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1.
Acta Pharmacol Sin ; 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824460

RESUMO

White matter injury is the major pathological alteration of subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion. It is characterized by progressive demyelination, apoptosis of oligodendrocytes and microglial activation, which leads to impairment of cognitive function. Triptolide exhibits a variety of pharmacological activities including anti-inflammation, immunosuppression and antitumor, etc. In this study, we investigated the effects of triptolide on white matter injury and cognitive impairments in mice with chronic cerebral hypoperfusion induced by the right unilateral common carotid artery occlusion (rUCCAO). We showed that triptolide administration alleviated the demyelination, axonal injury, and oligodendrocyte loss in the mice. Triptolide also improved cognitive function in novel object recognition test and Morris water maze test. In primary oligodendrocytes following oxygen-glucose deprivation (OGD), application of triptolide (0.001-0.1 nM) exerted concentration-dependent protection. We revealed that the protective effect of triptolide resulted from its inhibition of oligodendrocyte apoptosis via increasing the phosphorylation of the Src/Akt/GSK3ß pathway. Moreover, triptolide suppressed microglial activation and proinflammatory cytokines expression after chronic cerebral hypoperfusion in mice and in BV2 microglial cells following OGD, which also contributing to its alleviation of white matter injury. Importantly, mice received triptolide at the dose of 20 µg·kg-1·d-1 did not show hepatotoxicity and nephrotoxicity even after chronic treatment. Thus, our results highlight that triptolide alleviates whiter matter injury induced by chronic cerebral hypoperfusion through direct protection against oligodendrocyte apoptosis and indirect protection by inhibition of microglial inflammation. Triptolide may have novel indication in clinic such as the treatment of chronic cerebral hypoperfusion-induced SIVD.

2.
Clin Interv Aging ; 16: 583-591, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33854308

RESUMO

Background: Prognostic evaluation of elderly patients with hip fracture is an issue that has been highly concerned by clinicians. Only a few studies have focused on organ dysfunction after hip fracture in the elderly. This study aimed to investigate the association between high-sensitivity troponin T (hs-TnT) at admission and organ dysfunction during hospitalization in elderly patients with hip fracture. Methods: We enrolled 168 patients with hip fracture who were aged 80 years and older at Geriatric Orthopaedic Center of Sichuan Provincial Orthopedic Hospital between January 2020 and August 2020. Baseline characteristics, perioperative information, and short-term clinical outcomes were analyzed. Results: Of the 208 patients admitted during the study period, 168 met the inclusion criteria; of these, 91 (54.2%) had higher hs-TnT than the 99th percentile in the normal population. After adjustment for confounders, elevated hs-TnT was independently associated with multiple organ dysfunction syndrome in the elderly (MODSE) (adjusted OR, 5.76; 95% CI, 1.74-19.10; P = 0.004), heart dysfunction (adjusted OR, 7.48; 95% CI, 2.17-25.82; P = 0.001), MODS severity score > 3 (adjusted OR, 5.22; 95% CI, 1.32-20.60; P = 0.018), and length of hospital stay > 14 days (adjusted OR, 2.38; 95% CI, 1.05-5.36; P = 0.037). Conclusion: Increased hs-TnT on admission is an independent risk factor for MODSE after hip fracture in patients aged 80 years and older. Effective measures should be applied to avoid progression of MODSE from pre-failure stage to failure stage.

3.
Int J Cancer ; 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33844851

RESUMO

Previous studies have suggested that gut microbiota plays a critical role in colorectal cancer (CRC). Although preliminary comparisons of the oral and gut microbiota between CRC and healthy control (HC) patients have been made, the association between microbiome abundance and host clinical factors has not been fully illustrated, especially oral health conditions. Matching samples of unstimulated saliva, cancer tissues or biopsies and stools were collected from 30 CRC and 30 HC patients from Shanghai Jiao Tong University affiliated Renji Hospital for 16S rRNA sequencing analysis. The diversity in salivary and mucosal microbiome, but not stool microbiome of CRC group, was significantly different from that of HC, as demonstrated by the Principal Component Analysis. Logistic regression analysis revealed that older age and higher oral hygiene index (OHI) were independent risk factors for CRC, with odds ratios and 95% confidence intervals of 1.159 (1.045-1.284) and 4.398 (1.328-14.567), respectively. Salivary Firmicutes to Bacteroides ratio in CRC was significantly higher than that in the HC group (P < 0.001), while the mucosal ratio was slightly decreased in CRC (P < 0.05). Salivary Rothia and Streptococcus levels were positively correlated with OHI, while Alloprevotella, Fusobacterium, Peptostreptoccus and Prevotella genera levels were negatively associated with OHI. NetShift analysis revealed that salivary Peptococcus, Centipeda and mucosal Subdoligranulum genus might act as key drivers during the process of carcinogenesis. In conclusion, the current study provides insights into the potential influence of host clinical factors on oral and gut microbiome composition and can be a guide for future studies.

4.
Mol Nutr Food Res ; : e2000845, 2021 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-33715285

RESUMO

SCOPE: Human milk can prevent the development of necrotizing enterocolitis (NEC). Human milk is rich in cargo-carrying exosomes that participate in intercellular communication. This study investigated the effects of term and preterm human milk-derived exosomes, and elucidated their lipid expression profiles. METHODS AND RESULTS: We collected milk from healthy mothers who had delivered full-term or preterm infants, and exosomes were isolated and quantified. Administration of term and preterm milk exosomes significantly enhanced epithelial proliferation and migration in vitro, and ameliorated the severity of NEC in vivo. A total of 395 lipids were identified in term and preterm human milk-derived exosomes. Bioinformatics analysis and western blotting revealed that top 50 lipids regulated intestinal epithelial cell function via the ERK/MAPK pathway. CONCLUSION: This study reveals for the first time the lipidomic complexities in exosomes derived from preterm and term milk. Our results provide novel mechanistic insight on how human milk prevents the development of NEC. This article is protected by copyright. All rights reserved.

5.
Huan Jing Ke Xue ; 42(3): 1354-1360, 2021 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-33742932

RESUMO

Phenol is widely used in the production of insulation and thermal insulation materials, adhesives, perfumes, coatings for food containers, paints, and pharmaceutical production, and is also widely detected in the aquatic environment. Long-term exposure to phenol can elicit adverse effects, such as skin burn, liver and central system damage. Here, phenol concentrations in the water and aquatic products of Poyang Lake were investigated. Human health risks from phenol to adults and adolescents were also assessed based on local population exposure parameters. The exposure concentration range of phenol in the studied water and aquatic products was not detected (ND)-556.26 ng·L-1 and 11.98-255.51 µg·kg-1, respectively. Human health risk based on drinking water in different areas ranged from 3.80×10-7-8.46×10-5. Higher human health risks from drinking water was detected in the southern area of Poyang Lake and at the confluence of the Yangtze River to the north. Health risks caused by different types of aquatic products ranges 2.65×10-5-1.47×10-4. In particular, human health risks from the consumption of yellow catfish and catfish are an order of magnitude higher than for other aquatic products. Probabilistic risk assessment was also conducted through Monte Carlo simulation to analyze the health risk to the population in the Poyang Lake Basin and assess its sensitivity of different exposure parameters. The 95th percentile health risk of drinking water and aquatic product consumption in the Poyang Lake Basin was calculated as being acceptable. Overall, the concentrations of phenol had the greatest impact on the calculated health risk values. This study provides valuable information for phenol risk management in the Poyang Lake basin.


Assuntos
Lagos , Fenol , Adolescente , China , Monitoramento Ambiental , Humanos , Lagos/análise , Medição de Risco , Rios , Água
6.
BMC Infect Dis ; 21(1): 302, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33765943

RESUMO

BACKGROUND: To explore population aging and the epidemic trend of pulmonary tuberculosis (PTB) in the elderly, and provide a basis for the prevention and control of pulmonary tuberculosis among the elderly. METHODS: We collected clinical information of 239,707 newly active PTB patients in Shandong Province from 2005 to 2017. We analyzed and compared the clinical characteristics, reported incidence and temporal trend of PTB among the elderly group (≥60 years) and the non-elderly group (< 60 years) through logistic model and Join-point regression model. RESULTS: Among the total PTB cases, 77,192(32.2%) were elderly. Compared with non-elderly patients, newly active elderly PTB patients account for a greater proportion of male cases (OR 1.688, 95% CI 1.656-1.722), rural population cases (OR 3.411, 95% CI 3.320-3.505) and bacteriologically confirmed PTB cases (OR 1.213, 95%CI 1.193-1.234). The annual reported incidence of total, elderly, pulmonary bacteriologically confirmed cases were 35.21, 68.84, 35.63 (per 100,000), respectively. The annual reported incidence of PTB in the whole population, the elderly group and the non-elderly group has shown a slow downward trend since 2008. The joinpoint regression model showed that the overall reported incidence of PTB in the elderly significantly decreased from 2007 to 2017 (APC = -5.3, P < 0.05). The reported incidence of bacteriologically confirmed PTB among elderly patients declined rapidly from 2005 to 2014(2005-2010 APC = -7.2%, P < 0.05; 2010-2014 APC = -22.6%, P < 0.05; 2014-2017 APC = -9.0%, P = 0.1). The reported incidence of clinically diagnosed PTB among elderly patients from 2005 to 2017 (11.48-38.42/100,000) increased by about 235%. It rose significantly from 2007 to 2014 (APC = 9.4, P<0.05). CONCLUSIONS: Compared with the non-elderly population, the reported incidence of PTB in the elderly population is higher. The main burden of PTB will shift to the elderly, men, rural population, and clinically diagnosed patients. With the intensification of aging, more researches on elderly PTB prevention and treatment will facilitate the realization of the global tuberculosis (TB) control targets.


Assuntos
Envelhecimento , Tuberculose Pulmonar/epidemiologia , Idoso , China/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , População Rural , Tuberculose Pulmonar/diagnóstico , População Urbana
7.
Nanoscale Horiz ; 6(4): 348-356, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33687417

RESUMO

Non-apoptotic cell death such as ferroptosis and pyroptosis has shed new light on cancer treatment, whereas combinational therapy using both these mechanisms has not yet been fully explored. Herein, a dual-inductive nano-system to realize ferroptosis/pyroptosis mediated anti-cancer effects is presented. The nanodrug (Tf-LipoMof@PL) is constructed with a piperlongumine (PL) loaded metal-organic framework (MOF) coated with transferrin decorated pH sensitive lipid layer. Intracellular iron was enriched with an iron-containing MOF, whose endocytosis can be further facilitated by transferrin decorated on the lipid layer, which provides a prerequisite for the occurrence of ferroptosis and pyroptosis. Piperlongumine as the ferroptosis inducer can strengthen the ferroptotic cell death, and provide H2O2 for the dual induction system to increase ROS generation through Fenton reaction. On the basis of validation of both ferroptosis and pyroptosis, the dual-inductive nanodrug demonstrated ideal anticancer effects in the xenograft mice model, which proved that the ferroptosis/pyroptosis dual-inductive nanoplatform could be an effective and promising anticancer modality.

9.
Artigo em Inglês | MEDLINE | ID: mdl-33599865

RESUMO

PURPOSE: Breast cancer is more likely attributed to a combination of genetic variations and lifestyle factors. Both one-carbon metabolism and diet-related factors could interfere with the carcinogenesis of breast cancer (BC), but whether diet consumed underlie a specific metabolism pathway could influence the impact of genetic variants on breast cancer risk remains equivocal. METHODS: A case-control study of the Chinese female population (818 cases, 935 controls). 13 SNPs in eight one-carbon metabolism-related genes (MTHFD1, TYMS, MTRR, MAT2B, CDO1, FOLR1, UNG2, ADA) were performed. Diet was assessed by a validated food-frequency questionnaire. We examined the associations of the adherence to the Mediterranean dietary pattern (MDP) and single-nucleotide polymorphisms (SNPs) of one-carbon metabolism with breast cancer risk. We constructed an aggregate polygenic risk score (PRS) to test the additive effects of genetic variants and analyzed the gene-diet interactions. RESULTS: High adherence (highest quartile) to the MDP decreased the risk of breast cancer among post- but not premenopausal women, respectively (OR = 0.54, 95% CI = 0.38 to 0.78 and 0.90, 0.53 to 1.53). Neither of the polymorphisms or haplotypes was associated with breast cancer risk, irrespective of menopause. However, a high PRS (highest quartile) was associated with more than a doubling risk in both post- and premenopausal women, respectively (OR = 1.95, 95% CI = 1.32 to 2.87 and 2.09, 1.54 to 2.85). We found a gene-diet interaction with adherence to the MDP for aggregate PRS (P-interaction = 0.000) among postmenopausal women. When adherence to the MDP was low (< median), carries with high PRS (highest quartile) had higher BC risk (OR = 2.80, 95% CI = 1.55 to 5.07) than low PRS (lowest quartile), while adherence to the MDP was high (≥ median), the association disappeared (OR = 1.57, 95% CI = 0.92 to 2.66). CONCLUSION: High adherence to the MDP may counteract the genetic predisposition associated with one-carbon metabolism on breast cancer risk in postmenopausal women.

10.
Histol Histopathol ; : 18316, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33604882

RESUMO

Fullerenes, as hydrophobic molecules, are limited in biomedical function due to their very low solubility. But taking C60 (OH) x as an example, the properties of fullerenols were analyzed. It was found that fullerenols had good stability, water solubility, good biocompatibility and low cytotoxicity by adding a hydroxyl group to carbon atoms. In the biomedical field, it has been found that fullerene C60 can be used as a powerful free radical scavenger, with antioxidant activity, with antibacterial and inhibitory effects on cancer cells. Fullerenols inherit the good properties of fullerenes, and are better used in cancer treatment, including loading drug therapy and directly as an anticancer drug. In addition, fullerenols are also used in the repair of myocardial injury, the treatment of myocardial infarction and neuroprotection. With the development of tissue engineering technology, the preparation of nerve scaffolds which can improve ischemia, hypoxia and oxidative stress after nerve injury has become a research hotspot. The electron absorption and reduction characteristics of fullerenols in biomedical research bring new ideas for the treatment of oxidative stress in the repair of peripheral nerve defects. It seems that the research on fullerenols loaded neural scaffold has great prospects.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33515089

RESUMO

Current approaches to screening for ADHD result in high rates of false positives. A proof of concept study to investigate the added benefits in the school-based detection of ADHD of adding a standardised teacher to teacher interview to traditional parent and teacher report questionnaires. A school-based study of diagnostic accuracy of ADHD using a novel 2-stage screening process. Participants were all 1026 pupils enrolled in grades 1 to 6 (ages 6-12 years) of a school in Hunan Province, China. The primary outcome was a diagnosis of ADHD on the Kiddie Schedule for Affective Disorders and Schizophrenia Present Lifetime version. 230 (22.4%) of the 1026 students screened positive at Stage 1 (parent and teacher questionnaires) (Sensitivity 0.86 [95% CI, 0.75 to 0.96], specificity 0.80 [95% CI, 0.78-0.83], false positive rate 0.20 (95% CI, 0.18 to 0.23), false negative rate was 0.14 (95% CI, 0.12 to 0.16). 65 remained screen-positive at the Stage 2 screen (teacher to teacher SNAP-IV interview). 36/65 (55.4%) of these Stage 2 screen positive participants and 1/144 (0.7%) of the screen negative subjects met DSM-IV criteria for ADHD (sensitivity 0.83 [95% CI, 0.71-0.95]; specificity of 0.97 [95% CI, 0.96-0.98]; false positive rate 0.03 [95% CI, 0.01 to 0.04], false negative rate 0.16 [95% CI, 0.15 to 0.19]. Adding teacher to teacher interviews to traditional questionnaire-based screening has the potential to improve the clinical utility of school-based screening for ADHD reducing the proportion of false positives, without a negative impact on sensitivity.

12.
World J Surg Oncol ; 19(1): 25, 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33485347

RESUMO

BACKGROUND: An emerging prediction tool, the Controlling Nutritional Status (CONUT) score, has shown good assessment ability of postoperative outcomes in cancer patients. This study evaluated the role of the preoperative CONUT score regarding the short-term outcomes of gastric cancer (GC) after laparoscopic gastrectomy. METHODS: Three hundred and nine GC patients undergoing laparoscopic gastrectomy from January 2016 to June 2019 were analysed, retrospectively. The patients were divided into two groups according to the CONUT optimal cut-off value. Clinical characteristics and postoperative complications in the two groups were analysed and evaluated. Risk factors for complications were identified by univariate and multivariate analyses. RESULTS: A total of 309 patients underwent laparoscopic gastrectomy; 91 (29.4%) patients experienced postoperative complications. The preoperative CONUT score showed a good predictive ability for postoperative complications (area under the curve (AUC) = 0.718, Youden index = 0.343) compared with other indices, with an optimal cut-off value of 2.5. Patients with high CONUT score had a significantly higher incidence of overall complications (P < 0.001). Age, haemoglobin, C-reactive protein, red blood cell levels, CONUT scores, surgical procedure type, T1, T4, N0 and N3 pathological TNM classification, and pathological stages of I and III were associated with postoperative complications (P < 0.05). Furthermore, the preoperative CONUT score was identified as an independent risk predictor of postoperative complications (P = 0.012; OR = 2.433; 95% CI, 1.218-4.862) after multivariate analysis. CONCLUSIONS: The preoperative CONUT score is a practical nutritional assessment for predicting short-term outcomes in GC patients after laparoscopy-assisted gastrectomy.

13.
Gut ; 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441378

RESUMO

OBJECTIVE: As a canonical membrane tethering factor, the function of synbindin has been expanding and indicated in immune response. Here, we investigated the role of synbindin in the regulation of toll-like receptor 4 (TLR4) signalling and macrophage response to microbiota during colitis. DESIGN: Three distinct mouse models allowing global, myeloid-specific or intestinal epithelial cell-specific synbindin heterozygous deletion were constructed and applied to reveal the function of synbindin during dextran sodium sulfate (DSS) colitis. Effects of synbindin on TLR4 signalling and macrophage activation in response to bacterial lipopolysaccharide (LPS) or Fusobacterium nucleatum were evaluated. The colocalisation and interaction between synbindin and Rab7b were determined by immunofluorescence and coimmunoprecipitation. Synbindin expression in circulating monocytes and intestinal mucosal macrophages of patients with active IBD was detected. RESULTS: Global synbindin haploinsufficiency greatly exacerbated DSS-induced intestinal inflammation. The increased susceptibility to DSS was abolished by gut microbiota depletion, while phenocopied by specific synbindin heterozygous deletion in myeloid cells rather than intestinal epithelial cells. Profoundly aberrant proinflammatory gene signatures and excessive TLR4 signalling were observed in macrophages with synbindin interference in response to bacterial LPS or Fusobacterium nucleatum. Synbindin was significantly increased in intestinal mucosal macrophages and circulating monocytes from both mice with DSS colitis and patients with active IBD. Interleukin 23 and granulocyte-macrophage colony-stimulating factor were identified to induce synbindin expression. Mechanistic characterisation indicated that synbindin colocalised and directly interacted with Rab7b, which coordinated the endosomal degradation pathway of TLR4 for signalling termination. CONCLUSION: Synbindin was a key regulator of TLR4 signalling and restrained the proinflammatory macrophage activation against microbiota during colitis.

14.
J Ovarian Res ; 14(1): 3, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33402208

RESUMO

BACKGROUND: Ovarian responsiveness to controlled ovarian stimulation is essential for a successful clinical outcome in assisted reproductive technology (ART) cycles. We aimed to find a suitable new ovulation stimulation protocol for poor ovarian response (POR) patients over 40 years old. METHODS: A retrospective analysis of 488 ART cycles was evaluated from January 2015 to June 2019. Comparisons were made between the flexible short protocol (FSP), routine short protocol and mild stimulation protocol. RESULTS: Compared with the routine short protocol, the FSP delayed the gonadotropin start time and reduced the total gonadotropin dose per stimulation cycle. At the same time, compared with the mild stimulation protocol, the FSP improved oocyte quality and embryo quality and improved embryo implantation potential after transfer. Furthermore, the use of the FSP reduced the probability of premature ovulation, as it inhibited the premature luteinizing hormone (LH) surge to a certain extent. CONCLUSIONS: The FSP yielded better outcomes than other protocols for patients with POR over 40 years old in our study. However, further prospective studies are needed to provide more substantial evidence and to determine whether the FSP can be successful for both patients over 40 years group and younger POR patients.

15.
Food Chem ; 338: 127928, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32919374

RESUMO

We investigated the inhibitory effect and binding mechanism of four selected compounds (ascorbic acid, l-cysteine, glutathione, and citric acid) on membrane-bound polyphenol oxidases (mPPO) using spectroscopic and molecular docking techniques. Kinetic analysis demonstrated that these inhibitors reversibly inhibited the mPPO activity. Fluorescence spectroscopy revealed that the intrinsic fluorescence intensity of mPPO was quenched by inhibitors with a single class of the inhibition site on mPPO. Amino acid residues His 180, His 201, His 366, Cys 184, Glu 328, and Asn 333 were the important binding sites in the active center. These sites were identified using molecular docking techniques. Our findings suggested that the inhibitors were allosterically bound to the active center of mPPO through hydrogen bonds and ion contacts. This study provides new insights into the active site residues responsible for catalyzing mPPO and provides applicable information about the design of mPPO inhibitors.


Assuntos
Catecol Oxidase/metabolismo , Malus/enzimologia , Simulação de Acoplamento Molecular , Proteínas de Plantas/metabolismo , Regulação Alostérica , Ácido Ascórbico/química , Ácido Ascórbico/metabolismo , Sítios de Ligação , Catecol Oxidase/antagonistas & inibidores , Cisteína/química , Cisteína/metabolismo , Glutationa/química , Glutationa/metabolismo , Cinética , Proteínas de Plantas/antagonistas & inibidores , Espectrometria de Fluorescência
16.
Public Health Nutr ; : 1-24, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33256868

RESUMO

OBJECTIVE: To determine if specific dietary patterns are associated with breast cancer risk in Chinese women. DESIGN: Latent class analysis (LCA) was performed to identify generic dietary patterns based on daily food-frequency data. SETTING: The Chinese Wuxi Exposure and Breast Cancer Study (2013-2014). PARTICIPANTS: A population-based case-control study (695 cases, 804 controls). RESULTS: Four dietary patterns were identified, Prudent, Chinese traditional, Western, and Picky, the proportion in the controls and cases were 0.30/0.32/0.16/0.23 and 0.29/0.26/0.11/0.33, respectively. Women in Picky class were characterized by higher extreme probabilities of non-consumption on specific foods, the highest probabilities of consumption of pickled foods, and the lowest probabilities of consumption of cereals, soy foods, and nuts. Compared with Prudent class, Picky class was associated with a higher risk (OR=1.42, 95%CI=1.06, 1.90), while the relevant association was only in post- (OR=1.44, 95%CI=1.01, 2.05) but not premenopausal women. The Western class characterized by high-protein, -fat, and -sugar foods, the Chinese traditional class characterized by typical consumption of soy foods and white meat over red meat, both of them showed no difference in BC risk compared with Prudent class did. CONCLUSIONS: LCA capture the heterogeneity of individuals embedded in the population, could be a useful approach in the study of dietary pattern and disease. Our results indicated that the Picky class might have a positive association with the risk of breast cancer.

17.
Gut ; 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33318144

RESUMO

OBJECTIVE: Microbiota disorder promotes chronic inflammation and carcinogenesis. High glycolysis is associated with poor prognosis in patients with colorectal cancer (CRC). However, the potential correlation between the gut microbiota and glucose metabolism is unknown in CRC. DESIGN: 18F-FDG (18F-fluorodeoxyglucose) PET (positron emission tomography)/CT image scanning data and microbiota PCR analysis were performed to measure the correlation between metabolic alterations and microbiota disorder in 33 patients with CRC. Multiple colorectal cancer models, metabolic analysis and Seahorse assay were established to assess the role of long non-coding RNA (lncRNA) enolase1-intronic transcript 1 (ENO1-IT1) in Fusobacterium (F.) nucleatum-induced glucose metabolism and colorectal carcinogenesis. RNA immunoprecipitation and chromatin immunoprecipitation sequencing were conducted to identify potential targets of lncRNA ENO1-IT1. RESULTS: We have found F. nucleatum abundance correlated with high glucose metabolism in patients with CRC. Furthermore, F. nucleatum supported carcinogenesis via increasing CRC cell glucose metabolism. Mechanistically, F. nucleatum activated lncRNA ENO1-IT1 transcription via upregulating the binding efficiency of transcription factor SP1 to the promoter region of lncRNA ENO1-IT1. Elevated ENO1-IT behaved as a guider modular for KAT7 histone acetyltransferase, specifying the histone modification pattern on its target genes, including ENO1, and consequently altering CRC biological function. CONCLUSION: F. nucleatum and glucose metabolism are mechanistically, biologically and clinically connected to CRC. Targeting ENO1 pathway may be meaningful in treating patients with CRC with elevated F. nucleatum.

18.
Sci Rep ; 10(1): 21969, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33319811

RESUMO

Obese individuals are more susceptible to comorbidities than individuals of healthy weight, including cardiovascular disease and metabolic disorders. MicroRNAs are a class of small and noncoding RNAs that are implicated in the regulation of chronic human diseases. We previously reported that miR-125b plays a critical role in adipogenesis in vitro. However, the involvement of miR-125b-2 in fat metabolism in vivo remains unknown. In the present study, miR-125b-2 knockout mice were generated using CRISPR/CAS9 technology, resulting in mice with a 7 bp deletion in the seed sequence of miR-125b-2. MiR-125b-2 knockout increased the weight of liver tissue, epididymal white fat and inguinal white fat. MiR-125b-2 knockout also increased adipocyte volume in HFD-induced obese mice, while there were no significant differences in body weight and feed intake versus mice fed a normal diet. Additionally, qRT-PCR and western blot analysis revealed that the expression of the miR-125b-2 target gene SCD-1 and fat synthesis-associated genes, such as PPARγ and C/EBPα, were significantly up-regulated in miR-125b-2KO mice (P < 0.05). Moreover, miR-125b-2KO altered HFD-induced changes in glucose tolerance and insulin resistance. In conclusion, we show that miR-125b-2 is a novel potential target for regulating fat accumulation, and also a candidate target to develop novel treatment strategies for obesity and diabetes.

19.
World J Gastrointest Oncol ; 12(11): 1216-1236, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33250957

RESUMO

BACKGROUND: Programmed death ligand 1 (PD-L1) immunotherapy remains poorly efficacious in colorectal cancer (CRC). The recepteur d'origine nantais (RON) receptor tyrosine kinase plays an important role in regulating tumor immunity. AIM: To identify the patterns of RON and PD-L1 expression and explore their clinical significance in CRC. METHODS: Gene expression data from the Gene Expression Omnibus database (GEO; n = 290) and patients at the First Affiliated Hospital, Zhejiang University School of Medicine (FAHZUSM; n = 381) were analyzed to determine the prognostic value of RON and PD-L1 expression within the tumor microenvironment of CRC. HT29 cell line was treated with BMS-777607 to explore the relationship between RON activity and PD-L1 expression. Signaling pathways and protein expression perturbed by RON inhibition were evaluated by cellular immunofluorescence and Western blot. RESULTS: In the GEO patient cohort, cut-off values for RON and PD-L1 expression were determined to be 7.70 and 4.3, respectively. Stratification of patients based on these cutoffs demonstrated that high expression of RON and PD-L1 was associated with a poor prognosis. In the FAHZUSM cohort, rates of high expression of RON in tumor cells, high PD-L1 expression in tumor cells and tumor infiltrating monocytes, and both high RON and high PD-L1 expression in the tumor microenvironment were 121 (32%), 43 (11%), 91 (24%), and 51 (13.4%), respectively. High expression of RON was significantly correlated with high expression of PD-L1 in the tumor cell compartment (P < 0.001). High expression of RON and that of PD-L1 were independent prognostic factors for poorer overall survival. Concurrent high expression of both RON and PD-L1 in the tumor microenvironment was significantly associated with a poor prognosis. In vitro, BMS-777607 inhibited the phosphorylation of RON, inhibited PD-L1 expression, and attenuated activation of the ERK1/2 and AKT signaling pathways in CRC cells. CONCLUSION: RON, PD-L1, and their crosstalk are significant in predicting the prognostic value of CRC. Moreover, phosphorylation of RON upregulates PD-L1 expression, which provides a novel approach to immunotherapy in CRC.

20.
Biomed Pharmacother ; 133: 110937, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33217689

RESUMO

BACKGROUND: Compound sophorae decoction (CSD), a Chinese Herbal decoction, is frequently clinically prescribed for patients suffered from ulcerative colitis (UC) characterized by bloody diarrhea. Yet, the underlying mechanism about how this formulae works is remain elusive. METHODS: In the present study, the experimental colitis in C57BL/6 J mice was induced by oral administration of standard diets containing 3% dextran sodium sulfate (DSS), and CSD was given orally for treatment at the same time. The clinical symptoms including stool and body weight were recorded each day, and colon length and its histopathological changes were observed. Apoptosis of colonic epithelium was studied by detecting protein expression of cleaved caspase-3, and cell proliferation by Ki-67 immunohistochemistry. Tight junction complex like ZO-1 and occludin were also determined by transmission electron microscope and immunofluorescence. The concentration of FITC-dextran 4000 was measured to evaluate intestinal barrier permeability and possible signaling pathway was investigated. Mucin2 (MUC2) and notch pathway were tested through western blot. The M1/M2 ratio in spleen and mesenteric lymph nodes were detected by flow cytometry. And the mRNA levels of iNOS and Arg1 were examined by qRT-PCR. RESULTS: CSD could significantly alleviate the clinical manifestations and pathological damage. Body weight loss and DAI score of mice with colitis were improved and shortening of colon was inhibited. The administration of CSD was able to reduce apoptotic epithelial cells and facilitate epithelial cell regeneration. Increased intestinal permeability was reduced in DSS-induced colitis mice. In addition, CSD treatment obviously up-regulated the expression of ZO-1 and occludin and the secretion of MUC2, regulated notch signaling, and decreased the ratio of M1/M2. CONCLUSIONS: These data together suggest that CSD can effectively mitigate intestinal inflammation, promote phenotypic change in macrophage phenotype and enhance colonic mucosal barrier function by, at least in part, regulating notch signaling in mice affected by DSS-induced colitis.

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