Dioscin alleviates Alzheimer's disease through regulating RAGE/NOX4 mediated oxidative stress and inflammation.

Alzheimer's disease (AD) is a neurodegenerative disease with amyloid beta (Aß) deposition and intracellular neurofibrillary tangles (NFTs) as its characteristic pathological changes. Ameliorating oxidative stress and inflammation has become a new trend in the prevention and treatment of AD. Dioscin, a natural steroidal saponin which exists in Dioscoreae nipponicae rhizomes, displays various pharmacological activities, but its role in Alzheimer's disease (AD) is still unknown. In the present work, effect of dioscin on AD was evaluated in injured SH-SY5Y cells induced by H2O2 and C57BL/6 mice with AD challenged with AlCl3 combined with D-galactose. Results showed that dioscin obviously increased cell viability and decreased reactive oxygen species (ROS) level in injured SH-SY5Y cells. In vivo, dioscin obviously improved the spatial learning and memory abilities as well as gait and interlimb coordination disorders of mice with AD. Moreover, dioscin distinctly restored the levels of malondialdehyde (MDA), superoxide dismutase (SOD), amyloid beta 42 (Aß42), acetylcholine (ACh) and acetylcholinesterase (AChE) of mice, and reversed the histopathological changes of brain tissue. Mechanism studies revealed that dioscin markedly down-regulated the expression levels of RAGE and NOX4. Subsequently, dioscin markedly up-regulated the expression levels of Nrf2 and HO-1 related to oxidative stress, and down-regulated the levels of p-NF-κB(p-p65)/NF-κB(p65), AP-1 and inflammatory factors involved in inflammatory pathway. RAGE siRNAs transfection further clarified that the pharmacological activity of dioscin in AD was achieved by regulating RAGE/NOX4 pathway. In conclusion, dioscin showed excellent anti-AD effect by adjusting RAGE/NOX4-mediated oxidative stress and inflammation, which provided the basis for the further research and development against AD.

Aß40 Promotes the Osteoblastic Differentiation of Aortic Valve Interstitial Cells through the RAGE Pathway.

Amyloid beta (Aß) peptide 40 enhances the activation of receptor for advanced glycation end products (RAGE) in immune-inflammatory diseases. RAGE exhibits several effects in the setting of numerous cardiovascular events. We hypothesized that the Aß40/RAGE pathway is involved in the osteoblastic differentiation of the valvular interstitial cell (VIC) phenotype, and RAGE knockout intervention could reduce the calcification of aortic valve interstitial cells (AVICs) by inhibiting the extracellular-regulated kinase1/2 (ERK1/2)/nuclear factor kappa-B (NF-κB) signaling pathway. To test this hypothesis, the activation of Aß40/RAGE pathway in human calcific AVs was evaluated with immunohistochemical staining. Cultured calcific VIC models were used in vitro. The VICs were stimulated using Aß40, with or without RAGE small interfering ribonucleic acid (siRNA), and ERK1/2 and NF-κB inhibitors for analysis. Our data revealed that Aß40 induced the ERK1/2/NF-κB signaling pathway and osteoblastic differentiation of AVICs via the RAGE pathway in vitro.

FABP4 contributes to renal interstitial fibrosis via mediating inflammation and lipid metabolism.

Fatty acid binding protein 4 (FABP4), a subtype of fatty acid-binding protein family, shows critical roles in metabolism and inflammation. However, its roles on regulating renal interstitial fibrosis (RIF) remain unclear. In this work, LPS-stimulated in vitro models on NRK-52E and NRK-49F cells, and in vivo UUO models in rats and mice were established. The results showed that comparing with control groups or sham groups, the expression levels of α-SMA, COL1A, COL3A, IL-1ß, IL-6, and TNF-α in LPS-stimulated cells or UUO animals were significantly increased. Meanwhile, the levels of TC, TG, and free fatty acid were also significantly increased as well as the obvious lipid droplets, and the serum levels of BUN, Cr were significantly increased with large amounts of collagen deposition in renal tissues. Further investigation showed that compared with control groups or sham groups, the expression levels of FABP4 in LPS-stimulated cells and UUO animals were significantly increased, resulting in down- regulating the expression levels of PPARγ, upregulating the levels of p65 and ICAM-1, and decreasing the expression levels of ACADM, ACADL, SCP-2, CPT1, EHHADH, and ACOX1. To deeply explore the mechanism of FABP4 in RIF, FABP4 siRNA and inhibitor interfered cell models, and UUO model on FABP4 knockout (KO) mice were used. The results showed that the expression levels of α-SMA, COL1A, and COL3A were significantly decreased, the deposition of lipid droplets decreased, and the contents of TC, TG, and free fatty acids were significantly decreased after gene silencing. Meanwhile, the expression levels of PPAR-γ, ACADM, ACADL, SCP-2, CPT1, EHHADH, and ACOX1 were upregulated, the levels of p65 and ICAM-1 were downregulated, and the mRNA levels of IL-1ß, IL-6, and TNF-α were decreased. Our results supported that FABP4 contributed to RIF via promoting inflammation and lipid metabolism, which should be considered as one new drug target to treat RIF.

Potent effects of dioscin against hepatocellular carcinoma through regulating TP53-induced glycolysis and apoptosis regulator (TIGAR)-mediated apoptosis, autophagy, and DNA damage.

BACKGROUND AND PURPOSE: Dioscin shows potent effects against cancers. We aimed to elucidate its pharmacological effects and mechanisms of action on hepatocellular carcinoma (HCC) in vivo and in vitro. EXPERIMENTAL APPROACH: Effects of dioscin were investigated in SMMC7721 and HepG2 cells, diethylnitrosamine-induced primary liver cancer in rats, and cell xenografts in nude mice. Isobaric tags for relative and absolution quantitation (iTRAQ)-based proteomics was used to find dioscin's targets and investigate its mechanism. KEY RESULTS: In SMMC7721 and HepG2 cells dioscin markedly inhibited cell proliferation and migration, induced apoptosis, autophagy, and DNA damage. It inhibited DEN-induced primary liver cancer in rats, markedly changed body weights and restored levels of α fetoprotein, alanine transaminase, aspartate transaminase, γ-glutamyltransferase, alkaline phosphatase, and Ki67. It also inhibited growth of xenografts in mice. In SMMC7721 cells, 191 differentially expressed proteins were found after dioscin, based on iTRAQ-based assay. TP53-inducible glycolysis and apoptosis regulator (TIGAR) was identified as being significantly down-regulated by dioscin. Dioscin induced cell apoptosis, autophagy, and DNA damage via increasing expression levels of p53, cleaved PARP, Bax, cleaved caspase-3/9, Beclin-1, and LC3 and suppressing those of Bcl-2, p-Akt, p-mammalian target of rapamycin (mTOR), CDK5, p-ataxia telangiectasia-mutated gene (ATM). The transfection of TIGAR siRNA into SMMC7721 cells and xenografts in nude mice further confirmed that the potent activity of dioscin against HCC is evoked by adjusting TIGAR-mediated inhibition of p53, Akt/mTOR, and CDK5/ATM pathways. CONCLUSIONS AND IMPLICATIONS: The data suggest that dioscin has potential as a therapeutic, and TIGAR as a drug target for treating HCC.

Pancreatic acinar cell carcinoma-case report and literature review.

BACKGROUND: Pancreatic acinar cell carcinoma (ACC) is a rare tumor that constitutes 1% of all pancreatic neoplasms. Pancreatic ACC has unique characteristics in terms of biological behavior, imaging and prognosis. CASE PRESENTATION: The present study reported two cases of pancreatic ACC confirmed by postoperative pathology and both cases exhibited several different imaging features and laboratory test results. Both cases had approximately 4 cm mass located in uncinate process of pancreas. Dilated intra- and extra-hepatic bile ducts was observed in one case, along with calcification. Heterogeneous enhancement of the tumor was exhibited in both patients with different intensities. Obstructive jaundice, elevated α-fetoprotein and CA 19-9 was found in one case, while the other case had normal liver function and tumor markers. CONCLUSIONS: It was difficult to accurately diagnose pancreatic ACC before the operation despite its unique characteristics. Radical resection was the best treatment modality for resectable pancreatic ACC.

Age, is it an obstacle for older surgeons to learn laparoscopic approach for colorectal cancer?

Laparoscopic colorectal resection has been extensively accepted for treatment of colorectal cancer. There are several reports about surgeon's age as a factor to have influence on learning laparoscopic approach, and there is no consensus on this point. This study was designed to evaluate the outcomes of laparoscopic colorectal resection in period of learning curve completed by surgeons with different age in order to make clear whether older surgeons may learn laparoscopic approach with more difficulty than younger. From July 2010 to August 2012, the first twenty patients underwent laparoscopic colorectal resection completed by each surgeon were selected for analysis. A total of 240 patients treated by 5 older surgeons with median age of 51 years (range 47-54 years) and 7 younger surgeons with median age of 37 years (range 34-43 years) were divided into group 1 (n = 100) and group 2 (n = 140). The short-term outcomes of laparoscopic surgery of the two groups were compared. Two groups were matched in age, gender, body mass index, American Society of Anesthesiologists (ASA), etc. The median number of lymph nodes harvested was 18 (range 7-63) in group 1 and 16 (range 3-66) in group 2 (P = 0.003); The median operative time in group 1 was 185 min (range 105-480 min) compared to 235 min (range 120-470 min) in group 2 (P < 0.001), and blood loss were 150 ml (range 50-400 ml) and 200 ml (range 50-800 ml), respectively (P < 0.001); Conversion rate in group 2 was lower than in group 1 (12.0 vs 18.6 %, P = 0.196). The mean time to passing of first flatus was 3 day (range 2-5 day) in group 1 and 4 day (range 2-6 day) in group 2 (P = 0.001). Older surgeons can master the laparoscopic skill more easily and quickly. Age is not an obstacle for older surgeons to learn laparoscopic approach for colorectal cancer.

Association of three single nucleotide polymorphisms of the E-cadherin gene with endometriosis in a Chinese population.

Endometriosis, one of the most frequent diseases in gynecology, is a benign but invasive and metastatic disease. The altered expression of E-cadherin may play an important role in developing endometriosis. In this paper, we discuss the association of three single nucleotide polymorphisms (SNPs) on the E-cadherin gene and risk of endometriosis. We examined the genotype frequency of three polymorphisms in 152 endometriosis patients and 189 control women. There was a significant difference in the frequency of the E-cadherin 3'-UTR C --> T genotypes between endometriosis and controls (P = 0.01). The frequency of the C allele in patients (71.1%) was significantly higher than in the controls (63.8%; P = 0.04). When compared with the T/T + T/C genotypes, the C/C genotype had a significantly increased susceptibility to endometriosis, with an adjusted odds ratio of 1.79 (95% confidence interval = 1.17-2.76). No significant difference was found between endometriosis and control women on two polymorphisms (-160 C --> A, -347 G --> GA) at the gene promoter region of E-cadherin. The -160 C --> A and -347 G --> GA polymorphisms displayed linkage disequilibrium (D' = 0.999). The -160 A/-347 GA haplotype was only detected in endometriosis patients (2%). These data show a relation between the E-cadherin 3'-UTR C --> T polymorphism, the -160 A/-347 GA haplotype of two promoter polymorphisms and risk of endometriosis, suggesting a potential role in endometriosis development, at least in North Chinese women.