Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.466
Filtrar
1.
Int Immunopharmacol ; 100: 108117, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34509933

RESUMO

FPS-ZM1 is an inhibitor of the receptor for advanced glycation end products (RAGE). Nevertheless, there are few reports about its direct effects on microglial inflammation, and the underlying molecular mechanisms remain to be clarified. The present study investigated the potential effects of FPS-ZM1 on lipopolysaccharide (LPS)-mediated microglial inflammation both in vivo and in vitro, and further elucidated the possible molecular mechanisms of action. FPS-ZM1 decreased LPS-induced overproduction of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and cyclooxygenase 2 (COX-2), in both BV-2 cells and primary microglial cells. FPS-ZM1 (10 mg/kg, i.p.) ameliorated proliferation and activation of microglia in the hippocampus of C57BL/6J mice subjected to LPS challenge (5 mg/kg, i.p.). Meanwhile, overproduction of pro-inflammatory cytokines IL-1ß and TNF-α in the hippocampus was alleviated after treatment with FPS-ZM1. RNA-Sequencing (RNA-Seq) analysis showed involvement of Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling pathway in the regulation of FPS-ZM1 on LPS-induced microglial inflammation. Further investigations demonstrated that FPS-ZM1 downregulated LPS-mediated increases in the phosphorylation levels of JAK/STAT both in vivo and in vitro. FPS-ZM1 also suppressed the nuclear translocation of transcription factor STAT1/3/5 in BV-2 cells. In addition, inhibition of JAK/STAT signaling pathway had an anti-inflammatory effect similar to FPS-ZM1 treatment. Taken together, our results verified the inhibitory effects of FPS-ZM1 against LPS-stimulated microglial inflammation, and for the first time demonstrated such anti-inflammatory activities on microglia are associated with regulation of JAK/STAT signaling pathway both in vivo and in vitro, which may shed new light on the pharmacological mechanisms of FPS-ZM1 against microglial inflammation.

2.
BMJ Open ; 11(9): e045165, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493501

RESUMO

OBJECTIVES: The aim was to elucidate the relationship between liver function and idiopathic pulmonary arterial hypertension (IPAH). DESIGN AND SETTING: Retrospective, longitudinal study in urban tertiary care centre in Shanghai, China. PARTICIPANTS: 407 IPAH consecutive incident patients age 18-65 years were retrospectively enrolled from January 2008 to December 2018. OUTCOME MEASUREMENTS: The primary endpoint was all-cause mortality. The cut-off value was determined by receiver operating characteristic curve (ROC), which was validated by Cox proportional hazard model was internally validated by bootstrap analysis and used for survival analysis. The Cox model was (internally) validated and cross-validated areas under the curve (AUC) should be reported. RESULTS: The prevalence of abnormal liver function tests (LFTs) at baseline was 77.6%. Hyperbilirubinaemia is the most common abnormal biochemical liver test: abnormal total bilirubin (TBIL in 51.6% patients). During the follow-up, 160 patients died. Patients with mixed liver dysfunction have worse prognosis than those with normal LFTs or isolated abnormal bilirubin metabolism. Comparing with patients with hepatocellular injury, the survival of patients with abnormal bilirubin metabolism is lower. Multivariable Cox models revealed a positive association between TBIL, γ-glutamyltransferase (GGT) and mortality showing that each Ig increment in TBIL and GGT was associated with a higher all-cause mortality (TBIL: HR 4. 29 (95% CI 1. 21 to 15. 27), p=0. 02; GGT: HR 2. 76 (95% CI 1. 18 to 6. 45), p=0. 02). A novel formula named Liver Function Predict Index (LFPI) was constructed (LFPI=-0.002*6MWD+1.014*lg GGT+1.458*lg TBIL) to predict prognosis. ROC curve analysis did further identify 2.729 as the best cut-off value for LFPI (AUC 0.75, p<0.001, sensitivity 79%, specificity 70%). CONCLUSIONS: Liver dysfunction is frequent in IPAH, and characterised by a predominantly cholestatic enzyme profile. LFTs abnormalities are associated with worse survival and LFPI was a new and simple predictor for prognosis of IPAH.

3.
BMC Cardiovasc Disord ; 21(1): 425, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34496747

RESUMO

BACKGROUND: Accelerated idioventricular rhythm (AIVR) is often transient, considered benign and requires no treatment. This observational study aims to investigate the clinical manifestations, treatment, and prognosis of frequent AIVR. METHODS: Twenty-seven patients (20 male; mean age 32.2 ± 17.0 years) diagnosed with frequent AIVR were enrolled in our study. Inclusion criteria were as follows: (1) at least three recordings of AIVR on 24-h Holter monitoring with an interval of over one month between each recording; and (2) resting ectopic ventricular rate between 50 to 110 bpm on ECG. Electrophysiological study (EPS) and catheter ablation were performed in patients with distinct indications. RESULTS: All 27 patients experienced palpitation or chest discomfort, and two had syncope or presyncope on exertion. Impaired left ventricular ejection fraction (LVEF) was identified in 5 patients, and LVEF was negatively correlated with AIVR burden (P < 0.001). AIVR burden of over 73.8%/day could predict impaired LVEF with a sensitivity of 100% and specificity of 94.1%. Seventeen patients received EPS and ablation, five of whom had decreased LVEF. During a median follow-up of 60 (32, 84) months, LVEF of patients with impaired LV function returned to normal levels 6 months post-discharge, except one with dilated cardiomyopathy (DCM). Two patients died during follow-up. The DCM patient died due to late stage of heart failure, and another patient who refused ablation died of AIVR over-acceleration under fever. CONCLUSIONS: Frequent AIVR has unique clinical manifestations. AIVR patients with burden of over 70%, impaired LVEF, and/or symptoms of syncope or presyncope due to over-response to sympathetic tone should be considered for catheter ablation.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34508625

RESUMO

The fusion gene of ABL1 is closely related to tumor proliferation, invasion, and migration. It has been reported recently that ABL1 itself is required for T-cell acute lymphoblastic leukemia (T-ALL) cell migration induced by CXCL12. Further experiments revealed that ABL1 inhibitor Nilotinib inhibited leukemia cell migration induced by CXCL12, indicating the possible application of Nilotinib in T-ALL leukemia treatment. However, the interacting proteins of ABL1 and the specific mechanisms of their involvement in this process need further investigation. In the present study, ABL1 interacting proteins were characterized and their roles in the process of leukemia cell migration induced by CXCL12 were investigated. Co-immunoprecipitation in combination with mass spectrometry analysis identified 333 proteins that interact with ABL1, including Cofilin1. Gene ontology analysis revealed that many of them were enriched in the intracellular organelle or cytoplasm, including nucleic acid binding components, transfectors, or co-transfectors. Kyoto Encyclopedia of Genes and Genomes analysis showed that the top three enriched pathways were translation, glycan biosynthesis, and metabolism, together with human diseases. ABL1 and Cofilin1 were in the same complex. Cofilin1 binds the SH3 domain of ABL1 directly; however, ABL1 is not required for the phosphorylation of Cofilin1. Molecular docking analysis shows that ABL1 interacts with Cofilin1 mainly through hydrogen bonds and ionic interaction between amino acid residues. The mobility of leukemic cells was significantly decreased by Cofilin1 siRNA. These results demonstrate that Cofilin1 is a novel ABL1 binding partner. Furthermore, Cofilin1 participates in the migration of leukemia cells induced by CXCL12. These data indicate that ABL1 and Cofilin1 are possible targets for T-ALL treatment.

5.
Eur Heart J ; 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34506618

RESUMO

AIMS : This study aimed to assess the clinical characteristics and long-term survival outcome in patients with Takayasu's arteritis-associated pulmonary hypertension (TA-PH). METHODS AND RESULTS: We conducted a nationally representative cohort study of TA-PH using data from the National Rare Diseases Registry System of China. Patients with pulmonary artery involvement who fulfilled the diagnostic criteria of Takayasu's arteritis and pulmonary hypertension were included. The primary outcome was the time from diagnosis of TA-PH to the occurrence of all-cause death. Between January 2007 and January 2019, a total of 140 patients were included, with a mean age of 41.4 years at diagnosis, and a female predominance (81%). Patients with TA-PH had severely haemodynamic and functional impairments at diagnosis. Significant improvements have been found in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and haemodynamic profiles in patients with TA-PH receiving drugs approved for pulmonary arterial hypertension. The overall 1-, 3-, and 5-year survival rates in TA-PH were 94.0%, 83.2%, and 77.2%, respectively. Predictors associated with an increased risk of all-cause death were syncope [adjusted hazard ratio (HR) 5.38 (95% confidence interval 1.77-16.34), P = 0.003], NT-proBNP level [adjusted HR 1.04 (1.03-1.06), P < 0.001], and mean right atrial pressure [adjusted HR 1.07 (1.01-1.13), P = 0.015]. CONCLUSION : Patients with TA-PH were predominantly female and had severely compromised haemodynamics. More than 80% of patients in our cohort survived for at least 3 years. Medical treatment was based on investigators' personal opinions, and no clear risk-to-benefit ratio can be derived from the presented data.

7.
Membranes (Basel) ; 11(8)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34436375

RESUMO

The thorny issue of membrane biofouling in membrane bioreactors (MBR) calls for new effective control measures. Herein, D-amino acid (DAA) was employed to mediate MBR membrane biofouling by inhibiting biofilm information and disintegrating formed biofilm. Different DAA control ways involving membrane property, DAA-adding timing, and DAA-control mode were explored through experiments and the multiple linear regression model and the response surface methodology. The optimized DAA control ways were acquired, involving DAA used as an active agent, and the DAA-adding timing of 4 h cultured before running, as well as both hydrophilic and hydrophobic membrane, resulting in an approximately 40.24% decrease in the membrane biofouling rate in comparison with the conventional MBR. DAA is an efficient membrane biofouling mediating approach for MBR under optimized control ways combination and a facile solution for solving membrane biofouling in actual membrane systems.

8.
Exp Cell Res ; 406(2): 112752, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34332983

RESUMO

It has been reported that ACBD3 is closely related to the malignant process of cells, but its role in gastric cancer has not been elucidated. This study aims to investigate the expression and function of ACBD3 in human gastric cancer. The Cancer Genome Atlas (TCGA) database were selected to analyze mRNA levels of ACBD3 in gastric cancer tissues and normal gastric epithelial tissues. qPCR and Western blot were conducted to detect the expression of ACBD3 in two normal gastric epithelial cell lines and five gastric cancer cell lines which were cultured in our laboratory. To exclude differences in individual background between different patients, we further detected the expression of ACBD3 in 8 pairs of malignant/non-malignant clinical gastric tissues. Through the establishment of stable cells, in vitro cell experiments and in vivo xenotransplantation models in mice, the role of ACBD3 in the proliferation of gastric cancer cells has been further explored. AKT inhibitors were used to deeply explore the molecular regulation mechanism of ACBD3. The results showed that the elevated ACBD3 in gastric cancer tissue were positively correlated with the clinical grade and prognosis of gastric cancer. In terms of molecular function, we found that ACBD3 can enhance the production and growth of gastric cancer cells. At the same time, the activation of AKT kinase played an important role in ACBD3's promotion of G1-to-S transition. The experiments generally indicate that ACBD3 is expected to become a potential diagnostic molecule or therapeutic target for gastric cancer.

9.
Int Immunopharmacol ; 99: 107988, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34333356

RESUMO

BACKGROUND: Hypoxia, a common feature of rheumatoid arthritis (RA), induces the over-expression of peptidyl arginine deiminase 4 (PADI4) in fibroblast-like synoviocytes (FLSs) and macrophages. However, the roles of PADI4 and its inducer hypoxia in the regulation of macrophage polarization remain unclear. This study aimed to investigate the role of hypoxia-PADI4 for macrophage polarization in RA patients. METHODS: Synovial tissue (ST) and synovial fluid (SF) were collected from 3 OA patients and 6 RA patients. The distribution of M1 and M2 in ST and cytokines in SF were examined by immunohistochemical analysis and Bio-Plex immunoassays. THP-1 macrophages and BMDM polarization were determined under normoxic (21% oxygen) or hypoxic (3% oxygen) conditions. The effects of PADI4 on macrophages were determined by transfection of adenovirus vector-coated PADI4 (AdPADI4) and the use of PADI4 inhibitor. Finally, the roles of PADI4 in joint synovial lesions on macrophage polarization were investigated in collagen-induced arthritis (CIA) rats. RESULTS: We found increased macrophage polarization of M1 and M2 in the RA ST, compared with OA ST. The ratio of M1/M2 for RA and OA was 1.633 ± 0.1443 and 2.544 ± 0.4429, respectively. The concentration of M1- and M2-type cytokines was higher in RA than that in OA patients. Hypoxia contributed to the increase of the gene and protein expression of M1 and M2 markers. M1- but not M2-type gene expression showed a positive relationship with PADI4 expressionwhile the level of expression of M2-type genes showed no significant difference. The degree of joint swelling and destruction was effectively alleviated, and the number of macrophages especially M1 decreased in CIA rats after down-regulating PADI4 expression. CONCLUSION: Hypoxia is responsible for the co-polarization of M1 and M2. Hypoxia-associated PADI4 is responsible for M1 macrophage activation, implying that the inflammatory environment can be eased by decreasing PADI4 expression and improving the hypoxic environment.

10.
J Ethnopharmacol ; 281: 114558, 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34438030

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Astragali, the dried root of Astragalus mongholicus Bunge, has long been used in traditional Chinese Medicine to treat diabetes. Astragaloside IV (AS-IV), one of the most active ingredients in the root, has been shown to have anti-diabetes ability; however, its underlying mechanism is still unclear. MATERIALS AND METHODS: In this study, we evaluated the hypoglycemic effect and possible mechanisms of AS-IV in diabetic mice and insulin resistance-HepG2 cells. The components of the intestinal microflora in mice with type 2 diabetes mellitus (T2DM) were determined using high-throughput 16S rRNA gene sequencing. Moreover, the molecular mechanisms of specific members of insulin signaling pathways were analyzed. RESULTS: AS-IV significantly reversed the abnormalities in blood lipids, glucose, insulin resistance, as well as oxidative stress levels in T2DM mice. Histological finding showed that AS-IV could protect the cellular architecture of the liver and pancreas. AS-IV also regulated the abundance and diversity of intestinal flora of T2DM mice in a positive direction and increased butyric acid levels. The active role of AS-IV as an anti-diabetic compound by regulating the AMPK/SIRT1 and PI3K/AKT signaling pathways was revealed using a T2DM model and verified through the intervention of inhibitors using insulin-resistance HepG2 cells. CONCLUSION: Our results suggested that AS-IV may be used as an anti-diabetic drug candidate owing to its effects of regulating gut microbiota and AMPK/SIRT1 and PI3K/AKT signaling pathways.

11.
J Ultrasound Med ; 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34415647

RESUMO

OBJECTIVES: To assess the diagnostic value of echogenic foci in papillary thyroid carcinoma (PTC) and the relationship between echogenic foci and aggressiveness of PTC. METHODS: From January 2018 to January 2021, a total of 950 patients diagnosed with thyroid nodules (n = 1113) in our hospital were retrospectively analyzed. Among the 1113 nodules, single PTC in 527 patients confirmed by surgery was studied for their aggressive biological behavior. The patterns of echogenic foci were classified as: no echogenic foci, sparse punctate echogenic foci, focal punctate echogenic foci, diffuse punctate echogenic foci, petal-like punctate echogenic foci, comet-tail artifacts, coarse echogenic foci, peripheral rim (eggshell echogenic foci), and mixed echogenic foci. The clinical and ultrasonographic characteristics were also analyzed. A univariate analysis was performed, and binary logistic regression was performed to screen independent risk factors. RESULTS: For the differential diagnosis of PTC, age < 50 years, size <1.1 cm, hypoechoic or very hypoechoic, aspect ratio > 1, irregular shape, types II (punctate echogenic foci) and VI (mixed echogenic foci) were independent risk factors. For the aggressive biological behavior of PTC, male sex, age<42 years, size <1.0 cm, types IIb (focal punctate echogenic foci), IIc (diffuse punctate echogenic foci), and VI (mixed echogenic foci) were independent risk factors for predicting cervical lymph node metastasis of PTC. CONCLUSION: Echogenic foci are useful in diagnosing PTC and predicting aggressiveness of PTC, which contribute to screening invasive PTC and avoiding overdiagnosis and overtreatment.

12.
Endokrynol Pol ; 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34378788

RESUMO

OBJECTIVE: To evaluate the effect of selenium supplementation on autoantibody titers, thyroid ultrasonography and thyroid function in patients with Hashimoto's thyroiditis (autoimmune thyroiditis) and normal thyroid reference range. METHODS: A total of 100 patients were given 200 ug/d selenium yeast orally, their thyroid function, levels of serum selenium, thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TGAb) and urine iodine were measured and thyroid ultrasonography was performed before administration and three and six months afterwards, and the data were statistically analysed. RESULTS: The subjects exhibited a selenium deficiency before the administration of selenium, and the serum levels increased to moderate levels three and six months after the selenium supplementation (p<0.05). The titers of TGAb decreased significantly in patients after six months of Selenium lack prevention measure(p<0.05). In the high antibody group, TgAb decreased after 6 months compared with baseline (P<0.05), and TPOAb decreased after 3 and 6 months of selenium supplementation compared with baseline (P<0.05). CONCLUSION: In patients with autoimmune thyroiditis and normal thyroid reference range, there was a general selenium deficiency but, after six months of treatment, it was shown that the Selenium lack prevention measure may be effective in reducing the titers of TGAb and TPOAb.

13.
Biochem Genet ; 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34453220

RESUMO

Stroke is a cerebrovascular disease with impaired nerve function. Long non-coding RNA (lncRNA) is considered to be an important regulator of various diseases. Nevertheless, the role of lncRNA small nucleolar RNA host gene 15 (SNHG15) in cerebral ischemia injury induced by stroke is still unclear. Cell-counting kit 8 assay and flow cytometry were used to detect cell viability and apoptosis, respectively. The caspase3 activity of cells was measured using Caspase3 Activity Assay Kit. Besides, the protein levels of apoptosis markers and TCCD-induced poly (ADP)-ribose polymerase (TIPARP) were determined using western blot analysis. Moreover, quantitative real-time polymerase chain reaction was employed to examine the relative expression of SNHG15 and miR-9-5p. Furthermore, dual-luciferase reporter assay was used to assess the interaction between miR-9-5p and SNHG15 or TIPARP. In addition, biotin-labeled RNA pull-down assay was performed to evaluate the interaction between miR-9-5p and SNHG15 further. Middle cerebral artery occlusion (MCAO) model was constructed to further explore the role of SNHG15 in neuronal injury in vivo. Our data showed that oxygen and glucose deprivation (OGD) could induce N-2a cell injury and enhance SNHG15 expression. Silenced SNHG15 could promote the viability and suppress the apoptosis of OGD-induced N-2a cells. Also, SNHG15 knockdown also could alleviate the neuronal injury of MCAO mice. Mechanistically, SNHG15 could sponge miR-9-5p, and miR-9-5p could target TIPARP. Further experiments revealed that miR-9-5p inhibition or TIPARP overexpression could reverse the suppressive effect of SNHG15 knockdown on OGD-induced N-2a cell injury. Our findings indicated that SNHG15 knockdown inhibited neuronal injury through the miR-9-5p/TIPARP axis, suggesting that SNHG15 might be a potential target for cerebral ischemia injury induced by stroke.

14.
Ann Palliat Med ; 10(7): 8134-8146, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34353098

RESUMO

BACKGROUND: Patients with chronic thromboembolic pulmonary hypertension (CTEPH) still have impaired exercise training and quality of life (QoL) despite pulmonary arterial hypertension (PAH)-targeted drugs. Exercise training is considered to improve exercise capacity and QoL in patients with pulmonary hypertension (PH), but this has not been fully studied in CTEPH patients. We conducted the meta-analysis and systematic review to evaluate the effectiveness and safety of exercise training in patients with CTEPH. METHODS: The relevant literature was retrieved for the meta-analysis using the PubMed, EMBASE, and Cochrane Library databases published before December 2020. The primary outcome was a change in six-minute walk distance (6MWD). We also assessed the effect of exercise training on peak oxygen uptake per kilogram (peak VO2/kg), mean pulmonary artery pressure (mPAP) assessed by right heart catheterization (RHC), N-terminal pro-brain-type natriuretic peptide (NT-proBNP), and QoL. RESULTS: A total of 6 studies with 234 exercise training patients were included. In the pooled analysis, 6MWD significantly improved by 70.14 m (WMD: 58.33 to 81.95, I2=0) after 3-week exercise training. After 12 or 15-week exercise training, 6MWD and peak VO2/kg significantly improved (WMD: 106.22 m, 95% CI: 65.90 to 146.55, I2=87.4%, P<0.0001; 1.84 mL/min/kg, 95% CI: 0.72 to 2.96, P=0.001, respectively). Furthermore, the mPAP decreased by 12.17 mmHg after 12-week exercise training (95% CI: -14.53 to -9.82, P<0.001, I2=99%). The subscales of QoL such as physical function, general health perception, and mental health improved in varying degrees. NT-proBNP did not improve significantly in the pooled analysis. In addition, exercise training was well tolerated without major adverse events occurred during training, and the dropout rate was low. DISCUSSION: Exercise training may improve exercise capacity, mPAP, and QoL, and was well tolerated among patients with CTEPH. However, more large-scale multicenter studies are needed to confirm the effectiveness and safety of exercise training in patients with CTEPH.


Assuntos
Hipertensão Pulmonar , Embolia Pulmonar , Doença Crônica , Exercício Físico , Tolerância ao Exercício , Humanos , Hipertensão Pulmonar/terapia , Qualidade de Vida
15.
J Transl Med ; 19(1): 295, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238315

RESUMO

BACKGROUND: Metastasis and invasion are crucial in determining the mortality of cervical carcinoma (CC) patients. The epithelial-mesenchymal transition (EMT) is now a universal explanation for the mechanisms of tumor metastasis. Α-chimeric protein (α-chimaerin, CHN1) plays an important role in the regulation of signal transduction and development. However, the molecular regulatory relationships between CHN1 and CC progression in relation to EMT have not yet been identified. METHODS: The expression of CHN1 in CC tissues, adjacent tissues, and lymph node metastases from CC patients was detected by immunohistochemistry. Upregulation and knockdown of CHN1 were achieved by transfection of CC cells. The effect of CHN1 on cell proliferation was determined by CCK-8 and plate clone formation assays. Changes in migration and invasion capabilities were evaluated using scratch migration and transwell invasion assays. The effect of CHN1 overexpression and interference on xenograft tumor growth was determined by tumor weight and pathological analyses. The expression of EMT-related mRNAs was measured by qRT-PCR in transfected CC cells. EMT-related proteins and Akt/GSK-3ß/Snail signaling pathway-related proteins were also evaluated by western blotting. RESULTS: CHN1 was overexpressed in CC tissues and was associated with lymph node metastasis and low survival in CC patients. Overexpression of CHN1 promoted cell proliferation, migration, and invasion in CC cells. In contrast, silencing of CHN1 inhibited these phenomena. Overexpression of CHN1 promoted tumor formation in an in vivo xenograft tumor mouse model, with increased tumor volumes and weights. In addition, CHN1 induced the expression of EMT-related transcription factors, accompanied by the decreased expression of epithelial markers and increased expression of mesenchymal markers. The Akt/GSK-3ß/Snail signaling pathway was activated by overexpression of CHN1 in vitro, and activation of this pathway was inhibited by the signaling pathway inhibitor LY294002. CONCLUSION: These results suggest that CHN1 promotes the development and progression of cervical carcinoma via the Akt/GSK-3ß/Snail pathway by inducing EMT.


Assuntos
Carcinoma , Transição Epitelial-Mesenquimal , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Quimerina 1 , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo
16.
Mol Cancer Ther ; 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34315767

RESUMO

Dilpacimab (formerly ABT-165), a novel dual-variable domain immunoglobulin, targets both delta-like ligand 4 (DLL4) and VEGF pathways. Here, we present safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy data from a phase I study (trial registration ID: NCT01946074) of dilpacimab in patients with advanced solid tumors. Eligible patients (≥18 years) received dilpacimab intravenously on days 1 and 15 in 28-day cycles at escalating dose levels (range, 1.25-7.5 mg/kg) until progressive disease or unacceptable toxicity. As of August 2018, 55 patients with solid tumors were enrolled in the dilpacimab monotherapy dose-escalation and dose-expansion cohorts. The most common treatment-related adverse events (TRAE) included hypertension (60.0%), headache (30.9%), and fatigue (21.8%). A TRAE of special interest was gastrointestinal perforation, occurring in 2 patients (3.6%; 1 with ovarian and 1 with prostate cancer) and resulting in 1 death. The PK of dilpacimab showed a half-life ranging from 4.9 to 9.5 days, and biomarker analysis demonstrated that the drug bound to both VEGF and DLL4 targets. The recommended phase II dose for dilpacimab monotherapy was established as 3.75 mg/kg, primarily on the basis of tolerability through multiple cycles. A partial response was achieved in 10.9% of patients (including 4 of 16 patients with ovarian cancer). The remaining patients had either stable disease (52.7%), progressive disease (23.6%), or were deemed unevaluable (12.7%). These results demonstrate that dilpacimab monotherapy has an acceptable safety profile, with clinical activity observed in patients with advanced solid tumors.

17.
ACS Appl Mater Interfaces ; 13(29): 34428-34437, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34278774

RESUMO

Two novel Ag(I) complexes containing synergistic pyridine and amidoxime ligands (Ag-DPAAO and Ag-PAAO) were first designed as complex monomers. Taking advantage of the molecular imprinting technique and solvothermal method, molecular imprinted porous cross-linked polymers (MIPCPs) were developed as a robust platform for the first time to incorporate Ag-PAAO into a polymer material as a recyclable catalyst. Advantageously, the observed pseudo first-order rate constant (kobs) of MIPCP-Ag-PAAO-20% for ethyl-parathion (EP) hydrolysis is about 1.2 × 104-fold higher than that of self-hydrolysis (30 °C, pH = 9). Furthermore, the reaction mechanism of the MIPCP-containing Ag-PAAO-catalyzed organothiophosphate was analyzed in detail using density functional theory and experimental spectra, indicating that the amidoxime can display dual roles for both the key coordination with the silver ion and nucleophilic attack to weaken the P-OAr bond in the catalytic active site.

19.
Environ Pollut ; 288: 117718, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34274650

RESUMO

The spread of antibiotic resistance genes (ARGs) is a global environmental issue. Dissolved biochar is more likely to contact bacteria in water, producing ecological risks. This study explored the effects of dissolved biochar on ARGs transfer in bacteria. Conjugative transfer efficiency was significantly different following treatment with different types of dissolved biochar. Typically, humic acid-like substance in dissolved biochar can significantly improve the transfer efficiency of ARGs between bacteria. When the concentration of dissolved biochar was ≤10 mg biochar/mL, humic acid-like substance substantially promoted ARGs transfer. An increase in dissolved biochar concentration weakened the ARGs transfer from humic acid-like substance. The inhibitory effects of small-molecule matters dominated, decreasing conjugative transfer frequency. At a concentration of 100 mg biochar/mL, the conjugative transfer efficiency of all treatments was lower than that of control. Compared with corn straw dissolved biochar, there were more transconjugants in pine sawdust dissolved biochar. Following treatment with 10 mg biochar/mL pine sawdust dissolved biochar, the number of transconjugants was at its maximum; approximately 7.3 folds higher than the control. We also explored mechanisms by which dissolved biochar impacts conjugative transfer. Due to the complex composition of dissolved biochar, its effects on the expression of conjugative transfer-related genes were also dynamic. This study investigates the ecological risk of biochar and guides its scientific application.

20.
Invest New Drugs ; 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34287773

RESUMO

Paraneoplastic neurologic syndromes(PNSs) caused by immune checkpoint inhibitors(ICIs) is rare and requires clinicians to differentiate between disease progression and immune-related adverse effects(irAEs). We hereby report the case of immune-related myelitis accompanied by positive paraneoplastic autoantibodies following durvalumab treatment for extensive-stage small cell lung cancer (ES-SCLC). A 70-year-old Chinese woman with ES-SCLC was administered durvalumab with etoposid-platinum(EP) as first-line treatment. Four cycles after treatment with EP plus ICI, she developed immune-related myelitis with positive paraneoplastic autoantibodies (CV2, SOX1, ZIC4). Spinal MRI showed diffuse abnormal signal shadow in the cervicothoracic spinal cord. She was discontinued for chemotherapy, and treated with high-dose steroids, intravenous immunoglobulin and plasmapheresis, maintenance therapy with steroids resulted in a favorable neurologic outcome. This is the first report of durvalumab-related PNSs. We supposed that the development of paraneoplastic myelitis was causally related to immune activation by durvalumab. Prompt diagnosis and therapeutic intervention are essential for the effective treatment of paraneoplastic myelitis.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...