Construction and validation of a m6A RNA methylation and ferroptosis-related prognostic model for pancreatic cancer by integrated bioinformatics analysis.

Background: Both N6-methyladenosine (m6A) ribonucleic acid (RNA) methylation and ferroptosis regulators are demonstrated to have significant effects on the malignant clinicopathological characteristics of pancreatic adenocarcinoma (PAAD) patients. However, the currently available clinical indexes are not sufficient to predict precise prognostic outcomes pf PAAD patients accurately. This study aims to examine the clinicopathologic features of m6A RNA methylation and ferroptosis regulators in predicting the outcomes of different types of cancer. Methods: As the foundation for this research, the differentially expressed genes (DEGs) between PAAD tissues and adjacent normal tissues were first identified. Next, dimensional reduction analysis (DCA) based on m6A RNA methylation regulators and ferroptosis regulators were performed and DEGs between good/poor prognosis PAAD patient clusters were identified. DEGs were then screened by Cox analysis, and finally a risk signature was established by least absolute shrinkage and selection operator (LASSO) analyses. The prediction model based on risk score was further evaluated by a validation set from Gene Expression Omnibus (GEO) database. Results: In total, 4 m6A RNA methylation regulator genes and 29 ferroptosis regulator genes were found to have close causal relationships with the prognosis of PAAD, and a risk score with 3 m6A methylation regulators (i.e., IGF2BP2, IGF2BP3, and METTL16) and 4 ferroptosis regulators (i.e., ENPP2, ATP6V1G2, ITGB4, and PROM2) was constructed and showed to be highly involved in PAAD progression and could serve as effective markers for prognosis with AUC value equaled 0.753 in training set and 0.803 in validation set. Conclusions: The combined prediction model, composed of seven regulators of m6A methylation and ferroptosis, in this study more effectively reflects the progression and prognosis of PAAD than previous single genome or epigenetic analysis. Our study provides a broader perspective for the subsequent establishment of prognostic models and the patients may benefit from more precision management.

Key Enzymes for the Mevalonate Pathway in the Cardiovascular System.

ABSTRACT: Isoprenylation is an important post-transcriptional modification of small GTPases required for their activation and function. Isoprenoids, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate, are indispensable for isoprenylation by serving as donors of a prenyl moiety to small G proteins. In the human body, isoprenoids are mainly generated by the mevalonate pathway (also known as the cholesterol-synthesis pathway). The hydroxymethylglutaryl coenzyme A reductase catalyzes the first rate-limiting steps of the mevalonate pathway, and its inhibitor (statins) are widely used as lipid-lowering agents. In addition, the FPP synthase is also of critical importance for the regulation of the isoprenoids production, for which the inhibitor is mainly used in the treatment of osteoporosis. Synthetic FPP can be further used to generate geranylgeranyl pyrophosphate and cholesterol. Recent studies suggest a role for isoprenoids in the genesis and development of cardiovascular disorders, such as pathological cardiac hypertrophy, fibrosis, endothelial dysfunction, and fibrotic responses of smooth-muscle cells. Furthermore, statins and FPP synthase inhibitors have also been applied for the management of heart failure and other cardiovascular diseases rather than their clinical use for hyperlipidemia or bone diseases. In this review, we focus on the function of several critical enzymes, including hydroxymethylglutaryl coenzyme A reductase, FPP synthase, farnesyltransferase, and geranylgeranyltransferase in the mevalonate pathway which are involved in regulating the generation of isoprenoids and isoprenylation of small GTPases, and their pathophysiological role in the cardiovascular system. Moreover, we summarize recent research into applications of statins and the FPP synthase inhibitors to treat cardiovascular diseases, rather than for their traditional indications respectively.

Heterotopic pancreas adenocarcinoma in the stomach: A case report and literature review.

BACKGROUND: Heterotopic pancreas is a common lesion found in the gastrointestinal tract and is usually considered a benign disease. Reports of malignant change of heterotopic pancreas are scarce. CASE SUMMARY: A 44-year-old Chinese female underwent a gastroscopy to assess abdominal distension that had persisted for 2 months. A protruding lesion in the gastric antrum was revealed but no malignant tissue was found in the biopsy specimen. The patient's symptom persisted and progressed to repeated vomiting. Endoscopy after 4 months revealed obstruction of the gastric outlet caused by the protruding lesion. A distal gastrectomy was performed. Histopathological examination of the surgical specimen showed the malignant transformation of aberrant pancreas in the stomach. Chemotherapy consisting of folinic acid, fluorouracil, and oxaliplatin was administered for three cycles, and was changed to gemcitabine monotherapy because of adverse effects and increased serum tumor marker levels. The patient remained asymptomatic during a 12-month follow-up. CONCLUSION: Pancreatic heterotopy should be considered as source of a potentially malignant lesion, and early treatment or close monitoring for aberrant pancreas is recommended.

[Efficacy of acupuncture-moxibustion on peripheral facial paralysis at different time points: a Meta-analysis].

OBJECTIVE: To systematically evaluate the efficacy and safety differences between acupuncture-moxibustion at acute stage and non-acute stage for peripheral facial paralysis. METHODS: The clinical trials regarding acupuncture- moxibustion for peripheral facial paralysis published before May 31st 2019 were searched in databases of CNKI, WF, VIP, SinoMed, PubMed, Cochrane Library and Google Scholar. The information of included studies was extracted and the quality was assessed by two independent researchers. The Meta-analysis was performed by using RevMan 5.3 software. RESULTS: A total of 11 trials were included, involving 1741 patients. The Meta-analysis results showed that: (1) the curative rate of acupuncture-moxibustion at acute stage was higher than that at non-acute stage (OR=2.45, 95%CI: 1.91-3.14, Z=7.06, P<0.01); (2) the average curative time of acupuncture-moxibustion at acute stage were shorter than that of non-acute stage (WMD=5.26, 95%CI: 3.44, 7.08, Z=5.67, P<0.01); (3) the incidence rate of sequelae in 6-month follow up of acupuncture-moxibustion at acute stage were lower than that of non-acute stage (OR=2.71, 95%CI: 1.26, 5.84, Z=2.56, P<0.05); (4) one study reported that there were no adverse reactions during treatment in both treatment group and control group. CONCLUSION: Based on current evidence, the efficacy of acupuncture-moxibustion at acute stage is superior to non-acute stage, which could promote the recovery of the disease and shorten the course of treatment, and reduce the occurrence of sequelae. More high-quality, large-sample randomized controlled trials are needed for further verification.

ß2-AR regulates the expression of AKR1B1 in human pancreatic cancer cells and promotes their proliferation via the ERK1/2 pathway.

Psychological stress has been recognized as a well-documented risk factor associated with ß2-adrenergic receptor (ß2-AR) in the development of pancreatic cancer. Aldo-keto reductase 1 member B1 (AKR1B1) is a potential interacting partner of ß2-AR, but the effect of their interaction on pancreatic cancer cells is not known at present. We found a positive correlation between AKR1B1 and ß2-AR expression in pancreatic cancer tissue samples, and co-localization of these proteins in the human pancreatic cancer BXPC-3 cell line. Compared to the controls, the CFPAC-1 and PANC-1 pancreatic cancer cells overexpressing ß2-AR and AKR1B1 respectively showed significantly higher proliferation rates, which is attributed to higher proportion of cells in the S phase and decreased percentage of early apoptotic cells. Furthermore, overexpression of ß2-AR led to a significant increase in the expression of AKR1B1 and phosphorylated extracellular signal-regulated kinase (p-ERK1/2). Overexpression of AKR1B1 significantly decreased ß2-AR levels and increased that of p-ERK1/2. Taken together, ß2-AR directly interacted with and up-regulated AKR1B1 in pancreatic cancer cells, and promoted their proliferation and inhibited apoptosis via the ERK1/2 pathway. Our findings also highlight the ß2-AR-AKR1B1 axis as a potential therapeutic target for pancreatic cancer.

[J774A.1 cell apoptosis induced by Leptospira interrogans and effects of caspase-3, -6 activation on apoptosis].

OBJECTIVE: To investigate the apoptosis of J774A.1 cells induced by Leptospira interrogans and the effect of caspase-3, -6 activation on the apoptosis. METHODS: Mouse monocyte-macrophage like cell line J774A.1 was infected by L.interrogans serogroup Icterohaemorrhagiae serovar icterohaemorrhagiae Lai strain 56601. The apoptosis or necrosis of infected cells was examined by flow cytometry using fluorescein labeling FITC-Annexin V/PI. The activity of caspase-3, -6, and their cleaved substrates PARP and Lamin A/C were measured by fluorometry and Western Blotting, respectively. RESULT: L. interrogans strain Lai was able to induce apoptosis of J774A.1 cells and the maximal apoptotic rate was(48.81+/-5.95)% when microbe: cell ratio was 100: 1. The maximal activities of caspase-3 and -6 in the infected J774A.1 cells were (1453.41+/-36.07) and (618.65+/-39.82) FU, respectively, which were 16.38- and 9.98-fold of those uninfected cells. PARP and Lamin A/C in the infected cells were detected. Caspase-3 and -6 inhibitors remarkably blocked the L. interrogans-induced apoptosis in J774A.1 cells. CONCLUSION: L. interrogans is able to induce the apoptosis of J774A.1 cells and intracellular caspase-3 and -6 are closely associated with the apoptosis.

[Inhibitory effects of emodin on proliferation of rat vascular smooth muscle cell induced by angiotensin II].

OBJECTIVE: To investigate the effects of emodin on the proliferation of cultured rat vascular smooth muscle cell (VSMC) induced by angiotensin II. METHOD: VSMCs were cultured by explant method. Cell proliferation model was established by stimulation with Ang II. Cell proliferation was measured by MTT assay to observe the effects of emodin (10, 20, 40 and 80 micromol x L(-1)) and N(G)-nitro-L-arginine methyl ester (L-NAME, 100 micromol x L(-1)) on VSMC proliferation induced by Ang II. The expression of PCNA was measured by immunohistochemical staining. Nitric oxide (NO) level was measured by Griess reagent. Nitric oxide synthase (NOS) and inducible nitric oxide synthase (iNOS) levels were detected by chemical colorimetric method. mRNA expression of iNOS was measured by reverse transcription polymerase chain reaction (RT-PCR). RESULT: Emodin at the doses range from 10 to 80 mol x L(-1) inhibited cell proliferation in a dose and time-dependent manner. The inhibitory effects were partly blocked by 100 mol x L(-1) of L-NAME. Emodin markedly decreased the expression of PCNA in VSMC, increased NO, NOS and iNOS levels, and increased iNOS mRNA expression in VSMC. CONCLUSION: Emodin could inhibite VSMCs proliferation induced by Ang II. Inhibiting the expression of PCNA, increasing the NO secretion and upregulating the iNOS gene expression might be associated with the inhibitory effects.