Analysis of Chemical Constituents of Miao Ethnomedicine Heiguteng Zhuifeng Huoluo Capsule (HZFC) and the Discovery of Active Substances in the Treatment of Rheumatoid Arthritis.

In this study, the chemical substances of Heiguteng Zhuifeng Huoluo Capsule (HZFC) and its potential active ingredients for the treatment of rheumatoid arthritis (RA) were characterized and analyzed by medicinal chemistry combined with bioinformatics methods. Also, the potential active ingredients of HZFC against RA were verified by lipopolysaccharide (LPS)-induced macrophage activation model. The results showed that 79 chemical constituents were successfully identified, mainly including phenylpropanoids, flavonoids, and alkaloids. Among them, 13 active components were closely related to the nine core targets (FASN, ALOX5, EGFR, MMP1, CYP2D6, CNR1, AR, MAOA, and FKBP5) of HZFC in the treatment of RA. Molecular docking further proved that 13 active components had strong docking activity with 9 core targets. In the verification experiment of the LPS-induced RAW 264.7 macrophage model, the verified components (magnoflorine, N-feruloyltyramine, canadine, rutin, quercetin-3-O-glucoside, and pseudocolumbamine) all showed a clear inhibitory effect on the secretion of inflammatory factors in model cells. The above research results suggest that 13 components such as stepharanine, rutin, quercetin-3-O-glucoside, corydine methyl ether, canadine, 8-oxoepiberberine, disinomenine, deosinomenine glucoside, tuduranine, magnoflorine, isosinomenine, pseudocolumbamine, and N-feruloyltyramine may be the main active substances of HZFC in the treatment of RA.

Nomogram predicts CR-POPF in open central pancreatectomy patients with benign or low-grade malignant pancreatic neoplasms.

Introduction: Central pancreatectomy (CP) is a standard surgical procedure for benign and low-grade malignant pancreatic neoplasms in the body and neck of the pancreas. Higher incidence of clinically relevant postoperative pancreatic fistula (CR-POPF) after CP than after pancreaticoduodenectomy (PD) or distal pancreatectomy (DP) has been reported, but no nomogram for prediction of CR-POPF after open CP has been previously established. Methods: Patients undergoing open CP for benign or low-grade malignant pancreatic neoplasms in the department of Hepatobiliary and Pancreatic (HBP) surgery of Shanghai Changhai Hospital affiliated to Naval Medical University between January 01, 2009 and December 31,2020 were enrolled. Pre-, intra- and post-operative parameters were analyzed retrospectively. Results: A total of 194 patients, including 60 men and 134 women, were enrolled with median age of 52 years (21~85 years). 84 patients (43.3%) were overweight (BMI>23.0 Kg/m2) and 14 (7.2%) were obese (BMI>28.0 Kg/m2). Pathological diagnoses ranged from serous cystic neoplasm (32.5%), solid pseudopapillary neoplasm (22.2%), pancreatic neuroendocrine tumor (20.1%), intraductal papillary mucinous neoplasm (18.0%) to mucinous cystic neoplasm (5.2%). All patients had soft pancreatic texture. Main pancreatic duct diameters were ≤0.3cm for 158 patients (81.4%) and were ≥0.5cm in only 12 patients (6.2%). A stapler (57.7%) or hand-sewn closure (42.3%) were used to close the pancreatic remnant. The pancreatic anastomosis techniques used were duct to mucosa pancreaticojejunostomy (PJ)-interrupted suture (47.4%), duct to mucosa PJ-continuous suture (43.3%), duct to mucosa "HO" half-purse binding PJ (5.2%) and invaginating pancreaticogastrostomy (4.1%). Post-surgical incidences of CR-POPF of 45.9%, surgical site infection of 28.9%, postpancreatectomy hemorrhage of 7.7% and delayed gastric emptying of 2.1% were found. Obesity and pancreatic anastomosis technique were independent risk factors of CR-POPF, with a concordance index of 0.675 and an Area Under the Curve of 0.678. Discussion: This novel nomogram constructed according to obesity and pancreatic anastomosis technique showed moderate predictive performance of CR-POPF after open CP.

Menin Coordinates C/EBPß-Mediated TGF-ß Signaling for Epithelial-Mesenchymal Transition and Growth Inhibition in Pancreatic Cancer.

Menin displays either tumor suppression or promotion functions in a context-dependent manner. Previously, we proposed that Menin acts as a tumor suppressor by inhibiting cell growth in pancreatic ductal adenocarcinoma (PDAC), whereas the relationship between the Menin expression and overall survival rate of PDAC patients has not been completely elucidated, indicating the complexity of Menin functions in PDAC progression. Here, we identify Menin as a promoter of epithelial-mesenchymal transition (EMT), which is largely associated with cell migration or metastasis, with modest activity in cell growth inhibition. Ectopic expression of Menin suppresses the expression of CCAAT/enhancer-binding protein beta (CEBPB) and epithelial-specific genes by histone deacetylation and further enhances the TGF-ß signaling-related EMT process. We also demonstrate that CCAAT/enhancer binding protein (C/EBP) beta (C/EBPß; encoded by CEBPB) acts downstream of Menin and TGF-ß signaling for balancing growth inhibition and EMT, and C/EBPß overexpression could restore the anti-cancer functions of Menin in pancreatic cancer by cooperatively activating CDKN2A/B genes and antagonizing EMT processes. Taken together, our results suggest that Menin functions as an oncogene for cancer metastasis upon C/EBPß depletion or acts as a tumor suppressor by cooperation with C/EBPß to activate CDKN2A transcription.

The Roles of MicroRNA-122 Overexpression in Inhibiting Proliferation and Invasion and Stimulating Apoptosis of Human Cholangiocarcinoma Cells.

Our study investigated whether microRNA-122 (miR-122) played important roles in the proliferation, invasion and apoptosis of human cholangiocarcinoma (CC) cells. QBC939 and RBE cells lines were chosen and divided into five groups: miR-122 mimic group, anti-miR-122 group, negative control (NC) group, mock group and blank group. MiR-122 expression was measured by qRT-PCR. Roles of miR-122 in cell proliferation, apoptosis and invasion were investigated using MTT assay, flow cytometer and Transwell invasion assay, respectively. MiR-122 expression was lower in CC tissues and QBC939 cell than that in normal bile duct tissues, HCCC-9810 and RBE cells. In both QBC939 and RBE cells lines, miR-122 expression was higher in miR-122 mimic group than that in NC group, mock group and blank group; opposite results were found in anti-miR-122 group. Cell proliferation and invasion were remarkably inhibited in miR-122 mimic group after 48 h/72 h transfection, while apoptotic cells numbers were much greater in miR-122 mimic group; the opposite results were obtained from anti-miR-122 group (all P < 0.05). MiR-122 expression was significantly weaker in CC tissues, and miR-122 overexpression might play pivotal roles in inhibiting proliferation, stimulating apoptosis and suppressing invasion of CC cells, suggesting a new target for CC diagnosis and treatment.

Alternative splicing of NUMB, APP and VEGFA as the features of pancreatic ductal carcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the most common form of malignancy in pancreatic carcinoma. Here we report our discovery on the correlations between transcriptional alternative splicing (AS) of NUMB, APP, VEGFA and PDAC in patients. METHODS: The expression of NUMB, APP, VEGFA from patient samples was determined by qRT-PCR. AS of these genes was examined through laser induced fluorescence capillary electrophoresis. Correlation between the AS of the genes and results from clinical laboratory examinations were analyzed. Expression of NOTHC1 and NOTCH4 as downstream target genes was examined by qRT-PCR and Western blot. RESULTS: Quantitative results indicated that expression of NUMB was significantly lower in tumor tissues (TT) than in para-tumor tissues (TP) (P<0.05), while APP (P<0.01) and VEGFA (P<0.05) were significantly higher. AS transcript percentage of NUMB PRR(S) was lower in TT than TP (P<0.05). AS transcript percentage of VEGFA (105+185) was significantly lower in TT than TP (P<0.05) compared to higher expression of VEGFA (206+338) (P<0.05). Regression analysis indicated that AS transcript of NUMB PRR(L) correlated with tumor size (P<0.01), while AS transcripts of APP and VEGFA correlated with results of laboratory examinations. To reveal the correlation between AS and its downstream targets, NOTCH1 and NOTCH4 were selected as NUMB gene targets and detected to be significantly higher in TT than TP (P<0.05). CONCLUSION: Alternative splicing of APP, VEGFA and NUMB may play an important role in pathogenesis of pancreatic ductal adenocarcinoma. Among the 3 genes, PRR(L) form of NUMB gene is highly expressed in TT and positively correlated with tumor size, while PRR(S) is lacking in TT and negatively correlated with NOTCH expression suggesting that PRR(S) might be protective in tumorogenesis and shows NOTCH pathway down regulation ability.

The c-Myc-LDHA axis positively regulates aerobic glycolysis and promotes tumor progression in pancreatic cancer.

The transcription factor c-Myc plays critical roles in cancer development and progression through regulating expression of targeted genes. Lactate dehydrogenase A (LDHA), which catalyzes the conversion of L-lactate to pyruvate in the final step of anaerobic glycolysis, is frequently upregulated in pancreatic cancer. However, little is known about the effects of c-Myc-LDHA axis in the progression of pancreatic cancer. In this study, we found that c-Myc and LDHA are concomitantly overexpressed in pancreatic cancer cell lines and clinical specimens. c-Myc overexpression and LDHA overexpression were correlated with TNM stage and tumor size and indicated poor prognosis in patients with pancreatic cancer. Knockdown of c-Myc reduced the protein expression of LDHA, lactate production and glucose consumption, and silencing of LDHA mimicked this effect. Meanwhile, reduced c-Myc-LDHA signaling resulted in decreased tumor growth and metastasis in pancreatic cancer. Treatment with 2-Deoxy-D-glucose, an inhibitor of anaerobic glycolysis, completely blocked the oncogenic roles of c-Myc-LDHA signaling. Taken together, dysregulated c-Myc-LDHA signaling plays important roles in aerobic glycolysis and facilitates tumor progression of pancreatic cancer.

[The role of full length superior mesenteric artery isolation in extended pancreaticoduodenectomy in the treatment of ductal adenocarcinoma of the pancreas in the uncinate process].

OBJECTIVE: To improve the prognosis and safety of extended pancreaticoduodenectomy for patients with pancreatic cancer in the uncinate process of pancreas. METHODS: From January 2004 to March 2008, 26 extended pancreaticoduodenectomies with full length superior mesenteric artery (SMA) isolation and mesentery root resection were performed for the ductal adenocarcinomas in the uncinate process of pancreas. There were 16 males and 10 females aging from 30 to 75 years old [medium age (55.0 +/- 13.0) years old]. Eleven of 26 patients were combined with portal vein-superior mesenteric vein resection. The effect and safety of this procedure were analyzed retrospectively. RESULTS: There was no operative mortality in all patients. The pathological examination showed that all the incisal margins were negative. After a follow-up of 7 to 45 months, the pain relief was occurred in all patients. The 1-year, 2-year accumulated survival rates were 72.2%, and 48.1%, respectively. CONCLUSIONS: Full length SMA isolation and the mesentery resection in extended pancreaticoduodenectomy are safe and effective. The procedure is also benefit for the patients in improving the survival rate and quality of life.