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1.
Adv Exp Med Biol ; 1287: 59-68, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33034026

RESUMO

Esophageal squamous cell carcinoma (ESCC) is a deadly disease that requires extensive research on its mechanisms, prevention, and therapy. Recent studies have shown that NOTCH mutations are commonly seen in human ESCC. This chapter summarizes our current understanding of the NOTCH pathway in normal esophagus and in ESCC. In normal esophagus, NOTCH pathway regulates the development of esophageal squamous epithelium, in particular, squamous differentiation. Exposure to extrinsic and intrinsic factors, such as gastroesophageal reflux, alcohol drinking, and inflammation, downregulates the NOTCH pathway and thus inhibits squamous differentiation of esophageal squamous epithelial cells. In ESCC, NOTCH plays a dual role as both a tumor suppressor pathway and an oncogenic pathway. In summary, further studies are warranted to develop NOTCH activators for the prevention of ESCC and NOTCH inhibitors for targeted therapy of a subset of ESCC with activated NOTCH pathway.

2.
Clin Lung Cancer ; 2020 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-33067127

RESUMO

BACKGROUND: There occurs huge heterogeneity in clinical outcomes for patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs). The purpose of this study was to indicate genetic biomarkers predicting primary resistance of EGFR-TKIs in these patients. PATIENTS AND METHODS: Using a next-generation sequencing panel with 168 cancer-related genes, matched tumor biopsy and plasma samples before treatments from patients with NSCLC were analyzed. Patients taking EGFR-TKIs were followed-up with imaging examination. Correlation of co-alterative genes with progression-free survival (PFS) was analyzed. RESULTS: Of the 48 patients treated with EGFR-TKIs, 46 (95.83%) had at least 1 genetic co-variant beyond EGFR mutation. Multivariate analysis indicated that RB1, PIK3CA, and ERBB2 co-alterations, rather than number of co-alterative genes, were independently associated with poorer PFS. Grouping patients by specific gene status showed best likelihood ratio χ2, Akaike information criterion, and Harrell concordance index. The median PFS for patients in group A (less genetic co-variations and wild specific genes), group B (more genetic co-variations and wild specific genes), group C (less genetic co-variations and altered specific genes), and group D (more genetic co-variations and altered specific genes) were 10.4, 9.13 (vs. group A; P = .3112), 6.33 (vs. group B; P = .0465), and 3.90 (vs. group C; P = .0309) months, respectively. CONCLUSIONS: This study revealed a high concomitant genetic alteration rate in patients with EGFR-mutated NSCLC. Specific gene variants were more important than number of altered genes in predicting poor PFS, and may help select patients needing new treatment strategies.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33047302

RESUMO

Previous designs for online calibration have only considered examinees' responses to items. However, the use of response time, a useful metric that can easily be collected by a computer, has not yet been embedded in calibration designs. In this article we utilize response time to optimize the assignment of new items online, and accordingly propose two new adaptive designs. These are the D-optimal per expectation time unit design (D-ET) and the D-optimal per time unit design (D-T). The former method uses the conditional maximum likelihood estimation (CMLE) method to estimate the expected response times, while the latter employs the nonparametric k-nearest-neighbour method to predict the response times. Simulations were conducted to compare the two new designs with the D-optimal online calibration design (D design) in the context of continuous online calibration. In addition, a preliminary study was carried out to evaluate the performance of CMLE prior to its application in D-ET. The results showed that, compared to the D design, the D-ET and D-T designs saved response time and accrued larger calibration information per time unit, without sacrificing item calibration precision.

4.
Phys Chem Chem Phys ; 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33030470

RESUMO

A systematic understanding of interactions at the nano-bio interface is critical for the development of bio-functional nanomaterials and nano-agents for medical applications, which essentially require high safety, biocompatibility and therapeutic efficiency. As a new member of the two-dimensional material family, α-phase phosphorene carbide (α-PC) has attracted significant research interest in recent years. Benefitting from the unique buckled structure and its rich physical and chemical features, the future applications of α-PC in biological and medical areas are intriguing. Using molecular dynamics simulations (MDs), herein, we theoretically explore the interactions of α-PC nanoribbons with the cell lipid membrane to evaluate the potential biological toxicity to lipids. Our results clearly demonstrate that the α-PC sheet can only penetrate the membrane along its zigzag direction by attracting the lipids to the groove regions. The membrane undergoes slight structural distortion, but quickly recovers after the penetration. Only localized impacts are detected on the membrane after the penetration. In contrast, the intrusion along armchair direction is highly blocked by lipids. Free energy analysis by the umbrella sampling method revealed that the fatty acid tails of lipids prefer to bind along the groove regions of α-PC rather than across the grooves, resulting in a high anisotropic penetration behavior. The overall attraction of α-PC to lipid is weaker than graphene, and the binding lipids cannot be fully extracted from the membrane environment. The self-equilibration of the membrane is fast enough to prevent lipids from escaping, leading to the well-preserved membrane integrity. Our present findings suggest that α-PC might offer new potential as bio-agents with high membrane-penetrating efficiency and lower cytotoxicity. The unique anisotropic behaviors can be further utilized for the design and fabrication of specialized nanomaterials with the capability of efficient and template-directed molecule delivery.

7.
Pathol Res Pract ; 216(11): 153227, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-33027752

RESUMO

Fatty acid synthase (FASN), a key enzyme essential for fatty acid (FA) synthesis, was reportedly implicated in the initiation and progression of various cancers. However, the clinical significance of FASN in renal cell carcinoma (RCC) has not been fully elucidated yet. Here we compare the expression profile and evaluate the prognostic significance of FASN in clear cell RCC (ccRCC) patients. FASN expression was examined in 3 pairs ccRCC and their adjacent nontumor tissues by western blotting (WB) analysis, and its expression was assessed in 145 ccRCC and 13 nontumor tissues by immunohistochemistry (IHC) analysis with tissue microarrays (TMAs). The prognosis of FASN was further investigated in large-scale database using LinkedOmics (n = 537) and The Cancer Protein Atlas (TCPA, n = 445), respectively. WB detected higher FASN expression in ccRCC than normal tissues, then IHC analysis revealed that FASN expression was positively associated with histological grade, pathological stage, tumor size and metastasis status, and negatively associated with cancer-specific survival (CSS). Univariate survival analysis demonstrated that high grade, advanced stage, large tumor, metastasis, and high FASN expression were significantly associated with a shorter CSS, and multivariate analysis revealed tumor grade, stage, metastasis and FASN were identified as independent predictors for CSS in patients with ccRCC. Further LinkedOmics and TCPA analyses confirmed that high FASN expression was correlated with a poorer overall survival (OS) of ccRCC. Collectively, these findings demonstrated FASN could be a poor prognostic factor in ccRCC patients, which indicated that FA synthesis might be implicated in the tumorigenesis and progression of ccRCC.

8.
Comput Biol Chem ; 89: 107385, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-33032038

RESUMO

PURPOSE: The aim of the study was to comprehensively evaluate the associations between tumor necrosis factor (TNF) gene polymorphism and influenza A (H1N1) susceptibility. METHODS: The relevant studies were identified through a search of PubMed, Embase, and Cochrane library database until February 29, 2020, without language restrictions. Two independent reviewers extracted the data, and any discrepancies were resolved by consensus. The quality of the eligible article was evaluated by Newcastle-Ottawa Quality Assessment Scale (NOS). Egger's test was applied to evaluate publication bias. All these analyses were performed using Stata15.1 software. RESULTS: A total of 5 studies with 474 cases and 805 controls were included. The results of meta-analysis showed that there were statistically significant for rs361525 in allelic model (A vs. G) [OR = 2.46 (1.10, 5.52)] and for rs1800750 in dominant model (AA + GA vs. GG) [OR = 2.42 (1.24, 4.71)] in cases vs. controls. Furthermore, subgroup analysis for race showed that for rs361525 in allelic model (A vs. G), there were significant differences for Caucasian [OR = 3.64 (1.18, 11.23)] and no significant difference for Mexican [OR = 2.25 (0.82, 6.13)] in cases vs. controls. There was publication bias for rs361525 in dominant model (AA + GA vs. GG, p = 0.042) and rs1800629 in recessive model (AA vs. GG + GA, p < 0.001). CONCLUSIONS: Caucasian with A site mutation of -238TNF G/A (rs361525) was more susceptible to influenza A (H1N1).The -376 dominant model AA + GA of TNF genes was associated with the susceptibility to influenza A (H1N1). However, more studies with large sample size are needed to confirm the results.

9.
Genome Biol ; 21(1): 258, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33023652

RESUMO

BACKGROUND: Genome structural variations (SVs) have been associated with key traits in a wide range of agronomically important species; however, SV profiles of peach and their functional impacts remain largely unexplored. RESULTS: Here, we present an integrated map of 202,273 SVs from 336 peach genomes. A substantial number of SVs have been selected during peach domestication and improvement, which together affect 2268 genes. Genome-wide association studies of 26 agronomic traits using these SVs identify a number of candidate causal variants. A 9-bp insertion in Prupe.4G186800, which encodes a NAC transcription factor, is shown to be associated with early fruit maturity, and a 487-bp deletion in the promoter of PpMYB10.1 is associated with flesh color around the stone. In addition, a 1.67 Mb inversion is highly associated with fruit shape, and a gene adjacent to the inversion breakpoint, PpOFP1, regulates flat shape formation. CONCLUSIONS: The integrated peach SV map and the identified candidate genes and variants represent valuable resources for future genomic research and breeding in peach.

10.
Biomed Res Int ; 2020: 1207809, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33029487

RESUMO

The aim of this study was to investigate the expression of the excision repair cross-complementation group 1 (ERCC1) in oral squamous cell carcinoma (OSCC) and the possible association of ERCC1 polymorphisms with susceptibility and response to chemotherapy of OSCC in a Chinese Han population. The expression of ERCC1 was determined by real-time PCR in eight patients. Four single-nucleotide polymorphisms (SNPs) rs11615, rs3212948, rs3212961, and rs735482 of ERCC1 were genotyped in 113 OSCC patients and 184 healthy controls using a PCR restriction matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) assay. We found that a higher gene expression of ERCC1 was observed in tumor tissue as compared to pericarcinomatous tissue in OSCC patients. All genotypic and allelic frequencies of the tested ERCC1 polymorphisms were in Hardy-Weinberg equilibrium. The genotypic and allelic frequencies of rs11615, rs3212948, rs3212961, and rs735482 of ERCC1 were not different between OSCC patients and controls. No correlation was observed between ERCC1 polymorphisms and the response to chemotherapy. Our results show that ERCC1 is increased in the tumor tissue of OSCC patients. The investigated ERCC1 gene polymorphisms (rs11615, rs3212948, rs3212961, and rs735482) are not associated with the susceptibility and response to chemotherapy of OSCC in our investigated Chinese Han population.

11.
Asian J Androl ; 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33037173

RESUMO

Oligoasthenoteratozoospermia (OAT) refers to the combination of various sperm abnormalities, including a decreased sperm count, reduced motility, and abnormal sperm morphology. Only a few genetic causes have been shown to be associated with OAT. Herein, we identified a novel homozygous frameshift mutation in meiosis-specific nuclear structural 1 (MNS1; NM_018365: c.603_604insG: p.Lys202Glufs*6) by whole-exome sequencing in an OAT proband from a consanguineous Chinese family. Subsequent variant screening identified four additional heterozygous MNS1 variants in 6/219 infertile individuals with oligoasthenospermia, but no MNS1 variants were observed among 223 fertile controls. Immunostaining analysis showed MNS1 to be normally located in the whole-sperm flagella, but was absent in the proband's sperm. Expression analysis by Western blot also confirmed that MNS1 was absent in the proband's sperm. Abnormal flagellum morphology and ultrastructural disturbances in outer doublet microtubules were observed in the proband's sperm. A total of three intracytoplasmic sperm injection cycles were carried out for the proband's wife, but they all failed to lead to a successful pregnancy. Overall, this is the first study to report a loss-of-function mutation in MNS1 causing OAT in a Han Chinese patient.

12.
Cell Rep ; 33(1): 108191, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33027667

RESUMO

Despite the important roles of protein kinase Cε (PKCε) and transient receptor potential vanilloind 1 (TRPV1) in inflammatory hypersensitivity, how PKCε is involved in the regulation of thermal hyperalgesia is not fully understood. We report here that PKCε is SUMOylated at a C-terminal lysine residue (K534), which enhances the sensitivity of the TRPV1 channel. We demonstrate that PKCε phosphorylation promotes its SUMOylation, which in turn regulates the phosphorylation level of TRPV1 serine 800 residue via controlling the binding of PKCε and TRPV1 and increased PKCε kinase activity. More importantly, the reduced ability of PKCε knockdown mice to develop inflammatory thermal hyperalgesia was rescued by viral infection of lumbar 4/5 dorsal root ganglia neurons of wild-type PKCε, but not the SUMOylation-deficient PKCε mutant. Therefore, the SUMOylation of PKCε potentiates inflammatory thermal hyperalgesia through stabilizing the interaction with TRPV1 to enhance its function by phosphorylation.

13.
Medicine (Baltimore) ; 99(40): e22431, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019422

RESUMO

BACKGROUND: In this analysis, we aimed to systematically compare the procedural and post-operative complications (POC) associated with laparoscopic versus open abdominal surgery for right-sided colonic cancer resection. METHODS: We searched MEDLINE, http://www.ClinicalTrials.gov, EMBASE, Web of Science, Cochrane Central, and Google scholar for English studies comparing the POC in patients who underwent laparoscopic versus open surgery (OS) for right colonic cancer. Data were assessed by the Cochrane-based RevMan 5.4 software (The Cochrane Community, London, UK). Mean difference (MD) with 95% confidence intervals (CIs) were used to represent the results for continuous variables, whereas risk ratios (RR) with 95% CIs were used for dichotomous data. RESULTS: Twenty-six studies involving a total number of 3410 participants with right colonic carcinoma were included in this analysis. One thousand five hundred and fifteen participants were assigned to undergo invasive laparoscopic surgery whereas 1895 participants were assigned to the open abdominal surgery. Our results showed that the open resection was associated with a shorter length of surgery (MD: 48.63, 95% CI: 30.15-67.12; P = .00001) whereas laparoscopic intervention was associated with a shorter hospital stay [MD (-3.09), 95% CI [-5.82 to (-0.37)]; P = .03]. In addition, POC such as anastomotic leak (RR: 0.96, 95% CI: 0.60-1.55; P = .88), abdominal abscess (RR: 1.13, 95% CI: 0.52-2.49; P = .75), pulmonary embolism (RR: 0.40, 95% CI: 0.09-1.69; P = .21) and deep vein thrombosis (RR: 0.94, 95% CI: 0.39-2.28; P = .89) were not significantly different. Paralytic ileus (RR: 0.87, 95% CI: 0.67-1.11; P = .26), intra-abdominal infection (RR: 0.82, 95% CI: 0.15-4.48; P = .82), pulmonary complications (RR: 0.83, 95% CI: 0.57-1.20; P = .32), cardiac complications (RR: 0.73, 95% CI: 0.42-1.27; P = .27) and urological complications (RR: 0.83, 95% CI: 0.52-1.33; P = .44) were also similarly manifested. Our analysis also showed 30-day re-admission and re-operation, and mortality to be similar between laparoscopic versus OS for right colonic carcinoma resection. However, surgical wound infection (RR: 0.65, 95% CI: 0.50-0.86; P = .002) was significantly higher with the OS. CONCLUSIONS: In conclusion, laparoscopic surgery was almost comparable to OS in terms of post-operative outcomes for right-sided colonic cancer resection and was not associated with higher unwanted outcomes. Therefore, laparoscopic intervention should be considered as safe as the open abdominal surgery for right-sided colonic cancer resection, with a decreased hospital stay.

14.
Blood ; 2020 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-33025009

RESUMO

Myeloid differentiation primary response protein 88 (MYD88) is a critical universal adapter that transduces signaling from the Toll-like receptors and interleukin receptors to downstream NF-kB. MYD88L265P (leucine changed to proline at position 265) is a gain-of-function mutation occurred frequently in B-cell malignancies such as Waldenstrom macroglobulinemia. Here we show that an E3 ligase RING finger protein family 138 (RNF138) catalyzed K63-linked non-proteolytic polyubiquitination of MYD88L265P, resulting in enhanced recruitment of interleukin 1 receptor-associated kinases and elevated NF-kB activation. However, RNF138 had little effect on wild-type MYD88 (MYD88WT). With either RNF138 knockdown or mutation on MYD88 ubiquitination sites, MYD88L265P was unable to constitutively activate NF-kB. A20, a negative regulator of NF-kB signaling, mediated K48-linked polyubiquitination of RNF138 for proteasomal degradation. Depletion of A20 further augmented MYD88L265P-mediated NF-kB activation and lymphoma growth. Furthermore, A20 expression was negatively correlated with RNF138 expression and NF-kB activation in lymphomas with MYD88L265P and in those without. Strikingly, RNF138 expression was positively correlated with NF-kB activation in lymphomas with MYD88L265P, but not in those without MYD88L265P. Collectively, our study reveals a novel mutation-specific biochemical reaction that drive B-cell oncogenesis, providing a therapeutic opportunity for targeting oncogenic MYD88L265P, while sparing MYD88WT that is critical to innate immunity.

15.
Surg Endosc ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33025251

RESUMO

BACKGROUND: To compare the efficacy and safety of laparoscopic common bile duct exploration plus laparoscopic cholecystectomy (LCBDE + LC) with intraoperative endoscopic retrograde cholangiopancreatography plus laparoscopic cholecystectomy (IO-ERCP + LC) for the treatment of gallbladder and common bile duct (CBD) stones. METHODS: We searched PubMed, Ovid, and Cochrane Library from their inception dates to April 2020, for studies that compared the efficacy and safety of LCBDE + LC with those of IO-ERCP + LC in patients with gallbladder and CBD stones. The technical success, morbidity, major morbidity, biliary leak, postoperative pancreatitis, conversion, retained stones, operative time, and postoperative hospital stay were compared between these two approaches. RESULTS: Five randomized controlled trials involving 860 patients were evaluated. Overall, no significant difference was found between LCBDE + LC and IO-ERCP + LC regarding technical success, morbidity, major morbidity, and the conversion rate. Biliary leak and retained stones were significantly more prevalent in the LCBDE + LC group, while postoperative pancreatitis was significantly more prevalent in the IO-ERCP + LC group. CONCLUSIONS: LCBDE + LC and IO-ERCP + LC have similar efficacy and safety in terms of technical success, morbidity, major morbidity, and conversion rate. However, LCBDE + LC is associated with a higher biliary leak rate, lower postoperative pancreatitis rate, and higher rate of retained stones.

16.
J Cell Mol Med ; 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33026174

RESUMO

Although miR-148a-3p has been reported to function as a tumour suppressor in various cancers, the molecular mechanism of miR-148a-3p in regulating epithelial-to-mesenchymal transition (EMT) and stemness properties of pancreatic cancer (PC) cells remains to be elucidated. In the present study, we demonstrated that miR-148a-3p expression was remarkably down-regulated in PC tissues and cell lines. Moreover, low expression of miR-148a-3p was associated with poorer overall survival (OS) in patients with PC. In vitro, gain-of-function and loss-of-function experiments showed that miR-148a-3p suppressed EMT and stemness properties as well as the proliferation, migration and invasion of PC cells. A dual-luciferase reporter assay demonstrated that Wnt1 was a direct target of miR-148a-3p, and its expression was inversely associated with miR-148a-3p in PC tissues. Furthermore, miR-148a-3p suppressed the Wnt/ß-catenin pathway via down-regulation of Wnt1. The effects of ectopic miR-148a-3p were rescued by Wnt1 overexpression. These biological functions of miR-148a-3p in PC were also confirmed in a nude mouse xenograft model. Taken together, these findings suggest that miR-148a-3p suppresses PC cell proliferation, invasion, EMT and stemness properties via inhibiting Wnt1-mediated Wnt/ß-catenin pathway and could be a potential prognostic biomarker as well as a therapeutic target in PC.

17.
Inorg Chem ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33002353

RESUMO

The reaction of In3+ ions with 2,5-di(2H-tetrazol-5-yl) terephthalic acid (H4dtztp) affords a 3D indium-organic framework, [In(dtztp)0.5(OH)(H2O)]·H2O (1) with a (3,6)-connected net. 1 shows good thermal (300 °C) and chemical stabilities (various organic solvents and acidic/basic solutions) and excellent water tolerance (7 days at room temperature or in boiling water). The acetylene (C2H2) sorption behavior of 1 indicates significant separation selectivity over CH4, as confirmed by breakthrough experiments on the realistic gas mixtures. Meanwhile, the MOF with the Lewis and Brønsted acidic bifunctional catalytic sites catalyzes the CO2 conversion with different epoxides with high yields. The fluorescent properties reveal the efficient probing performance of 1 for nitrofurantoin (NFT) and metronidazole (MDZ) in water with a low detection limit (ppm).

18.
Arch Biochem Biophys ; : 108611, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-33002446

RESUMO

BACKGROUND: Sepsis-induced cardiac dysfunction is one of the leading complications of sepsis, contributing to the high morbidity and mortality of septic patients. Several lines of evidence have demonstrated that autophagy and pyroptosis may be involved in septic cardiac dysfunction. In this study, we examined the impact of zinc finger antisense 1 (ZFAS1) on sepsis-induced myocardial dysfunction via regulating pyroptosis and autophagy. METHOD: Mice with cecal ligation and puncture (CLP)-induced sepsis was constructed in vivo. Myocardial injury was assessed by H&E staining, immunohistochemistry (IHC) for NLRP3, caspase 1, and interleukin (IL)-1ß, as well as ELISA assay for serum levels of creatine kinase (CK), CK-MB, tumor necrosis factor α (TNF-α), and IL-1ß. Primary cardiomyocytes exposed to lipopolysaccharide (LPS) were established to simulate sepsis-induced cardiac dysfunction in vitro. Cell viability was examined by MTT assay and concentration of TNF-α and IL-1ß was measured by ELISA. Flow cytometry, immunofluorescent staining and western blotting were performed to assess pyroptosis and autophagy. The transcriptional regulation of SP1 on ZFAS1 was determined using ChIP assay. Luciferase reporter assay was performed to verify the ZFAS1/miR-590-3p interaction. Besides, activation of AMPK/mTOR signaling was detected using western blotting. RESULTS: Highly expressed ZFAS1 was observed in sepsis-induced cardiac dysfunction in the in vivo and in vitro model. Knockdown of ZFAS1 robustly abolished LPS-induced pyroptosis and attenuated the inhibition of autophagy. SP1 was identified to be an essential transcription factor to positively regulate ZFAS1 expression. Moreover, miR-590-3p functioned as a downstream effector to reverse ZFAS1-mediated sepsis-induced cardiac dysfunction. AMPK/mTOR signaling was involved in miR-590-3p-regulated autophagy and pyroptosis of cardiomyocytes. Furthermore, the regulatory network of ZFAS1/miR-590-3p on AMPK/mTOR signaling was verified in vivo. CONCLUSION: ZFAS1, activated by SP1, aggravates the progression of sepsis-induced cardiac dysfunction via targeting miR-590-3p/AMPK/mTOR signaling-mediated autophagy and pyroptosis of cardiomyocytes.

19.
Theranostics ; 10(25): 11820-11836, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33052248

RESUMO

Background: E-cigarette and other novel electronic nicotine delivery systems (ENDS) have recently entered the market at a rapid pace. The community desperately needs answers about the health effects of ENDS. The present study tested the hypothesis that perinatal nicotine exposure (PNE) causes a gender-dependent increase in vulnerability of the heart to ischemia-reperfusion (I/R) injury and cardiac dysfunction in male rat offspring via reprogramming of the miRNA-181a (miR-181a)-mediated signaling pathway and that miR-181a antisense could rescue this phenotype. Methods: Nicotine or saline was administered to pregnant rats via subcutaneous osmotic minipumps from gestational day 4 until postnatal day 10. Cardiac function and molecular biological experiments were conducted in ~3- month-old offspring. Results: PNE enhanced I/R-induced cardiac dysfunction and infarction in adult male but not in female offspring, which was associated with miR-181a over-expression in left ventricle tissues. In addition, PNE enhanced offspring cardiac angiotensin receptor (ATR) expressions via specific CpG hypomethylation of AT1R/AT2R promoter. Furthermore, PNE attenuated cardiac lncRNA H19 levels, but up-regulated cardiac TGF-ß/Smads family proteins and consequently up-regulated autophagy-related protein (Atg-5, beclin-1, LC3 II, p62) expression in the male offspring. Of importance, treatment with miR-181a antisense eliminated the PNE's effect on miR-181a expression/H19 levels and reversed PNE-mediated I/R-induced cardiac infarction and dysfunction in male offspring. Furthermore, miR-181a antisense also attenuated the effect of PNE on AT1R/AT2R/TGF-ß/Smads/autophagy-related biomarkers in the male offspring. Conclusion: Our data suggest that PNE could induce a reprogramming of cardiac miR-181a expression/DNA methylation pattern, which epigenetically modulates ATR/TGF-ß/autophagy signaling pathways, leading to gender-dependent development of ischemia-sensitive phenotype in postnatal life. Furthermore, miR-181a could severe as a potential therapeutic target for rescuing this phenotype.

20.
Life Sci ; 260: 118418, 2020 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-32931799

RESUMO

AIMS: Stroke is a devastating event with a limited choice of intervention. Benzoinum is frequently used to treat stroke in traditional Chinese medicine. Our team has found that the neuroprotection of benzoinum may related to angiogenesis, but the exact biological mechanism is unclear. The objective of this study was to explore its biological mechanism of angiogenesis in cerebral ischemia model rats. MAIN METHODS: First, network pharmacology and molecular docking were performed to predict the possible targets and mechanisms of benzoinum in treating ischemic stroke. The best dose was then selected according to pharmacodynamic indexes such as those for neurological deficit, cerebral infarction rate, and brain histopathology in middle cerebral artery occlusion (MCAO) model rats. Finally, RT-PCR, Western Blot and immunohistochemical analysis were applied to verify the prediction results from molecular docking. KEY FINDINGS: Network pharmacology and molecular docking demonstrated that the targets of treating cerebral ischemia were PDE4D, ACE and TTR, and the mechanism may be related to the ACE-AngI-VEGF signaling pathway. Experimental verification results suggested that 0.50 g/kg and 1.00 g/kg benzoinum could significantly protect against neurological deficit and reduce cerebral infarction rate in the cerebral cortex and hippocampus in MCAO model rats. At an optimal dose, benzoinum could significantly up-regulate VEGF, SHH and ANG-1, yet down-regulate ACE expression in MCAO model rats. SIGNIFICANCE: Balsamic acid is the active ingredient of benzoinum that protects against ischemic stroke and the possible mechanism is related to the promotion of angiogenesis via regulating ACE-AngI-VEGF pathway.

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