis of AD in affected neurons.Here we summarize the current evidence for autophagy dysfunction in the pathophysiology of AD and discuss the role of autophagy in the regulation of AD-related protein degradation and neuroinflammation in neurons and glial cells.Finally,we review the autophagy modulators reported in the treatment of AD models and discuss the obstacles and opportunities for potential clinical application of the novel autophagy activators for AD therapy.

Effect of c-Jun NH2-terminal kinase-mediated p53 expression on neuron autophagy following traumatic brain injury in rats

Background Activation of c-Jun NH2-terminal kinase （JNK） has been implicated in neuron apoptosis as well as autophagy in response to various stressors after traumatic brain injury （TBI）. However, the underlying molecular pathway remains unclear. Our study assessed whether JNK-mediated p53 phosphorylation might be an important mechanism for enhancing neuron autophagy in response to TBI. Methods A total of 186 male Sprague-Dawley （SD） rats （300-350 g） were used in this study. By randomized block method rats were randomly divided into four groups： sham-operated （n=46）, TBI （n=60）, TBI ＋ dimethyl sulfoxide （DMSO） （n=40）, and TBI ＋ SP600125 （n=40）. JNK was treated with SP600125, a specific JNK inhibitor. JNK, p-P53, Beclin-1, damage-regulated autophagy modulator （DRAM） and p-bcl-2 were evaluated by Western blotting analysis. The cellular localization and expression of Beclin-1 and DRAM was observed by immunofluorescence and immunohistochemistry, and the expression of Beclin-l-Bcl-2/Bcl-xL complexes was evaluated by immunoprecipitation. Multiple-group comparisons were conducted using analysis of variance （ANOVA）. P values of less than 0.05 were considered statistically significant. Results It was observed that the expression of JNK, p-P53, Beclin-1, DRAM and p-bcl-2 was increasing after TBI, and the expression of Beclin-1 and DRAM was mainly located in the cytoplasm of neurons. But these were significantly inhibited in SP600125 group compared with sham group and TBI＋SP600125 group （P 〈0.05）. The expression of Beclin-l-Bcl-2/Bcl-xL complexes was reduced after TBI. Conclusion JNK-mediated p53 phosphorylation might be an important mechanism for enhancing neuron autophagy in response to TBI.

Tumor-suppressing effects of autophagy on hepatocellular carcinoma

Evasion of apoptosis is one of the hallmarks of hepatocellular carcinoma(HCC)that results in treatment resistance.Recently,autophagy was reported to induce cell death in HCC,highlighting the tumorsuppressing effects of autophagy on HCC.This review summarizes our current understanding of the HCC-suppressing effects of macroautophagy(hereafter referred to as autophagy)to provide insights into the molecular mechanisms that may be essential for the development of autophagy-targeting therapeutic strategies for HCC.