Publications by authors named "Jian Hu"

935 Publications

Targeting the αv integrin-TGF-β axis improves natural killer cell function against glioblastoma stem cells.

J Clin Invest 2021 Jun 17. Epub 2021 Jun 17.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, United States of America.

Glioblastoma, the most aggressive brain cancer, recurs because glioblastoma stem cells (GSCs) are resistant to all standard therapies. We showed that GSCs, but not normal astrocytes, are sensitive to lysis by healthy allogeneic natural killer (NK) cells in vitro. Mass cytometry and single cell RNA sequencing of primary tumor samples revealed that glioblastoma-infiltrating NK cells acquired an altered phenotype associated with impaired lytic function relative to matched peripheral blood NK cells from glioblastoma patients or healthy donors. We attributed this immune evasion tactic to direct cell-cell contact between GSCs and NK cells via integrin-mediated TGF-β activation. Treatment of GSC-engrafted mice with allogeneic NK cells in combination with inhibitors of integrin or TGF-β signaling, or with TGFBR2 gene-edited allogeneic NK cells prevented GSC-induced NK cell dysfunction and tumor growth. These findings revealed an important mechanism of NK cell immune evasion by GSCs and implicated the integrin-TGF-β axis as a potentially useful therapeutic target in glioblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI142116DOI Listing
June 2021

A novel nomogram with preferable capability in predicting the overall survival of patients after radical esophageal cancer resection based on accessible clinical indicators: A comparison with AJCC staging.

Cancer Med 2021 Jun 15. Epub 2021 Jun 15.

Department of Thoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Background: Esophageal cancer (EC) is a malignant tumor with high mortality. Nomogram is an important tool used in clinical prognostic assessment. We aimed to establish a novel nomogram to predict the overall survival (OS) of EC patients after radical esophagectomy.

Methods: Data pertaining to the survival, demography, and clinicopathology of 311 EC patients who underwent radical esophagectomy were retrospectively investigated. The nomogram was established based on Cox hazard regression analysis. The calibration curves and Harrell's concordance index (C-index) were used to verify the predictive accuracy and ROC curves were used to assess the efficacy of the nomogram. Kaplan-Meier curves showed the prognostic value of the related risk classification system. Pearson correlation test was performed to determine the correlation between the risk classification system and TNM staging.

Results: The median OS and 5-year survival rates in the primary and validation cohorts were 44 months and 29.8%, and 52 months and 27.1%, respectively. We used six independent prognostic factors-age, Sex, AGR, PRL, N stage, and PNI-in the nomogram. The C-index of nomogram was 0.75 and 0.70 in the primary and validation cohorts, respectively. Calibration curves indicated high consistency between actual and predicted OS. ROC curves showed that nomogram has a better efficacy compared with TNM staging in both cohorts. Patients were divided into three risk groups according to the total nomogram score, the median OS in each group was significantly different in both cohorts. Furthermore, the risk classification system was strongly correlated with the T and N staging system and exhibited a better OS prediction capability.

Conclusions: We established a novel and practical nomogram with a subordinate risk classification system to predict the OS of patients after radical esophagectomy. Compared with AJCC staging, this nomogram had preferable clinical capability in terms of individual prognosis assessment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.3878DOI Listing
June 2021

MicroRNA-340-5p inhibits endothelial apoptosis, inflammatory response, and pro-coagulation by targeting KDM4C in anti-neutrophil cytoplasmic antibody (ANCA)-mediated glomerulonephritis through activation of B cells.

Autoimmunity 2021 Jun 14:1-10. Epub 2021 Jun 14.

Department of Pediatrics, Jinling Hospital, Nanjing Medical University, Nanjing, China.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, a class of systemic autoimmune diseases, results in damage of various critical organs including kidneys, lungs, eyes, and nervous system. MicroRNA-340-5p was confirmed to be downregulated in autoimmune pathogenesis. However, the role of miR-340-5p remains unknown in ANCA-induced glomerulonephritis (GN). The current study aimed to explore the role of miR-340-5p in ANCA-induced GN. The animal models of ANCA-induced GN was established by experimental autoimmune vasculitis (EAV) operation. The primary glomerular endothelial cells (PGEnCs) were treated with anti-myeloperoxidase (anti-MPO) to mimic cell injury . The renal function was analysed by measuring serum creatinine, blood urea nitrogen, urine blood, urine protein and urine leukocytes. The levels of RNA and proteins were examined by RT-qPCR and western blot analysis, respectively. The binding capacity between miR-340-5p and KDM4C was detected by luciferase reporter assay. Cell apoptosis was analysed by flow cytometry . Cell viability was determined by CCK-8 assay. The cleaved caspase-3 activity was analysed by immunofluorescent assay. Cell inflammation was measured by western blot. Cell procoagulant activity was assessed by FXa generation assay. The histological changes of renal tissues were assessed by Haematoxylin and eosin (H&E) staining assay. The correlation between miR-340-5p and KDM4C level (or content of TNF-α and IL-6) was analysed by Pearson correlation analysis. The injection of anti-MPO IgG induced a significant elevation of Serum creatinine and blood urea nitrogen in serum, as well as urine blood, urine protein and urine leukocytes. Importantly, KDM4C was downregulated in model group. In mechanism, we identified that miR-340-5p bound with KDM4C 3'untranslated region (UTR), negatively regulated KDM4C in endothelial cells and negatively correlated with KDM4C in serum of GN rats. In function, we found that miR-340-5p promoted B cell activation and proliferation by downregulating KDM4C. The assays showed that the decrease of cell viability induced by anti-MPO was reversed by miR-340-5p overexpression, and further reduced by KDM4C overexpression. Inversely, the suppressive effects of miR-340-5p mimics on cell apoptosis, cleaved caspase-3 activity, inflammatory response and pro-coagulation were countervailed by KDM4C overexpression in anti-MPO-treated cells. The assays validated that miR-340-5p overexpression mitigated the impairment of renal function, and histological changes induced by anti-MPO IgG injection in model group. Finally, we found the negative correlation between miR-340-5p and TNF-α (or IL-6) content in serum of GN rats. In conclusion, we found that miR-340-5p inhibited endothelial apoptosis and inflammatory response by targeting KDM4C in ANCA-mediated GN through activation of B cells, implying a potential novel insight for treatment of ANCA-mediated GN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/08916934.2021.1937609DOI Listing
June 2021

Association of smoking with postoperative atrial fibrillation in patients with cardiac surgery: A PRISMA-compliant article.

Medicine (Baltimore) 2021 Jun;100(23):e26179

Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang of Jiangxi.

Background: Cigarette smoking is an important modifiable risk factor for incident atrial fibrillation. However, the impact of smoking on postoperative atrial fibrillation in patients undergoing cardiac surgery remains controversial. We performed this meta-analysis to explore the association of smoking with postoperative atrial fibrillation in patients with cardiac surgery.

Methods: We systematically searched 2 computer-based databases (PubMed and EMBASE) up to July 2019 for all relevant studies. A random-effects model was selected to pool the odds ratios (ORs) and 95% confidence intervals (CIs). In this meta-analysis, the protocol and reporting of the results were based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement.

Results: A total of 36 studies were included in this meta-analysis. Overall, smoking was not associated with an increased risk of postoperative atrial fibrillation in patients undergoing cardiac surgery (odds ratio [OR] = 0.89; 95% confidence interval [CI] 0.79-1.02). The corresponding results were stable in the subgroup analyses. Specifically, smoking was not associated with an increased risk of postoperative atrial fibrillation regardless of the type of cardiac surgery: coronary artery bypass grafting (OR = 0.91; 95% CI 0.77-1.07), valve surgery (OR = 0.15; 95% CI 0.01-1.56), and coronary artery bypass grafting+valve surgery (OR = 0.91; 95% CI 0.70-1.18).

Conclusions: Based on currently published studies, smoking was not associated with an increased risk of postoperative atrial fibrillation in patients undergoing cardiac surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000026179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202588PMC
June 2021

The impact of ultrasound-guided transmuscular quadratus lumborum block combined with local infiltration analgesia for arthroplasty on postoperative pain relief.

J Clin Anesth 2021 Oct 4;73:110372. Epub 2021 Jun 4.

Department of Anesthesiology, West China Hospital, Sichuan University, No. 37 Wainan Guoxue Road, Chengdu 610041, China. Electronic address:

Study Objective: This study aimed to evaluate the efficacy of ultrasound-guided transmuscular quadratus lumborum block (QLB) combined with local infiltration analgesia (LIA) for pain management and recovery in patients who have undergone total hip arthroplasty (THA) via a posterolateral approach.

Design: This was a prospective, randomized controlled trial.

Setting: We collected data in the preoperative area, operating room, and bed ward.

Patients: A total of 80 patients with American Society of Anesthesiology functional status scores of II-III were included and assigned to two groups, and all 80 patients were included in the final analysis.

Interventions: All included patients were randomly assigned to the nerve block (group N) or the control group (group C). Patients in the group N received transmuscular QLB combined with LIA, while patients in the group C received only LIA.

Measurements: The primary outcome was postoperative pain during the first active motion: it was measured at six hours after surgery and assessed using a visual analog scale (VAS). Secondary outcomes were the resting VAS scores in the post-anesthesia care unit (PACU) and at 2, 6, 12, 24, 48, and 72 h after surgery; VAS scores during motion at 12, 24, 48, and 72 h after surgery; intraoperative consumption of opioids; postoperative consumption of morphine hydrochloride; frequency of sleep interruption due to pain on the night of surgery; time until the first "walk out of the bed" after surgery; muscle strength of the quadriceps femoris; and postoperative adverse effects.

Main Results: Compared to the group C, patients in the group N had significantly lower VAS scores during motion at 6, 12, and 24 h after surgery, as well as lower resting VAS scores in the PACU and at 2, 6, 12, and 24 h after surgery. Patients in the group N also consumed significantly smaller amounts of intraoperative opioids and morphine after surgery. Patients in the group N reported significantly fewer interruptions in sleep due to pain on the night of surgery and were able to "walk out of the bed" significantly earlier than those in the group C. There was no significant difference between the two groups in muscle strength of the quadriceps femoris or incidence of postoperative adverse effects.

Conclusions: Compared to treatment with LIA alone, ultrasound-guided transmuscular QLB combined with LIA can provide better postoperative pain relief and enhance the recovery of THA patients, since it does not cause quadriceps femoris muscle weakness and is associated with significantly lower need for intraoperative opioids.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jclinane.2021.110372DOI Listing
October 2021

Diagnostic Accuracy of PET for Differentiating True Glioma Progression From Post Treatment-Related Changes: A Systematic Review and Meta-Analysis.

Front Neurol 2021 20;12:671867. Epub 2021 May 20.

Medical School of Chinese People's Liberation Army, Beijing, China.

To evaluate the diagnostic accuracy of PET with different radiotracers and parameters in differentiating between true glioma progression (TPR) and post treatment-related change (PTRC). Studies on using PET to differentiate between TPR and PTRC were screened from the PubMed and Embase databases. By following the PRISMA checklist, the quality assessment of included studies was performed, the true positive and negative values (TP and TN), false positive and negative values (FP and FN), and general characteristics of all the included studies were extracted. Results of PET consistent with reference standard were defined as TP or TN. The pooled sensitivity (Sen), specificity (Spe), and hierarchical summary receiver operating characteristic curves (HSROC) were generated to evaluate the diagnostic accuracy. The 33 included studies had 1,734 patients with 1,811 lesions suspected of glioma recurrence. Fifteen studies tested the accuracy of F-FET PET, 12 tested F-FDG PET, seven tested C-MET PET, and three tested F-DOPA PET. F-FET PET showed a pooled Sen and Spe of 0.88 (95% CI: 0.80, 0.93) and 0.78 (0.69, 0.85), respectively. In the subgroup analysis of FET-PET, diagnostic accuracy of high-grade gliomas (HGGs) was higher than that of mixed-grade gliomas ( = 0.04). F-FDG PET showed a pooled Sen and Spe of 0.78 (95% CI: 0.71, 0.83) and 0.87 (0.80, 0.92), the Spe of the HGGs group was lower than that of the low-grade gliomas group (0.82 vs. 0.90, = 0.02). C-MET PET had a pooled Sen and Spe of 0.92 (95% CI: 0.83, 0.96) and 0.78 (0.69, 0.86). F-DOPA PET had a pooled Sen and Spe of 0.85 (95% CI: 0.80, 0.89) and 0.70 (0.60, 0.79). FET-PET combined with MRI had a pooled Sen and Spe of 0.88 (95% CI: 0.78, 0.94) and 0.76 (0.57, 0.88). Multi-parameters analysis of FET-PET had pooled Sen and Spe values of 0.88 (95% CI: 0.81, 0.92) and 0.79 (0.63, 0.89). PET has a moderate diagnostic accuracy in differentiating between TPR and PTRC. The high Sen of amino acid PET and high Spe of FDG-PET suggest that the combination of commonly used FET-PET and FDG-PET may be more accurate and promising, especially for low-grade glioma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2021.671867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173157PMC
May 2021

Efficacy of Two Unique Combinations of Nerve Blocks on Postoperative Pain and Functional Outcome After Total Knee Arthroplasty: A Prospective, Double-Blind, Randomized Controlled Study.

J Arthroplasty 2021 May 19. Epub 2021 May 19.

Department of Orthopaedics Surgery, West China Hospital, Sichuan University, Chengdu, People's Republic of China.

Background: This study aimed to explore the efficacy of two unique combinations of nerve blocks on postoperative pain and functional outcome after total knee arthroplasty (TKA).

Methods: Patients scheduled for TKA were randomized to receive a combination of adductor canal block (ACB) + infiltration between the popliteal artery and capsule of the posterior knee block (IPACK) + sham obturator nerve block (ONB) + sham lateral femoral cutaneous nerve block (LFCNB) (control group), or a combination of ACB + IPACK + ONB + sham LFCNB (triple nerve block group), or a combination of ACB + IPACK + ONB + LFCNB (quadruple nerve block group). All patients received local infiltration analgesia. Primary outcome was postoperative morphine consumption. Secondary outcomes were the time until first rescue analgesia, postoperative pain assessed on the visual analog scale (VAS), QoR-15 score, functional recovery of knee, and postoperative complications.

Results: Compared with the control group, the triple and quadruple nerve block groups showed significantly lower postoperative morphine consumption (17.2 ± 9.7 mg vs. 11.2 ± 7.0 mg vs. 11.4 ± 6.4 mg, P = .001). These two groups also showed significantly longer time until first rescue analgesia (P = .007 and .010, respectively, analyzed with Kaplan-Meier method), significantly lower VAS scores on postoperative day 1 (P < .01), significantly better QoR-15 scores on postoperative days 1 and 2 (P < .001), and significantly better functional recovery of knee including range of motion (P = .002 and .001 on postoperative days 1 and 2), and daily ambulation distance (P < .001 and P = .004 on postoperative days 1 and 2). However, the absolute change in morphine consumption, VAS scores, and QoR-15 scores did not exceed the reported minimal clinically important differences (MCIDs) (morphine consumption: 10 mg; VAS scores: 1.5 at rest and 1.8 during movement; QoR-15 scores: 8.0). The MCIDs of other outcomes have not been reported in literature. The triple and quadruple nerve block groups showed no significant differences in these outcomes between each other. The three groups did not show a significant difference in complication rates.

Conclusion: Adding ONB or ONB + LFCNB to ACB + IPACK can statistically reduce morphine consumption, improve early pain relief, and functional recovery. However, the absolute change in morphine consumption, VAS scores, and QoR-15 scores did not exceed the MCIDs. Based on our findings and considering the sample size of this study, there is not enough clinical evidence to support the triple or quadruple nerve block use within a multimodal analgesic pathway after TKA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.arth.2021.05.014DOI Listing
May 2021

The ATP Level in the mPFC Mediates the Antidepressant Effect of Calorie Restriction.

Neurosci Bull 2021 Jun 5. Epub 2021 Jun 5.

State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brian Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.

Food deprivation can rescue obesity and overweight-induced mood disorders, and promote mood performance in normal subjects. Animal studies and clinical research have revealed the antidepressant-like effect of calorie restriction, but little is known about the mechanism of calorie restriction-induced mood modification. Previous studies have found that astrocytes modulate depressive-like behaviors. Inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is the predominant isoform in mediating astrocyte Ca signals and its genetic knockout mice are widely used to study astrocyte function in vivo. In this study, we showed that deletion of IP3R2 blocked the antidepressant-like effect induced by calorie restriction. In vivo microdialysis experiments demonstrated that calorie restriction induced an increase in ATP level in the medial prefrontal cortex (mPFC) in naïve mice but this effect disappeared in IP3R2-knockout mice, suggesting a role of astrocytic ATP in the calorie restriction-induced antidepressant effect. Further experiments showed that systemic administration and local infusion of ATP into the mPFC induced an antidepressant effect, whereas decreasing ATP by Apyrase in the mPFC blocked calorie restriction-induced antidepressant regulation. Together, these findings support a role for astrocytic ATP in the antidepressant-like effect caused by calorie restriction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12264-021-00726-4DOI Listing
June 2021

The osteoimmunomodulatory effect of nanostructured TiF/TiOcoating on osteogenesis induction.

Biomed Mater 2021 Jun 18;16(4). Epub 2021 Jun 18.

Key Laboratory for Anisotropy and Texture of Materials (ATM), Ministry of Education (MoE), School of Material Science and Engineering, Northeastern University, Shenyang 110819, People's Republic of China.

Macrophages play a central role in the host response and the integration of implant materials. The nanostructured TiF/TiOcoating (FOTi) on titanium surfaces has shown multiple properties, including antibacterial properties and bioactivity. However, little is known about the effects of these coatings on the regulation of macrophage activity and the subsequent immunomodulatory effects on osteogenesis. In this study, the behavior of macrophages on the FOTi samples was evaluated, and conditioned medium was collected and used to stimulate MC3T3-E1 cells. The results showed that the FOTi samples stimulated macrophage elongation and promoted the production of proinflammatory cytokines at 24 h, while induced macrophage polarization to the anti-inflammatory M2 phenotype at 72 h. Furthermore, the immune microenvironment generated by macrophage/ FOTi samples interactions effectively promoted the osteogenic differentiation of MC3T3-E1 cells, as evidenced by improved cell adhesion, enhanced alkaline phosphatase activity and extracellular matrix mineralization, and upregulated osteogenesis-related gene expression. In summary, the FOTi samples mediated macrophage phenotype behaviors and induced beneficial immunomodulatory effects on osteogenesis, which could be a potential strategy for the surface modification of bone biomaterials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1088/1748-605X/ac0863DOI Listing
June 2021

Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice.

Nat Commun 2021 05 31;12(1):3321. Epub 2021 May 31.

State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P. R. China.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder. The mechanisms underlying ASD are unclear. Astrocyte alterations are noted in ASD patients and animal models. However, whether astrocyte dysfunction is causal or consequential to ASD-like phenotypes in mice is unresolved. Type 2 inositol 1,4,5-trisphosphate 6 receptors (IP3R2)-mediated Ca release from intracellular Ca stores results in the activation of astrocytes. Mutations of the IP3R2 gene are associated with ASD. Here, we show that both IP3R2-null mutant mice and astrocyte-specific IP3R2 conditional knockout mice display ASD-like behaviors, such as atypical social interaction and repetitive behavior. Furthermore, we show that astrocyte-derived ATP modulates ASD-like behavior through the P2X2 receptors in the prefrontal cortex and possibly through GABAergic synaptic transmission. These findings identify astrocyte-derived ATP as a potential molecular player in the pathophysiology of ASD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-23843-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166865PMC
May 2021

Determination of acetylgestagens in animal-derived matrix samples using enhanced matrix removal lipid clean-up in combination with ultra performance liquid chromatography-tandem mass spectrometry.

J Chromatogr A 2021 Jul 7;1649:462227. Epub 2021 May 7.

School of Food and Health, Beijing Technology and Business University, Beijing, 100048, China. Electronic address:

A robust and confirmative method was established for the determination of six acetylgestagen residues, namely, flurogestone acetate (FGA), megestrol (MA), melengestrol acetate (MGA), chlormadinone acetate (CMA), medroxyprogesterone (MPA), and hydroxyprogesterone acetate (HPA) in animal-derived matrix samples by utilizing enhanced matrix removal lipid (EMR-lipid) clean-up in combination with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The analytes were extracted with acetonitrile, purified with a EMR-lipid cartridge, and separated with a reversed-phase C18 column. The limit of quantification (S/N ≥ 10) for CMA, FGA, HPA, MA, and MGA in all matrices was 0.5 ng/g, and for MPA, it was 1.0 ng/g; the limit of detection (S/N ≥ 3) for CMA, FGA, HPA, MA, and MGA in all matrices was 0.1 ng/g, and for MPA, it was 0.2 ng/g. The recoveries were between 61.0% and 114.8%, and the relative standard deviations (RSDs) were below 12%. The method was calibrated in a matrix-assisted standard solution in various linear ranges for the analytes and matrices, and the correlation coefficients (R) exceeded 0.99 for all the matrices.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chroma.2021.462227DOI Listing
July 2021

Opening of the blood-brain barrier using low-intensity pulsed ultrasound enhances responses to immunotherapy in preclinical glioma models.

Clin Cancer Res 2021 May 24. Epub 2021 May 24.

Northwestern University

Purpose: The blood brain barrier (BBB) inhibits adequate dosing/penetration of therapeutic agents to malignancies in the brain. Low-intensity pulsed ultrasound (LIPU) is a safe therapeutic method of temporary blood-brain barrier disruption (BBBD) to enhance chemotherapeutic delivery to the tumor and surrounding brain parenchyma for treatment of glioblastoma.

Experimental Design: We investigated if LIPU could enhance therapeutic efficacy of anti-PD-1 in C57BL/6 mice bearing intracranial GL261 gliomas, epidermal growth factor receptor variant III (EGFRvIII) chimeric antigen receptor (CAR) T cells in NSG mice with EGFRvIII-U87 gliomas, and a genetically-engineered antigen-presenting cell (APC)-based therapy producing the T cell attracting chemokine CXCL10 in the GL261-bearing mice.

Results: Mice treated with anti-PD-1 and LIPU-induced BBBD had a median survival duration of 58 days compared with 39 days for mice treated with anti-PD-1, and long-term survivors all remained alive after contralateral hemisphere rechallenge. CAR T cell administration with LIPU-induced BBBD resulted in significant increases in CAR T cell delivery to the CNS after 24 (<0.005) and 72 (<0.001) hours and increased median survival by greater than 129%, in comparison with CAR T cells alone. Local deposition of CXCL10-secreting APCs in the glioma microenvironment with LIPU enhanced T cell glioma infiltration during the therapeutic window (p=0.004) and markedly enhanced survival (p<0.05).

Conclusions: LIPU increases immune therapeutic delivery to the tumor microenvironment with an associated increase in survival and is an emerging technique for enhancing novel therapies in the brain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-3760DOI Listing
May 2021

YTHDF1 Is a Potential Pan-Cancer Biomarker for Prognosis and Immunotherapy.

Front Oncol 2021 6;11:607224. Epub 2021 May 6.

Department of Urology, Xiangya Hospital, Central South University, Changsha, China.

Background: YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) has been indicated proven to participate in the cross-presentation of tumor antigens in dendritic cells and the cross-priming of CD8+ T cells. However, the role of YTHDF1 in prognosis and immunology in human cancers remains largely unknown.

Methods: All original data were downloaded from TCGA and GEO databases and integrated R 3.2.2. YTHDF1 expression was explored with the Oncomine, TIMER, GEPIA, and BioGPS databases. The effect of YTHDF1 on prognosis was analyzed GEPIA, Kaplan-Meier plotter, and the PrognoScan database. The TISIDB database was used to determine YTHDF1 expression in different immune and molecular subtypes of human cancers. The correlations between YTHDF1 expression and immune checkpoints (ICP), tumor mutational burden (TMB), microsatellite instability (MSI), and neoantigens in human cancers were analyzed the SangerBox database. The relationships between YTHDF1 expression and tumor-infiltrated immune cells were analyzed the TIMER and GEPIA databases. The relationships between YTHDF1 and marker genes of tumor-infiltrated immune cells in urogenital cancers were analyzed for confirmation. The genomic alterations of YTHDF1 were investigated with the c-BioPortal database. The differential expression of YTHDF1 in urogenital cancers with different clinical characteristics was analyzed with the UALCAN database. YTHDF1 coexpression networks were studied by the LinkedOmics database.

Results: In general, YTHDF1 expression was higher in tumors than in paired normal tissue in human cancers. YTHDF1 expression had strong relationships with prognosis, ICP, TMB, MSI, and neoantigens. YTHDF1 plays an essential role in the tumor microenvironment (TME) and participates in immune regulation. Furthermore, significant strong correlations between YTHDF1 expression and tumor immune-infiltrated cells (TILs) existed in human cancers, and marker genes of TILs were significantly related to YTHDF expression in urogenital cancers. TYHDF1 coexpression networks mostly participated in the regulation of immune response and antigen processing and presentation.

Conclusion: YTHDF1 may serve as a potential prognostic and immunological pan-cancer biomarker. Moreover, YTHDF1 could be a novel target for tumor immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.607224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134747PMC
May 2021

NmFGF1-Regulated Glucolipid Metabolism and Angiogenesis Improves Functional Recovery in a Mouse Model of Diabetic Stroke and Acts the AMPK Signaling Pathway.

Front Pharmacol 2021 7;12:680351. Epub 2021 May 7.

The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Diabetes increases the risk of stroke, exacerbates neurological deficits, and increases mortality. Non-mitogenic fibroblast growth factor 1 (nmFGF1) is a powerful neuroprotective factor that is also regarded as a metabolic regulator. The present study aimed to investigate the effect of nmFGF1 on the improvement of functional recovery in a mouse model of type 2 diabetic (T2D) stroke. We established a mouse model of T2D stroke by photothrombosis in mice that were fed a high-fat diet and injected with streptozotocin (STZ). We found that nmFGF1 reduced the size of the infarct and attenuated neurobehavioral deficits in our mouse model of T2D stroke. Angiogenesis plays an important role in neuronal survival and functional recovery post-stroke. NmFGF1 promoted angiogenesis in the mouse model of T2D stroke. Furthermore, nmFGF1 reversed the reduction of tube formation and migration in human brain microvascular endothelial cells (HBMECs) cultured in high glucose conditions and treated with oxygen glucose deprivation/re-oxygenation (OGD). Amp-activated protein kinase (AMPK) plays a critical role in the regulation of angiogenesis. Interestingly, we found that nmFGF1 increased the protein expression of phosphorylated AMPK (-AMPK) both and . We found that nmFGF1 promoted tube formation and migration and that this effect was further enhanced by an AMPK agonist (A-769662). In contrast, these processes were inhibited by the application of an AMPK inhibitor (compound C) or siRNA targeting AMPK. Furthermore, nmFGF1 ameliorated neuronal loss in diabetic stroke mice AMPK-mediated angiogenesis. In addition, nmFGF1 ameliorated glucose and lipid metabolic disorders in our mouse model of T2D stroke without causing significant changes in body weight. These results revealed that nmFGF1-regulated glucolipid metabolism and angiogenesis play a key role in the improvement of functional recovery in a mouse model of T2D stroke and that these effects are mediated by the AMPK signaling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2021.680351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139577PMC
May 2021

Qki activates Srebp2-mediated cholesterol biosynthesis for maintenance of eye lens transparency.

Nat Commun 2021 05 21;12(1):3005. Epub 2021 May 21.

Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Defective cholesterol biosynthesis in eye lens cells is often associated with cataracts; however, how genes involved in cholesterol biosynthesis are regulated in lens cells remains unclear. Here, we show that Quaking (Qki) is required for the transcriptional activation of genes involved in cholesterol biosynthesis in the eye lens. At the transcriptome level, lens-specific Qki-deficient mice present downregulation of genes associated with the cholesterol biosynthesis pathway, resulting in a significant reduction of total cholesterol level in the eye lens. Mice with Qki depletion in lens epithelium display progressive accumulation of protein aggregates, eventually leading to cataracts. Notably, these defects are attenuated by topical sterol administration. Mechanistically, we demonstrate that Qki enhances cholesterol biosynthesis by recruiting Srebp2 and Pol II in the promoter regions of cholesterol biosynthesis genes. Supporting its function as a transcription co-activator, we show that Qki directly interacts with single-stranded DNA. In conclusion, we propose that Qki-Srebp2-mediated cholesterol biosynthesis is essential for maintaining the cholesterol level that protects lens from cataract development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-22782-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139980PMC
May 2021

Qki activates Srebp2-mediated cholesterol biosynthesis for maintenance of eye lens transparency.

Nat Commun 2021 05 21;12(1):3005. Epub 2021 May 21.

Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Defective cholesterol biosynthesis in eye lens cells is often associated with cataracts; however, how genes involved in cholesterol biosynthesis are regulated in lens cells remains unclear. Here, we show that Quaking (Qki) is required for the transcriptional activation of genes involved in cholesterol biosynthesis in the eye lens. At the transcriptome level, lens-specific Qki-deficient mice present downregulation of genes associated with the cholesterol biosynthesis pathway, resulting in a significant reduction of total cholesterol level in the eye lens. Mice with Qki depletion in lens epithelium display progressive accumulation of protein aggregates, eventually leading to cataracts. Notably, these defects are attenuated by topical sterol administration. Mechanistically, we demonstrate that Qki enhances cholesterol biosynthesis by recruiting Srebp2 and Pol II in the promoter regions of cholesterol biosynthesis genes. Supporting its function as a transcription co-activator, we show that Qki directly interacts with single-stranded DNA. In conclusion, we propose that Qki-Srebp2-mediated cholesterol biosynthesis is essential for maintaining the cholesterol level that protects lens from cataract development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-22782-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139980PMC
May 2021

Genetic variations for egg internal quality of ducks revealed by genome-wide association study.

Anim Genet 2021 May 19. Epub 2021 May 19.

State Key Laboratory of Animal Nutrition; Key Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.

Egg internal quality traits are important traits related to egg production in poultry industry. To better understand the genetic architecture of egg internal quality traits in ducks, we performed genetic parameters estimates and a genome-wide association study (GWAS). The phenotypic values of egg weight, yolk color, albumin height (AH), yolk weight, and Haugh unit (HU) were collected individually from 352 F laying ducks produced by reciprocal crosses between mallards and Pekin ducks, and their genotypes were assayed by whole genome re-sequencing. The results showed that the AH and HU traits have a clear coefficient of variance, around 15% for both mallards and Pekin ducks. The pedigree-based genetic parameters estimates rane from 0.26 to 0.71 for all eight egg quality traits, while the highest heritability was 0.71 for egg weight. The GWAS showed that a clear signal was associated with AH and HU traits. The locus zoom analysis and conditional GWAS helped to narrow the candidate region to ~5.8-Mb spanning from 14.7 to 20.5 Mb on Chromosome 5, which harbored 111 candidate genes. MUC6 and LDLRAD3 were finally promised as the major candidate genes affecting albumen composition. Our data revealed the egg internal quality traits for the first time in ducks, which provides a theoretical basis and technological support for improving duck egg internal quality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/age.13063DOI Listing
May 2021

Does a thoracoscopic approach provide better outcomes for pulmonary metastases?

J Thorac Dis 2021 Apr;13(4):2692-2697

Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Traditional open thoracotomy (OT) is the gold standard treatment for patients with pulmonary metastases. However, it remains controversial whether video-assisted thoracic surgery (VATS) can provide comparable outcomes to OT. We conducted this review to compare the outcomes of VATS with OT in pulmonary metastasectomy (PM). Relevant studies published up to November 2019 were identified from PubMed data base and screened. Studies were then selected by the researchers based on our selection criteria. Data including the type of study, patient groups, outcomes and key results were extracted from the included studies and summarized. Screening of 2,788 papers identified 9 that were relevant to our research question. The authors, dates of publication, journal details, type of study, patient groups, outcomes and key results from these papers were summarized. All 9 studies documented the survival rate (1-, 3- and 5-year survival). Metastases from colorectal cancer were investigated in three studies, and metastases from sarcoma were investigated in one study. The overall survival rate of VATS was not inferior to that of OT in patients with pulmonary metastases. VATS was also associated with better perioperative results compared with OT. In conclusion, VATS is suitable as an alternative surgical technique for PM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/jtd-19-3958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107522PMC
April 2021

One-year outcome of single-stent crossover versus accurate ostial stenting for isolated left anterior descending ostial stenosis.

Coron Artery Dis 2021 May 18. Epub 2021 May 18.

Department of Cardiology, Rui Jin Hospital Institute of Cardiovascular Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.

Background: The optimal strategy of percutaneous coronary intervention (PCI) for isolated left anterior descending (LAD) ostial lesions remains debatable. This study aimed to compare clinical outcomes of patients with isolated LAD ostial stenosis treated by single-stent crossover versus accurate ostial stenting.

Methods: A total of 216 eligible consecutive patients with isolated de novo LAD ostial stenosis were enrolled, and were stratified according to the stenting techniques. Clinical follow-up was performed by review of medical charts or telephone contact with the patients, and repeat angiography was made at 9-12 months after the procedure. Major adverse cardiovascular events (MACE) including cardiac death, myocardial infarction, non-fatal stroke and target vessel revascularization (TVR) were recorded.

Results: Single-stent crossover and accurate ostial stenting were applied to 78 (36%) and 138 (64%) patients, respectively. During a mean of 13 ± 4.1 months of follow-up, the rate of composite MACE (19.6 vs. 8.9%; P = 0.040) was higher in LAD ostial stenosis patients treated with accurate ostial stenting than those treated with single-stent crossover technique, mainly driven by more frequent TVR (17.4 vs. 7.7%; P = 0.048). PCI strategy was an independent predictor of MACE (hazard ratio 2.561; 95% CI, 1.041-6.299; P = 0.021) in the multivariable Cox regression analysis.

Conclusions: Our retrospective study suggests that the single-stent crossover technique is associated with a better 1-year clinical outcome compared with accurate ostial stenting in patients with isolated LAD ostial stenosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MCA.0000000000001071DOI Listing
May 2021

Roles of Fibroblast Growth Factors and Their Therapeutic Potential in Treatment of Ischemic Stroke.

Front Pharmacol 2021 22;12:671131. Epub 2021 Apr 22.

School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.

Stroke is the leading cause of death worldwide, and its treatment remains a challenge. Complex pathological processes are involved in stroke, which causes a reduction in the supply of oxygen and energy to the brain that triggers subsequent cascade events, such as oxidative stress, inflammatory responses and apoptosis, resulting in brain injury. Stroke is a devastating disease for which there are few treatments, but physical rehabilitation can help improve stroke recovery. Although there are very few treatments for stroke patients, the discovery of fibroblast growth factors (FGFs) in mammals has led to the finding that FGFs can effectively treat stroke in animal models. As presented in this review, FGFs play essential roles by functioning as homeostatic factors and controlling cells and hormones involved in metabolism. They could be used as effective therapeutic agents for stroke. In this review, we will discuss the pharmacological actions of FGFs on multiple targets, including their ability to directly promote neuron survival, enhance angiogenesis, protect against blood-brain barrier (BBB) disruption, and regulate microglial modulation, in the treatment of ischemic stroke and their theoretical mechanisms and actions, as well as the therapeutic potential and limitations of FGFs for the clinical treatment of stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2021.671131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102031PMC
April 2021

Haploidentical Peripheral Stem Cell Transplantation for Young Patients with Severe Aplastic Anemia Using Post-Transplantation Cyclophosphamide and Methotrexate.

Transplant Cell Ther 2021 May 19;27(5):429.e1-429.e7. Epub 2021 Feb 19.

Department of Hematology, Xiangya Hospital of Central South University, Changsha, Hunan, China. Electronic address:

Severe aplastic anemia (SAA) is a serious bone marrow failure disorder that is often cured with hematopoietic stem cell transplantation (HSCT). The absence of a matched related donor is common, however, and thus novel approaches are needed to safely expand the donor pool to include alternative donors, especially haploidentical related donors, for patients with SAA. This study aimed to explore a novel approach to HSCT for patients with SAA without an available HLA-identical sibling or a matched unrelated donor, termed haploidentical peripheral blood stem cell transplantation (haplo-PBSCT), using a conditioning regimen comprising cyclophosphamide, busulfan, and fludarabine (CBF) and a graft-versus-host disease (GVHD) prophylaxis regimen with post-transplantation cyclophosphamide (PTCy), low-dose methotrexate (LD-MTX), and calcineurin inhibitors. This prospectively designed nonrandomized study included 29 patients with SAA who underwent haplo-PBSCT between November 2017 and May 2020. The median patient age was 17 years (range, 14 to 30 years), and the median time to neutrophil recovery was 13 days (range, 13 to 15 days). There was 1 primary graft failure (GF) in the group receiving PTCy at a dose of 50 mg/kg and no GFs in the group receiving PTCy at a dose of 100 mg/kg. The median duration of follow-up was 736 days (95% confidence interval, 512 to 879 days). The estimated 1-year overall survival and disease-free survival were 91.7 ± 5.7% and 89.7 ± 5.7%, respectively. Only 1 of the 27 patients developed grade II acute GVHD. Four patients developed limited and mild chronic GVHD, involving only the skin or/and oral mucosa. Haplo-PBSCT following CBF and followed by PTCy and LD-MTX represents a novel approach for safely expanding the donor pool to include alternative donors for young patients with SAA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.02.014DOI Listing
May 2021

Predicting the mortality risk of acute respiratory distress syndrome: radial basis function artificial neural network model versus logistic regression model.

J Clin Monit Comput 2021 May 6. Epub 2021 May 6.

Surgical Intensive Care Unit, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China.

To predict the mortality of acute respiratory distress syndrome (ARDS) by using a radial basis function (RBF) artificial neural network (ANN) model. This study included 217 patients who were admitted between June 2013 and November 2019. The RBF ANN model and logistic regression (LR) model were based on twelve factors related to ARDS. Statistical indexes were used to determine the value of the prediction in the two models. The sensitivity, specificity and accuracy of the RBF ANN model to predict mortality were 83.6%, 88.5% and 82.5%, respectively. Significant differences were found between the RBF ANN and LR models (P < 0.05). When the RBF ANN model was used to identify ARDS, the area under the ROC curve was 0.854 ± 0.029. LDH, organ failure, SP-D and PaO2/FiO2 were the most important independent variables. The RBF ANN model was more likely to predict the mortality of ARDS than the LR model. In addition, it can extract informative risk factors for ARDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10877-021-00716-xDOI Listing
May 2021

Qki regulates myelinogenesis through Srebp2-dependent cholesterol biosynthesis.

Elife 2021 May 4;10. Epub 2021 May 4.

Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, United States.

Myelination depends on timely, precise control of oligodendrocyte differentiation and myelinogenesis. Cholesterol is the most abundant component of myelin and essential for myelin membrane assembly in the central nervous system. However, the underlying mechanisms of precise control of cholesterol biosynthesis in oligodendrocytes remain elusive. In the present study, we found that Qki depletion in neural stem cells or oligodendrocyte precursor cells in neonatal mice resulted in impaired cholesterol biosynthesis and defective myelinogenesis without compromising their differentiation into AspaGstpi myelinating oligodendrocytes. Mechanistically, Qki-5 functions as a co-activator of Srebp2 to control transcription of the genes involved in cholesterol biosynthesis in oligodendrocytes. Consequently, Qki depletion led to substantially reduced concentration of cholesterol in mouse brain, impairing proper myelin assembly. Our study demonstrated that Qki-Srebp2-controlled cholesterol biosynthesis is indispensable for myelinogenesis and highlights a novel function of Qki as a transcriptional co-activator beyond its canonical function as an RNA-binding protein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.60467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139834PMC
May 2021

Transcriptome-Wide Analysis for Ginsenoside Rb3 Synthesis-Related Genes and Study on the Expression of Methyl Jasmonate Treatment in .

Life (Basel) 2021 Apr 25;11(5). Epub 2021 Apr 25.

College of Life Science, Jilin Agricultural University, Changchun 130118, China.

C. A. Meyer is a kind of renascent herb that belongs to the genus in the family . It is a traditional Chinese precious herbal medicine with a long history of medicinal use. Ginsenoside Rb3 is one of the important active ingredients in ginseng and has important physiological activity in the treatment of many diseases. In this study, we screened and systematically analyzed the candidate genes related to ginsenoside Rb3 synthesis through bioinformatics methods; discussed the functions, expression patterns, and interactions of the genes related to ginsenoside Rb3 synthesis; and finally, selected seven genes, mainly that directly contribute to the synthesis of ginsenoside Rb3. This study provides a reference for revealing the expression rules of ginsenoside Rb3 synthesis-related genes and elucidating the regulatory mechanism of methyl jasmonate, lays a theoretical foundation for the research of ginsenoside Rb3 synthesis, and provides theoretical and technical support for the factory production of ginsenoside monomer saponins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/life11050387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146951PMC
April 2021

Probiotics alleviate depressive behavior in chronic unpredictable mild stress rat models by remodeling intestinal flora.

Neuroreport 2021 May;32(8):686-693

Department of Psychiatry.

Objective: To explore the effects of probiotics on depressive behavior in a chronic unpredictable mild stress (CUMS) rat model by remodeling intestinal flora.

Methods: Twenty-four male SD rats aged 6-8 weeks were randomly divided into four groups: control group, depression group (CUMS), depression+paroxetine group (Paro) and depression+probiotics group (Pro). Sucrose preference, open field and forced swimming tests were used to assess depression-like behavior in rats. ELISA was used to detect the levels of adrenocorticotropic hormone (ACTH), and corticosterone, norepinephrine and 5-hydroxytryptamine in rat serum. Real-time PCR was used to determine the changes of Lactobacillus, Bifidobacterium, Enterococcus faecalis and Escherichia coli in rat cecum.

Results: Compared with the control group, CUMS led to significant decreases of body weight, total traveled distance, duration in central area, immobility time, norepinephrine and 5-hydroxytryptamine contents in hippocampal tissues, as well as Lactobacillus and Bifidobacterium in the cecum. It also resulted in marked increases of the contents of E. faecalis and E. coli in the cecum, ACTH and corticosterone contents in the serum of rats. Paroxetine and probiotic treatment each diminished or prevented these changes.

Conclusion: By remodeling intestinal flora, probiotics can reduce the CUMS-induced depressive behavior of rats, increase the levels of norepinephrine and 5-hydroxytryptamine, and inhibit the expression of ACTH and corticosterone. Significantly, the effect of both paroxetine and probiotic on microorganisms is similar.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/WNR.0000000000001637DOI Listing
May 2021

Nicotinamide Mononucleotide Combined With TKSN041 Reduces the Photoaging Damage in Murine Skin by Activating AMPK Signaling Pathway.

Front Pharmacol 2021 25;12:643089. Epub 2021 Mar 25.

Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing, China.

Long-term exposure to UVB (280-320 nm) can cause oxidative skin damage, inflammatory injury, and skin cancer. Research on nicotinamide mononucleotide (NMN) and lactic acid bacteria (LAB) with regard to antioxidation, anti-inflammation, and prevention of other age-related diseases has received increasing attention. In the present study, the antioxidant analysis showed that NMN combined with TKSN041 ( TKSN041) has a high scavenging ability on hydroxyl (OH), 2, 2'-azino-bis (3-ethylbenzthiazoline-6-sulphonic acid) diammonium salt (ABTS) and 1, 1-diphenyl-2-picrylhydrazyl (DPPH), and it also possess a good total antioxidant capacity. The animal experimental results show that NMN combined with LAB maintained normal liver morphology of mice and reduced pathological damage to murine skin. NMN combined with LAB significantly increased the serum levels of total superoxide dismutase (T-SOD), catalase (CAT), and interleukin (IL)-10, but reduced the levels of malondialdehyde, advanced glycation end products, tumor necrosis factor (TNF)-α, and IL-6. NMN combined with LAB increased T-SOD, CAT, IL-10, Na-K-ATPase, and NAD levels in the skin, but reduced TNF-α level in the skin. NMN combined with LAB increased the mRNA expression levels of SOD1, CAT, glutathione (GSH), inhibitor of NF-κB (IκB-α), IL-10, AMP-activated protein kinase (AMPK), adaptor protein, phosphotyros ineinteraction, PH domain and leucine zipper containing 1 (APPL1), peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α), and forkhead transcription factor O (FOXO) in the skin and liver, but decreased the mRNA expression levels of nuclear factor (NF)-κBp65, TNF-α, IL-6, and rapamycin target protein (mTOR). NMN combined with LAB increased the protein expression levels of AMPK, IκB-α, SOD1, and CAT in the skin tissues and reduced protein expression of NF-κBp65. NMN combined with TKSN041 improved murine skin damage caused by UVB irradiation, and the protective mechanism may be related to activation of the AMPK signaling pathway. The results of this study are expected to provide a reference for preventing and the treating skin photoaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2021.643089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027253PMC
March 2021

Zinc transporter mutations linked to acrodermatitis enteropathica disrupt function and cause mistrafficking.

J Biol Chem 2021 Jan 8;296:100269. Epub 2021 Jan 8.

Department of Chemistry, Michigan State University, East Lansing, Michigan, USA; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, USA. Electronic address:

ZIP4 is a representative member of the Zrt-/Irt-like protein (ZIP) transporter family and responsible for zinc uptake from diet. Loss-of-function mutations of human ZIP4 (hZIP4) drastically reduce zinc absorption, causing a life-threatening autosomal recessive disorder, acrodermatitis enteropathica (AE). These mutations occur not only in the conserved transmembrane zinc transport machinery, but also in the extracellular domain (ECD) of hZIP4, which is only present in a fraction of mammalian ZIPs. How these AE-causing ECD mutations lead to ZIP4 malfunction has not be fully clarified. In this work, we characterized all seven confirmed AE-causing missense mutations in hZIP4-ECD and found that the variants exhibited completely abolished zinc transport activity in a cell-based transport assay. Although the variants were able to be expressed in HEK293T cells, they failed to traffic to the cell surface and were largely retained in the ER with immature glycosylation. When the corresponding mutations were introduced in the ECD of ZIP4 from Pteropus Alecto, a close homolog of hZIP4, the variants exhibited structural defects or reduced thermal stability, which likely accounts for intracellular mistrafficking of the AE-associated variants and as such a total loss of zinc uptake activity. This work provides a molecular pathogenic mechanism for AE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jbc.2021.100269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949036PMC
January 2021

Low-temperature (< 200 °C) degradation of electronic nicotine delivery system liquids generates toxic aldehydes.

Sci Rep 2021 Apr 8;11(1):7800. Epub 2021 Apr 8.

Pacific Northwest National Laboratory, Richland, WA, 99354, USA.

Electronic cigarette usage has spiked in popularity over recent years. The enhanced prevalence has consequently resulted in new health concerns associated with the use of these devices. Degradation of the liquids used in vaping have been identified as a concern due to the presence of toxic compounds such as aldehydes in the aerosols. Typically, such thermochemical conversions are reported to occur between 300 and 400 °C. Herein, the low-temperature thermal degradation of propylene glycol and glycerol constituents of e-cigarette vapors are explored for the first time by natural abundance C NMR and H NMR, enabling in situ detection of intact molecules from decomposition. The results demonstrate that the degradation of electronic nicotine delivery system (ENDS) liquids is strongly reliant upon the oxygen availability, both in the presence and absence of a material surface. When oxygen is available, propylene glycol and glycerol readily decompose at temperatures between 133 and 175 °C over an extended time period. Among the generated chemical species, formic and acrylic acids are observed which can negatively affect the kidneys and lungs of those who inhale the toxin during ENDS vapor inhalation. Further, the formation of hemi- and formal acetals is noted from both glycerol and propylene glycol, signifying the generation of both formaldehyde and acetaldehyde, highly toxic compounds, which, as a biocide, can lead to numerous health ailments. The results also reveal a retardation in decomposition rate when material surfaces are prevalent with no directly observed unique surface spectator or intermediate species as well as potentially slower conversions in mixtures of the two components. The generation of toxic species in ENDS liquids at low temperatures highlights the dangers of low-temperature ENDS use.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-87044-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032854PMC
April 2021

Handover method: Simple, classic and harmonized intracorporeal closure of stapled duodenal stump during laparoscopic gastrectomy.

J Surg Oncol 2021 Jul 8;124(1):41-48. Epub 2021 Apr 8.

Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jso.26484DOI Listing
July 2021

CTLA-4 +49 A/G Polymorphism and the Risk of Lung Cancer: a Meta-analysis.

Zhongguo Fei Ai Za Zhi 2021 03;24(3):173-181

Department of Cardiothoracic Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou 310006, China.

Background: Lung cancer is one of the malignant tumors. Gene mutations associated with cellular immune function and regulating the activation and proliferation of immune cells. Several publications have explored the relationship between cytotoxic T lymphocyte antigen-4 (CTLA-4) +49 adenine (A)/guanine (G) polymorphism and susceptibility of lung cancer, but the results remain controversial. Thus, we performed this meta-analysis to derive a more comprehensive estimation of the relationship.

Methods: All articles addressed lung cancer and polymorphisms of CTLA-4 were searched from the PubMed, EMBASE databases published up to June 29, 2019. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. Publication bias of relevant studies was examined via Begg's test and funnel plots.

Results: The meta-analysis included 8 case-control studies covering 4,430 lung cancer patients and 5,198 healthy controls from September 2008 to April 2020. The overall eligible data indicated that CTLA-4 +49A/G polymorphisms did not correlate with the elevated lung cancer risk in all genetic comparison models (dominant model: OR=1.037, 95%CI: 0.925-1.161; recessive model: OR=0.968, 95%CI: 0.888-1.055; allele model: OR=0.992, 95%CI: 0.933-1.054; homozygous model: OR=0.980, 95%CI: 0.857-1.121; heterozygous model: OR=1.023, 95%CI: 0.906-1.154). In further stratified analyses, CTLA-4 +49A/G polymorphism was found to be significantly associated with susceptibility to NSCLC in these models (dominant model: OR=1.404, 95%CI: 1.074-1.836; allele model: OR=1.273, 95%CI: 1.034-1.565; homozygous model: OR=1.553, 95%CI: 1.044-2.310; heterozygous model: OR=1.308, 95%CI: 1.062-1.611).

Conclusions: CTLA-4 +49A/G polymorphism were not associated with the risk of lung cancer but might be a risk factor only in NSCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3779/j.issn.1009-3419.2021.102.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143968PMC
March 2021