Curcumin protects islet beta cells from streptozotocin­induced type 2 diabetes mellitus injury via its antioxidative effects.

Streptozotocin (STZ)-induced diabetes rodent models are widely used to study the pathogenesis and metabolic function in diabetes (DM). The aim of this study was to assess the antioxidant effect of curcumin in STZ-induced type 2 diabetes mellitus (T2DM). In this research, rats were randomly divided into 3 groups (8 in each group): a nondiabetic group (Control), a diabetic group (DM), and a curcumin treatment group (DM + Cur 200 mg/kg group). Meanwhile, after intraperitoneal injection (i.p.), associated-oxidative stress parameters were observed, malondialdehyde (MDA) was decreased, and glutathione peroxidase (GPX) and super oxide dismutase (SOD) were restored in pancreatic tissues of curcumin-treated DM rats. In addition, curcumin improved the survival and function of islet cells with decreased cell apoptosis in Langerhans islet and increased insulin secretion in the STZ-induced T2DM rat model. Our findings suggest that curcumin is a potent candidate for the prevention and therapy of DM.

Multi-stimuli responsive hollow MnO2-based drug delivery system for magnetic resonance imaging and combined chemo-chemodynamic cancer therapy.

The exploration and application of hollow manganese dioxide nanoparticle (HMDN) for biosensing and biomedicine has gained significant research attention in the past decade. In this study, a type of biodegradable HMDN is prepared for multi-stimuli responsive tumor-targeted drug delivery, which was successfully loaded with doxorubicin hydrochloride (DOX). Then, the drug-loaded HMDN is functionalized with polyethyleneimine (PEI) as a gatekeeper followed by citraconic anhydride (cit) functionalized poly-L-lysine (PLL(cit)) as a charge reversal moiety successively to yield the resultant DOX@HMDN-PEI-PLL(cit) nanoparticles. In vitro study showed that DOX@HMDN-PEI-PLL(cit) exhibited a ''stealthy'' property under physiological conditions and enhanced cellular uptake activity in response to the mild acidic tumor microenvironment due to the departure of cit. In vitro release profiles proved that the decomposition of HMDN to Mn2+ under acidic condition/high glutathione (GSH) concentration triggered the release of DOX and Fenton-like reaction for improved therapeutic effect. And Mn2+ could also act as a T1-weighted magnetic resonance imaging (MRI) contrast agent. In vivo studies further proved with both the charge reversal and combined therapy properties, DOX@HMDN-PEI-PLL(cit) showed a good tumor enrichment ability and therapeutic effect with few side effects to the mice. These results demonstrate that DOX@HMDN-PEI-PLL(cit) nanoparticles are promising drug delivery systems for targeted cancer therapy. STATEMENT OF SIGNIFICANCE: Traditional chemotherapy based on anticancer drugs such as doxorubicin hydrochloride (DOX) shows limited efficacy with serious side effects. We employed hollow manganese dioxide nanoparticle (HMDN) to loaded DOX and coated it with polyethyleneimine and then citraconic anhydride functionalized poly-L-lysine to endow it with a charge reversal property to obtain a multi-stimuli responsive drug delivery system named DOX@HMDN-PEI-PLL(cit). It was ''stealthy'' with low cellular uptake capability by normal cells, but could be "acid-activated" in tumors for endocytosis by cancer cells to reduce side effects. HMDN could be decomposed to Mn2+ under acidic conditions/high glutathione concentration to release DOX intracellular. DOX and Mn2+ catalyzed Fenton-like reaction could achieve a combined chemo-chemodynamic therapy. And Mn2+ could be used for T1-weighted magnetic resonance imaging.

MicroRNA­19b inhibitors can attenuate the STAT3 signaling pathway in NPC C666­1 cells.

MicroRNA (miR)-19b is expressed in various types of tumors and may serve as a potential therapeutic target. The miR­17­92 cluster is upregulated in nasopharyngeal carcinoma (NPC) tissues and cells. miR­19b is a member of the miR­17­92 cluster; however, its expression and function in NPC are largely unknown. The present study aimed to investigate the expression and function of miR­19b in NPC cells. The miRCURY LNATM miRNA Inhibitor (miR­19b inhibitor and negative control) were transfected into C666­1 cells. The proliferation, apoptosis and migration of the cells were subsequently detected by the Cell Counting Kit­8 assay, flow cytometry and Transwell assay, respectively. Additionally, the expression of STAT3 signaling pathway­associated proteins [STAT3, pSTAT3 and suppressor of cytokine signaling 1 (SOCS1)] and the transcriptional targets of pSTAT3 [Bcl­2, myeloid leukemia protein 1 (Mcl­1) and cyclin D1] were detected by western blotting. The miR­19b inhibitor inhibited proliferation and migration and induced apoptosis of C666­1 cells. Furthermore, the miR­19b inhibitor upregulated the expression of SOCS1, a predicted target gene of miR­19b, and decreased the phosphorylation of STAT3 at Tyr705 and Ser727. These data indicated that upregulation of SOCS1, an endogenous inhibitor of STAT3 phosphorylation, attenuated the STAT3 signaling pathway in C666­1 cells. Moreover, the expression level of the proproliferative protein cyclin D1 and antiapoptotic proteins Mcl­1 and Bcl­2 was significantly decreased following transfection with the miR­19b inhibitor. The aforementioned three proteins are downstream transcriptional targets of the activated STAT3 signaling pathway. The results of the present study revealed that inhibition of miR­19b negatively modulated the malignant behavior of NPC cells via the STAT3 signaling pathway. Therefore, miR­19b inhibition may serve as a novel therapeutic target for the treatment of NPC.

Loss of AKR1C1 is a good prognostic factor in advanced NPC cases and increases chemosensitivity to cisplatin in NPC cells.

Cisplatin resistance is one of the main obstacles in the treatment of advanced nasopharyngeal carcinoma (NPC). AKR1C1 is a member of the Aldo-keto reductase superfamily (AKRs), which converts aldehydes and ketones to their corresponding alcohols and has been reported to be involved in chemotherapeutic resistance of multiple drugs. The expression and function of AKR1C1 in NPC have not been reported until now. The aim of this research was to investigate the expression of AKR1C1 and it is role in cisplatin resistance in NPC. AKR1C1 protein expression was detected by immunohistochemistry in human NPC tissues and by Western blot assays in NPC and immortalized nasopharyngeal epithelial cells. The effects of AKR1C1 knock-down by siRNA on proliferation, migration and invasion in NPC cells were evaluated by CCK8, wound healing and transwell assays. To evaluate the effects of AKR1C1 silencing on cisplatin sensitivity in NPC cells, CCK8 assays were used to detect cell proliferation, flow cytometry was used to detect cell cycle distribution, and flow cytometry and DAPI staining were used to detect cell apoptosis. AKR1C1 down-regulation was associated with advanced clinicopathological characters such as larger tumor size, more lymphatic nodes involvement, with metastasis and later clinical stages, while AKR1C1 down-regulation was a good prognostic factor for overall survival (OS) in NPC patients. In vitro study showed that AKR1C1 was not directly involved in the malignant biological behaviours such as proliferation, cell cycle progression and migration of NPC cells, whereas AKR1C1 knock-down could enhance cisplatin sensitivity of NPC cells. These results suggest that AKR1C1 is a potential marker for predicting cisplatin response and could serve as a molecular target to increase cisplatin sensitivity in NPC.

F factor plasmid-mediated Epstein-Barr virus genome introduction establishes an EBV positive NPC cell model.

BACKGROUND: Most Epstein-Barr virus (EBV)-positive cells lose the EBV episomes upon prolonged propagation. PURPOSE: The purposes of this study were to establish a simple cell model for nasopharyngeal carcinoma (NPC) research by introducing a plasmid with the EBV genome into NPC cells and then to investigate the resulting changes in malignant biological behaviour and NPC-associated signalling pathways. METHODS: HONE1 NPC cells were transfected with F-factor plasmids including the EBV genome (HONE1-EBV cells). Then cell proliferation, migration, cell cycle distribution and apoptosis were evaluated in vitro by using CCK8, transwell and flow cytometry assays respectively. EBV-encoded proteins and cell signal tranducting proteins were detected by western blot assays. EBV-encoded RNAs were detected by in situ hybridization. EBV particles were assayed by transmission electron microscope (TEM). The morphology of cells were detected by immunofluorescence assays for alpha-tubulin. RESULTS: Latent membrane protein 1 (LMP1), latent membrane protein 2A (LMP2A), Epstein-Barr nuclear antigen 1 (EBNA1) and EBV-encoded small RNAs (EBERs) were successfully expressed in HONE1-EBV cells. No EBV particles were founded by TEM. Introduction of the EBV genome significantly promoted proliferation, cell cycle progression and migration and inhibited apoptosis in HONE1 cells. Immunofluorescence assays showed that the morphology of HONE1-EBV cells changed into spindle. Furthermore, EBV genome introduction significantly inhibited the JAK/STAT signalling pathway, while it activated the PI3K-AKT and NF-κB signalling pathways in HONE1 cells. CONCLUSION: These findings suggest that F-factor plasmid-mediated EBV genome introduction was successful in constructing an EBV positive cell model, which showed deteriorated biological behavior and activated NPC-associated signalling pathways. This model can serve as a good tool for studying EBV in NPC, but the subtle differences in cancer-associated pathways must be considered.

Sarcomatoid Chromophobe Renal Cell Carcinoma: A Case Report and Review of the Literature.

BACKGROUND Sarcomatoid renal cell carcinoma is not a distinct histologic entity transformed from different subtypes of renal cell carcinoma. The sarcomatoid transformation was accepted as the result of dedifferentiation of the primary tumor. Here we present a case of sarcomatoid chromophobe renal cell carcinoma and review the clinicopathological characteristics of sarcomatoid chromophobe renal cell carcinoma. CASE REPORT A 63-year-old female complained of painless gross hematuria for 3 months. Routine urine test showed that urinary protein was ++ and white blood cells were +++; serum CA153 was moderately elevated at 71.08 U/mL (normal <28 U/mL). Ultrasonography and a computed tomography scan showed a mass in the lower pole of the right kidney, measuring 13.4×15.4×11.4 cm. She underwent a right radical nephrectomy with lymph nodes dissection under general anesthetic. There was no evidence of recurrence and lymphadenopathy 12 months after surgery. CONCLUSIONS Sarcomatoid chromophobe renal cell carcinoma is an uncommon tumor characterized by a biphasic tumor with both classical epithelial components and sarcomatoid components. The prognosis of sarcomatoid chromophobe renal cell carcinoma is worse than classical chromophobe renal cell carcinoma. It is important to recognize that sarcomatoid change of chromophobe renal cell carcinoma has the potential to behave aggressively and to metastasize.

Loss of ARID1A promotes proliferation, migration and invasion via the Akt signaling pathway in NPC.

Background: AT-rich interactive domain-containing protein 1A (ARID1A) is a member of the switch/sucrose nonfermentable chromatin remodeling complex, which has been observed to be mutated in various tumors. The loss of ARID1A is reported to be frequently associated with PI3K/Akt pathway activation. Objective: The roles of ARID1A in nasopharyngeal carcinoma (NPC) have not been reported until now. The aim of this research was to explore the clinical significance and potential mechanism of ARID1A in NPC development and progression. Methods: ARID1A expression levels were investigated in human NPC tissues and cell lines. The effects of ARID1A knockdown on nasopharyngeal cancer cell proliferation, migration and invasion were evaluated in vitro using CCK8, wound healing, transwell and flow cytometry assays. The expression of relevant proteins was evaluated by Western blot assays. Results: In this study, ARID1A was significantly downregulated in NPC tissues and cells. Furthermore, low ARID1A expression was significantly associated with aggressive clinicopathological characteristics and poor survival in NPC patients. Depletion of endogenous ARID1A by siRNA promoted proliferation, migration and invasion in CNE1 and HNE1 cells. Additionally, ARID1A knockdown increased the phosphorylation of Akt in NPC cells. High levels of p-Akt were also observed in NPC biopsies and correlated with ARID1A downregulation. These results imply that the loss of ARID1A could activate Akt signaling. In addition, MK-2206 (a highly selective inhibitor of Akt) partially suppressed NPC cell proliferation, migration and invasion, which were induced by ARID1A knockdown. Conclusion: Our findings indicate that ARID1A plays an essential role in modulating the Akt pathway, functions as a tumor suppressor in NPC and may be a potential target for NPC treatment.