Phospholipid peroxidation inhibits autophagy via stimulating the delipidation of oxidized LC3-PE.

Phospholipid peroxidation of polyunsaturated fatty acids at the bis-allylic position drives ferroptosis. Here we identify a novel role for phospholipid peroxidation in the inhibition of autophagy. Using in vitro and in vivo models, we report that phospholipid peroxidation induced by glutathione peroxidase-4 inhibition and arachidonate 15-lipoxygenase overexpression leads to overload of peroxidized phospholipids and culminate in inhibition of autophagy. Functional and lipidomics analysis further demonstrated that inhibition of autophagy was associated with an increase of peroxidized phosphatidylethanolamine (PE) conjugated LC3. We further demonstrate that autophagy inhibition occurred due to preferential cleavage of peroxidized LC3-PE by ATG4B to yield delipidated LC3. Mouse models of phospholipid peroxidation and autophagy additionally supported a role for peroxidized PE in autophagy inhibition. Our results agree with the recognized role of endoplasmic reticulum as the primary source for autophagosomal membranes. In summary, our studies demonstrated that phospholipid peroxidation inhibited autophagy via stimulating the ATG4B-mediated delipidation of peroxidized LC3-PE.

Silencing of perilipin by short hairpin RNA inhibits proliferation and induces apoptosis in liposarcoma cells.

Previous studies have identified that perilipin-1 (PLIN1) is a highly specific marker for liposarcoma. However, its functions have yet to be fully elucidated. The aim of the present study was to investigate the potential role of PLIN1 in the proliferation, migration and apoptosis of liposarcoma cells. Short hairpin RNA was designed to inhibit PLIN1 levels. Cell proliferation was monitored by Cell Counting Kit­8 assay and cell migration determined by wound healing assay. Flow cytometry was performed to assess the cell cycle distributions and apoptosis in liposarcoma cells. The results demonstrated that the expression of PLIN1 was significantly upregulated in liposarcoma tumor tissues compared with normal adipose tissues. Silencing of PLIN1 by short hairpin RNA significantly inhibited proliferation and migration and induced G1 phase cell cycle arrest and apoptosis in liposarcoma cell lines. It was identified that PLIN1 serves a crucial role in the pathogenesis and progression of liposarcoma and may be a potential therapeutic target for its clinical management.

Trastuzumab modified silica nanoparticles loaded with doxorubicin for targeted and synergic therapy of breast cancer.

Untargeted delivery as well as low efficacy are two main obstacles for effective breast cancer therapy. Here in this study, we surface modified silica nanoparticles (SLN) with Trastuzumab (Tra) to construct a tumor-targeting carrier (Tra-SLN) for specific drug delivery to human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer cells. In addition, Tra-SLN could also loaded with broad-spectrum anticancer drug doxorubicin (DOX) to finally construct a drug delivery system (DDS) capable of co-delivering Tra and DOX (Tra-SLN/DOX). Our results demonstrated that the as-prepared Tra-SLN/DOX was nanoscale particles with spheroid appearance which showed preferable stability in physiological environments. In addition, the Tra-SLN/DOX could specifically target to HER2 overexpressed MCF-7 cells. Both in vitro and in vivo experiments revealed that the Tra-SLN/DOX exerted enhanced anticancer efficacy when compared with Tra or DOX alone. It was suggested that Tra-SLN/DOX might be a promising platform for enhanced therapy of breast cancer.

NFκB mediated elevation of KCNJ11 promotes tumor progression of hepatocellular carcinoma through interaction of lactate dehydrogenase A.

It has been well documented that changes in ion fluxes across cellular membranes is fundamental in maintaining cellular homeostasis. Dysregulation and/or malfunction of ion channels are critical events in the pathogenesis of diverse diseases, including cancers. In this study, we focused on the study of K+ channels in hepatocellular carcinoma (HCC). By data mining TCGA cohort, the expression of 27 K+ channels was investigated and KCNJ11 was identified as a key dysregulated K+ channels in HCC. KCNJ11 was differentially expressed in HCC and predicted a poor prognosis in HCC patients. Inhibition of NFκB signaling suppressed KCNJ11 expression in HCC cells. Knockdown of KCNJ11 expression inhibited cell proliferation, promoted cell apoptosis, and reduced cell invasive capacity. Mechanistically, we found that KCNJ11 promotes tumor progression through interaction with LDHA and enhancing its enzymatic activity. Pharmacological inhibition of LDHA largely compromised the oncogenic function of KCNJ11 in cell proliferation, cell apoptosis, and cell invasion. Collectively, our data, as a proof of principle, demonstrate that KCNJ11 acts as an oncogene in HCC though forming a complex with LDHA and suggest that targeting KCNJ11 can be developed as a candidate tool to dampen HCC.

Auxin transport and activity regulate stomatal patterning and development.

Stomata are two-celled valves that control epidermal pores whose spacing optimizes shoot-atmosphere gas exchange. They develop from protodermal cells after unequal divisions followed by an equal division and differentiation. The concentration of the hormone auxin, a master plant developmental regulator, is tightly controlled in time and space, but its role, if any, in stomatal formation is obscure. Here dynamic changes of auxin activity during stomatal development are monitored using auxin input (DII-VENUS) and output (DR5:VENUS) markers by time-lapse imaging. A decrease in auxin levels in the smaller daughter cell after unequal division presages the acquisition of a guard mother cell fate whose equal division produces the two guard cells. Thus, stomatal patterning requires auxin pathway control of stem cell compartment size, as well as auxin depletion that triggers a developmental switch from unequal to equal division.

[Advanced schistosomiasis prevalence in Jingmen City from 2004 to 2013].

OBJECTIVE: To understand the advanced schistosomiasis prevalence trend in Jingmen City, so as to provide the evidence for improving the disease prevention and control. METHODS: The changes of advanced schistosomiasis prevalence were investigated and the distribution characteristics of the patients were analyzed in Jingmen City from 2004 to 2013. RESULTS: In recent 10 years, the incidence of advanced schistosomiasis dropped from 0.014/thousand to 0.009/thousand, and the regional distribution of the patients did not change. The number of male patients was still more than that of female patients, but more old aging patients were found. The ascetic type and splenomegaly type of advanced schistosomiasis patients were the most. CONCLUSION: In the next few years, the advanced schistosomiasis patients Jingmen City will reduce quickly, and concentrate on the aging group and ascetic type.

[Molluscicidal effect of plastic film mulch covering method].

OBJECTIVE: To evaluate the molluscicidal effect of the plastic film mulch covering method. METHODS: In the barren land with a lot of Oncomelania hupensis snails, 3 experimental groups were set up, in which respectively using 3 different methods: a simple plastic film mulch covering method, film assisted with ammonium bicarbonate, and film assisted with amine molluscicide. In the canals, two experimental groups were set up, in which respectively using 2 different methods: simple plastic film mulch covering method and film assisted with ammonium bicarbonate. In above-mentioned areas, obstacles were cleared artificially. In each experiment group, 4 observation spots were set up, and 100 living snails were pot in each spot, and then, the plastic film mulch was evenly covered. The status of the snails was observed 3, 7, 15 and 30 days after the intervention. RESULTS: In the barren land, the snail death rates of the simple plastic film group were 20.77% and 96.92% 15 days and 30 days after the intervention, respectively. The snail death rate of the film assisted with amine molluscicide group was 80.46% 3 days after the intervention. In all the experiment groups, the snail death rates were from 96.92 to 100% 30 days after the intervention. CONCLUSION: The plastic film mulch covering method has a great molluscicide effect in the hill subtype and water network type of schistosomiasis epidemic areas.

[Causes of re-emergence of Oncomelania snails in hardened ditches].

OBJECTIVE: To understand the impact factors of the re-emergence of Oncomelania snails in hardened ditches so as to find out the measures to improve the effect of snail eradication. METHODS: Thirteen infected townships from Jingmen City were randomly selected and investigated with the retrospective method and the field survey. All the data were analyzed for evaluating the effect of the hardened ditches on snail eradication and finding out the causes of the re-emergence of snails in hardened ditches RESULTS: After on-site investigation of 151 hardened ditches, the eradication rate of snail areas was 78.79%, and 71 ditches were founded with snails and the re-emergence rate was 47.02%. The major factors of the snail re-emergence were the spread of the snails from the upstream, the dilapidation of the hardened ditches, no using molluscicides before the hardened ditches, and the snails being brought by the engineering construction. CONCLUSIONS: The only hardened ditches can not eradicate the snails. We should manage an overall plan when processing the ditches hardening project, implementation with molluscicides before the project and strengthen the maintenance of the hardened ditches.

Neurotrophic artemin promotes motility and invasiveness of MIA PaCa-2 pancreatic cancer cells.

OBJECTIVE: To analyze the capacity of neurotrophic artemin to promote the motility and invasiveness of MIA PaCa-2 pancreatic cancer cells. METHODS: MIA PaCa-2 was cultured in vitro and studied using transwell chambers for motility and invasiveness on treatment with different concentrations of aArtemin or its receptor GFRα3 were also determined. Expression of matrix metalloproteinase-2 (MMP-2) and epithelial cadherin (E-cadherin) was quantified using RT-PCR and Western blotting. RESULTS: MIA PaCa-2 pancreatic cancer cell motility and invasiveness was significantly increased with artemin and its receptor GFRα3 with dose dependence (P<0.01). MMP-2 production was also significantly increased (t=6.35, t=7.32), while E-cadherin was significantly lowered (t=4.27, t=5.61) (P<0.01). CONCLUSION: Artemin and its receptor GFRα3 can promote pancreatic cancer cell motility and invasiveness and contribute to aggressive behavior. The mechanism may be related to increased expression of MMP-2 molecule and down-regulation of E-cadherin expression.

[Discussion of schistosomiasis infection source control].

At present, the strategy of schistosomiasis control is comprehensive control based on infectious source control. This paper discusses the comprehensive control measures, and suggests that we should strengthen the investigation of infectious sources and strengthen the control of infected Oncomelania snails.

[Surveillance of schistosomiasis in Jingmen City from 2001 to 2010].

OBJECTIVE: To understand the endemic situation of schistosomiasis in Jingmen City so as to provide the evidence for formulating schistosomiasis control program. METHODS: According to the "Schistosomiasis Control Manual" and the "Schistosomiasis Prevention and Control Practices", a surveillance was carried out, and the areas with Oncomelania snails, and the infection rates of residents and cattle were investigated and calculated, and the changes of these indexes were analyzed. RESULTS: The area with snails was 1 135.45 hm2 in 2003 which was rebounded from that in 2001, and gradually increased to 1 700 hm2. The infection rates of residents and cattle increased and they were 3.19% and 8.6% respectively in 2004, and after that these indexes gradually declined. CONCLUSION: The schistosomiasis classification control and comprehensive measures should still be strengthened in Jingmen City.

[The expression and significance of nerve growth factor and its receptors in pancreatic ductal adenocarcinoma].

OBJECTIVE: To investigate nerve growth factor (beta-NGF) and its receptors expression in human pancreatic ductal adenocarcinoma. METHODS: Expression and distribution of beta-NGF, tyrosine kinase A (TrKA) and P75(NGFR) were detected in operation tissue specimens of pancreatic ductal adenocarcinoma with immunohistochemistry and real-time PCR. Relations of beta-NGF and its receptors with clinical pathological characters, especially nerve invasion were analyzed. RESULTS: beta-NGF and TrKA expression are higher in pancreatic adenocarcinoma than normal pancreas, and the differences are significant (P < 0.01). beta-NGF and TrKA expression are associated with the differentiation grades (DG), lymphatic node metastasis, nerve invasion and surgical pathological stages. Poorer of DG and later stages, more expression of beta-NGF and TrKA. beta-NGF and TrKA expression have positive correlations. beta-NGF, TrKA and P75(NGFR) mRNA expression have significantly increased 3.84, 4.23 and 2.41 times than normal tissues by real-time PCR, respectively. CONCLUSIONS: beta-NGF and TrKA might play potential roles in carcinogenesis for pancreatic cancer, have affinity with clinicopathological characters of pancreatic cancer. beta-NGF and TrKA may have mutual effect in signal transduction leading to perineural invasion of pancreatic carcinoma.