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1.
J Cell Physiol ; 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33400820

RESUMO

C1q/tumor necrosis factor-related protein-6 (CTRP6) is a newly identified adipokine involved in diverse biological processes. However, its role in salivary glands remains unknown. Here, we demonstrated that CTRP6 was mainly distributed in the nuclei, apicolateral membranes, and cytoplasm of human submandibular glands (SMGs), serous cells of parotid glands, and ducts and apicolateral membranes of serous cells in rats and mice. CTRP6 inhibited the apoptosis rate and reversed the increased levels of cleaved caspase 3, caspase 8, caspase 9, and cytochrome C and the decreased Bcl-2 expression induced by tumor necrosis factor (TNF)-α in both SMG-C6 cells and cultured human SMG tissues. Microarray analysis identified 43 differentially expressed microRNAs (miRNAs) in the SMGs of nonobese diabetic mice. miR-34a-5p was selected due to its upregulation by TNF-α, which was abolished by CTRP6. The miR-34a-5p inhibitor promoted whereas the miR-34a-5p mimic suppressed the effects of CTRP6 on TNF-α-induced apoptosis. CTRP6 increased AMP-activated protein kinase (AMPK) phosphorylation and reversed TNF-α-induced SIRT1 downregulation in salivary cells. AraA, an AMPK inhibitor, reversed the effects of CTRP6 on TNF-α-induced alterations in the levels of SIRT1, miR-34a-5p, Bcl-2, and cleaved caspase 3 in vitro and ex vivo, whereas activating AMPK by AICAR reversed the decrease in SIRT1 expression and increase in miR-34a-5p expression induced by TNF-α. Inhibition of SIRT1 by EX527 suppressed the effects of CTRP6 on TNF-α-induced changes in miR-34a-5p and apoptosis-related proteins. Our findings indicate that salivary glands are novel sites for CTRP6 synthesis and secretion. CTRP6 protects acinar cells against TNF-α-induced apoptosis via AMPK/SIRT1-modulated miR-34a-5p expression.

2.
Life Sci ; 268: 119009, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33412210

RESUMO

AIMS: Salivary gland dysfunction is a common complication of diabetes mellitus (DM). Long non-coding RNA (lncRNA) is evidenced to involve in the functional regulation of salivary gland, however, its role in DM-impaired gland is unknown. Therefore, this study aimed to investigate the expression profiles and functional networks of lncRNA in the parotid glands (PGs) of DM mice. MAIN METHODS: Microarray was used to detect lncRNA and messenger RNA (mRNA) expression profiles in the PGs from db/db and db/m mice. Eleven differently expressed (DE) lncRNAs validated by qRT-PCR were selected for coding-non-coding gene co-expression (CNC) and competing endogenous RNA (ceRNA) network analysis, as well as the following Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Pearson's coefficient correlation analysis was used to analyze the correlations between DE lncRNAs expression and DM pathology. KEY FINDINGS: By using a 2-fold change and P < 0.05 as the cutoff criteria, 1650 DE lncRNAs (758 upregulated and 892 downregulated) and 1073 mRNAs (563 upregulated and 510 downregulated) were identified in the PGs of db/db mice compared to db/m mice. GO and KEGG analysis of DE mRNA suggested that activated inflammation response and downregulated ion transport might count for the dysfunction of diabetic PG. CNC and ceRNA networks analysis of 11 DE lncRNAs showed that the inflammation process and its related signaling pathways including advanced glycation end product (AGE)-receptor for AGE (RAGE) signaling pathway in diabetic complications, cytokine-cytokine receptor interaction, chemokine signaling pathway, apoptosis, and cell adhesion molecules were significantly enriched. The alterations of lncRNAs were closely correlated with higher blood glucose and serum insulin levels in mice. SIGNIFICANCE: We identified multiple lncRNAs/mRNAs and several signaling pathways that may involve in the pathogenesis of diabetic salivary injury, providing new insight into potential target of diabetic hyposalivation.

3.
Sheng Li Xue Bao ; 72(6): 743-750, 2020 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-33349832

RESUMO

Formative assessment aims at cultivating and improving students' comprehensive qualities and abilities. It acquires and analyzes the dynamic changes of students' learning process through flexible and diverse assessment methods. The assessment contents cover multiple aspects including knowledge, abilities, attitudes, literacy, etc., which help teachers and students to formulate practical and efficient improvement strategies and to meet the inherent needs of students for comprehensive development. This review describes the connotation of formative assessment and summarizes its application in higher education of basic medical science in China. The existing shortcomings and the reasonable advice are proposed. We also introduce our experience in the application of formative assessment in pathophysiology education. This review will provide reference and enlightenment for the reform and innovation of the assessment system in higher education of basic medical science.


Assuntos
Educação Médica , China , Avaliação Educacional , Humanos
4.
Adv Physiol Educ ; 44(4): 726-733, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33155832

RESUMO

Current interdisciplinary medical training calls for reforms and innovations in the assessment of pathophysiology education. Formative assessment is used to monitor student learning to provide ongoing feedback that can improve both learning and teaching. Beginning in 2016, we implemented a formative assessment composed of case-based multiple-choice questions (MCQs) for all students in all majors. In 2017, case study questions began to be employed in the formative assessment, and student-set, case-based questions were further introduced. Aiming to gather the students' suggestions and feedback on the mixed-method assessment, we conducted a survey on aspects such as the effectiveness of the assessment, assessment content and completion, opinions on student-set questions, and the impact on pathophysiology learning for students from 2017 to 2019. In addition, we compared students' semesterly final scores with those of previous students and evaluated the relationship between formative and summative assessment scores. The results for 1,277 students clearly showed that the reformed formative assessment system was well received by the students. The students thought that the formative assessment not only allowed for the provision of real-time feedback on the effectiveness of teaching and learning but also nurtured self-motivation, the development of analytical and problem-solving skills, and collaborative efforts. Both the semesterly final scores and the proportions of students scoring in higher score ranges increased after the implementation of the formative assessment, and the summative assessment scores were positively related to the formative assessment scores. Consequently, the reformed formative assessment system significantly improved the quality of pathophysiology education.

5.
Arch Oral Biol ; 120: 104947, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33113460

RESUMO

OBJECTIVE: Hyposalivation is a common symptom of diabetes. Although microRNAs (miRNAs) play a role in the pathogenesis of diabetes, the specific effects of miRNAs on diabetic salivary glands are not clear. DESIGN: We used high-throughput technologies to screen differentially expressed (DE) miRNAs and mRNAs in submandibular gland (SMG) tissues from db/db mice and db/m mice. DE miRNAs and mRNAs were confirmed using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Twenty-eight DE miRNAs and 1146 DE mRNAs were identified between the SMG tissues of db/db mice and db/m mice. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis demonstrated that the DE miRNAs were highly associated with terms related to diverse biological processes and signalling pathways. Of the related pathways, the tight junction pathway, autophagy pathway and transforming growth factor-ß (TGF-ß) signalling pathway were notable. AKT serine/threonine kinase 3 (AKT3) and phosphoinositide-3 kinase catalytic subunit delta (PIK3CD) may also play important roles in the development of diabetes-mediated hyposalivation. CONCLUSIONS: Our research described the miRNA-mRNA expression profiles and miRNA-mRNA network in the SMG tissues of db/db mice. These results provide possible molecular mechanisms of diabetes-induced hyposalivation and information for further studies.

6.
Oral Dis ; 2020 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-32892462

RESUMO

OBJECTIVE: In this study, we sought to determine the expression profiles of long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) and construct functional networks to analyze their potential roles following botulinum toxin type A (BTXA)-mediated inhibition of salivary secretion. METHODS: The submandibular gland of rats in the BTXA and control groups was injected with BTXA and saline, respectively. Microarray analysis was used to identify the differentially expressed lncRNAs and mRNAs. Gene ontology and pathway analysis were performed to examine the biological functions. Functional networks, including lncRNA-mRNA co-expression and competing endogenous RNA (ceRNA) networks, were constructed to reveal the interaction between the coding and non-coding genes. RESULTS: Microarray analysis revealed that 254 lncRNAs and 631 mRNAs were differentially expressed between the BTXA and control groups. Bioinformatic analysis revealed that most of the mRNAs were closely related to transmembrane transporter activity. lncRNA-mRNA co-expression and ceRNA networks were constructed, and several critical mRNA-lncRNA axes and key microRNAs related to salivary secretion were identified. CONCLUSIONS: Our study identified differentially expressed lncRNAs and mRNAs through microarray analysis and explored the interactions between the coding and non-coding genes through bioinformatic analysis. These findings provide new insights into the mechanism of BTXA-mediated inhibition of salivary secretion.

7.
J Crohns Colitis ; 2020 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-32770194

RESUMO

Inflammatory bowel disease (IBD) is characterized by abnormal host-microbe interactions. Proinflammatory cytokine IFNγ and a novel TNF superfamily member, TL1A, have been implicated in epithelial barrier dysfunction. The divergent regulatory mechanisms of transcellular versus paracellular hyperpermeability remain poorly understood. Intestinal epithelia express two splice variants of long myosin light chain kinase (MLCK), of which the full-length MLCK1 differ from the shorter isoform MLCK2 by a Src kinase phosphorylation site. The aim was to investigate the roles of MLCK splice variants in gut barrier defects under proinflammatory stress. Upregulated expression of TL1A, IFNγ, and two MLCK variants was observed in human IBD biopsy specimens. The presence of intraepithelial bacteria preceded tight junction (TJ) damage in dextran sodium sulfate-treated and TL1A-transgenic mouse models. Lack of barrier defects was observed in long MLCK(-/-) mice. TL1A induced MLCK-dependent terminal web (TW) contraction, brush border fanning, and transepithelial bacterial internalization. The bacterial taxa identified in the inflamed colonocytes included Escherichia, Enterococcus, Staphylococcus,and Lactobacillus. Recombinant TL1A and IFNγ at low doses induced PI3K/Akt/MLCK2-dependent bacterial endocytosis, whereas high-dose IFNγ caused TJ opening via the iNOS/Src/MLCK1 axis. Bacterial internalization was recapitulated in MLCK-knockout cells individually expressing MLCK2 but not MLCK1. Immunostaining showed different subcellular sites of phosphorylated MLC localized to the TJ and TW in the MLCK1- and MLCK2-expressing cells, respectively. In conclusion, proinflammatory cytokines induced bacterial influx through transcellular and paracellular routes via divergent pathways orchestrated by distinct MLCK isoforms. Bacterial transcytosis induced by TL1A may be an alternative route causing symptom flares in IBD.

8.
Cardiovasc Drugs Ther ; 34(5): 591-604, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32424654

RESUMO

PURPOSE: Cardiac fibrosis is characterized by net accumulation of extracellular matrix (ECM) components in the  myocardium and facilitates the development of heart failure. C1q/tumor necrosis factor-related protein 15 (CTRP15) is a novel member of the CTRP family, and its gene expression is detected in adult mouse hearts. The present study was performed to determine the effect of CTRP15 on pressure overload-induced fibrotic remodeling. METHODS: Mice were subjected to transverse aortic constriction (TAC) surgery, and adeno-associated virus serotype 9 (AAV9)-carrying mouse CTRP15 gene was injected into mice to achieve CTRP15 overexpression in the myocardium. Adenovirus carrying the gene encoding CTRP15 or small interfering RNA (siRNA) of interest was infected into cultured neonatal mouse ventricular cardiomyocytes (NMVCs) or cardiac fibroblasts (CFs). Gene expression was measured by quantitative real-time PCR, and protein expression and distribution were determined by Western blotting, immunocytochemistry, and immunofluorescence staining. RESULTS: CTRP15 was predominantly produced by cardiac myocytes. CTRP15 expression in the left ventricles was downregulated in mice that underwent TAC. AAV9-mediated CTRP15 overexpression alleviated ventricular remodeling and dysfunction in the pressure-overloaded mice. Treatment of CFs with recombinant CTRP15 or the conditioned medium containing CTRP15 inhibited transforming growth factor (TGF)-ß1-induced Smad3 activation and myofibroblast differentiation. CTRP15 increased phosphorylation of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and Akt. Blockade of IR/IRS-1/Akt pathway reversed the inhibitory effect of CTRP15 on TGF-ß1-induced Smad3 activation. CONCLUSION: CTRP15 exerts an anti-fibrotic effect on pressure overload-induced cardiac remodeling. The activation of IR/IRS-1/Akt pathway contributes to the anti-fibrotic effect of CTRP15 through targeting Smad3.


Assuntos
Cardiomiopatias/prevenção & controle , Citocinas/metabolismo , Fibroblastos/efeitos dos fármacos , Proteínas Musculares/metabolismo , Miócitos Cardíacos/metabolismo , Comunicação Parácrina , Fator de Crescimento Transformador beta1/farmacologia , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Células Cultivadas , Citocinas/genética , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Masculino , Camundongos Endogâmicos C57BL , Proteínas Musculares/genética , Miócitos Cardíacos/patologia , Transdução de Sinais
9.
J Anat ; 237(3): 556-567, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32374057

RESUMO

Tight junction (TJ) plays an important role in regulating paracellular fluid transport in salivary glands; however, little is known about the involvement of TJs in diabetes salivary glands. This study aimed to investigate the alterations of TJs and their possible contribution in diabetes-induced hyposalivation. Here, we observed that the morphologies of submandibular glands (SMGs) were impaired, characterized by enlarged acini accumulation with giant secretory granules, which were significantly reduced in atrophic ducts in SMGs of db/db mice, a spontaneous model of type-2 diabetes. However, the secretory granules were increased and scattered in the acini of diabetes parotid glands (PGs). Other ultrastructural damages including swollen mitochondria, expansive endoplasmic reticulum, and autophagosomes were observed in the diabetes group. The levels of TJ proteins including claudin-1 (Cldn1) and claudin-3 (Cldn3) were increased, whereas those of claudin-4 (Cldn4), occludin (Ocln), and zonula occludens-1 (ZO-1) were decreased in SMGs of db/db mice. Higher Cldn1 and Cldn3 and lower claudin-10 (Cldn10) and Ocln levels were observed in PGs of diabetes mice. Taken together, the structures of SMGs and PGs were impaired in diabetes mice, and the disruption of TJ integrity in both SMGs and PGs may contribute to diabetes-induced hyposalivation.

10.
J Biomed Sci ; 27(1): 70, 2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32466788

RESUMO

BACKGROUND: Hepatitis B virus (HBV) persistently infected about 250 million people worldwide, and a curative treatment remains an unmet medical need. Among many approaches to treat chronic hepatitis B (CHB), therapeutic vaccines have been developed for two decades, but none have yielded promising results in clinical trials. Therefore, dissection of HBV clearance mechanisms during therapeutic vaccination in appropriate models, which could give rise to new curative therapies, is urgently needed. Growing evidence indicates that prolonged and intensive exposure of antigen-specific T cells to viral antigens is a major cause of T cell exhaustion, and decreases anti-HBV immunity efficacy of therapeutic vaccination. HBV X protein (HBx) is expressed at low levels, and the understanding of its immunogenicity and potential in therapeutic CHB vaccines is limited. METHODS: HBV genome sequences from CHB patients were cloned into a pAAV plasmid backbone and transfected into immunocompetent mouse hepatocytes through hydrodynamic injection. Mice carrying > 500 IU/mL serum HBV surface antigen (HBs) for more than 4 weeks were considered HBV carriers mimicking human CHB and received 3 doses of weekly HBx vaccine by subcutaneous immunization. Serum HBV clearance was evaluated by monitoring serum HBs and HBV-DNA titers. Residual HBV in the liver was evaluated by western blotting for HBV core antigen. The splenic antigen-specific T cell response was quantified by a 15-mer overlapping peptide-stimulated interferon-γ enzyme-linked immunospot assay. Blood and hepatic immune cells were quantified by flow cytometric analysis. RESULTS: Our HBx-based vaccine induced systemic HBx-specific CD4+ and CD8+ T cell responses in HBV carrier mice and demonstrated significant HBs and HBV-DNA elimination. The protective effect persisted for at least 30 days without additional booster immunization. Different infiltrating myeloid cell subsets, each with distinctive roles during immune-mediated HBV clearance, were found in the liver of vaccinated mice. During vaccine therapy, inflammatory monocyte depletion resulted in sustained HBV clearance inhibition, whereas phagocytic monocyte-derived macrophage and Kupffer cell elimination resulted in only transient inhibition of vaccine-induced HBV clearance. CONCLUSIONS: We report the potential role of HBx as a major immunogen in an HBV therapeutic vaccine and the significance of a liver-infiltrating monocyte subset during hepatic viral clearance.


Assuntos
Antígenos da Hepatite B/metabolismo , Vacinas contra Hepatite B/administração & dosagem , Vírus da Hepatite B/imunologia , Fígado/virologia , Monócitos/metabolismo , Transativadores/administração & dosagem , Proteínas Virais Reguladoras e Acessórias/administração & dosagem , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA
11.
Proc Natl Acad Sci U S A ; 117(12): 6717-6725, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32139604

RESUMO

Most hepatocellular carcinomas (HCCs) develop in patients with chronic hepatitis, which creates a microenvironment for the growth of hepatic progenitor cells (HPCs) at the periportal area and subsequent development of HCCs. We investigated the signal from the inflammatory liver for this pathogenic process in the hepatic conditional ß-catenin knockout mouse model. Senescent ß-catenin-depleted hepatocytes in aged mice create an inflammatory microenvironment that stimulates periportal HPC expansion but arrests differentiation, which predisposes mice to the development of liver tumors. The release of complement C1q from macrophages in the inflammatory niche was identified as the unorthodox signal that activated the ß-catenin pathway in periportal HPCs and was responsible for their expansion and de-differentiation. C1q inhibitors blocked the ß-catenin pathway in both the expanding HPCs and the liver tumors but spared its orthodox pathway in pericentral normal hepatocytes. This mechanism has been validated in human liver specimens from patients with chronic hepatitis. Taken together, these results demonstrate that C1q- mediated activation of ß-catenin pathway in periportal HPCs is a previously unrecognized mechanism for replenishing hepatocytes in the inflammatory liver and, if unchecked, for promoting hepatocarcinogenesis. C1q may become a new target for blocking carcinogenesis in patients with chronic hepatitis.


Assuntos
Carcinoma Hepatocelular/etiologia , Complemento C1q/metabolismo , Hepatite Crônica/complicações , Neoplasias Hepáticas/etiologia , Fígado/patologia , Células-Tronco/patologia , beta Catenina/fisiologia , Animais , Carcinogênese , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Diferenciação Celular , Senescência Celular , Humanos , Fígado/imunologia , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Transdução de Sinais , Células-Tronco/imunologia , Células-Tronco/metabolismo , Microambiente Tumoral
12.
J Cell Physiol ; 235(1): 232-244, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31190343

RESUMO

Diabetes is often accompanied by dysfunction of salivary glands. However, the molecular mechanism remains unclear. The mechanisms that underlie diabetic hyposalivation were studied by db/db mice and SMG-C6 cells. We found morphological changes and decreased stimulated salivary flow rates of the submandibular gland (SMG) in diabetic mice. We observed structural changes and dysfunction of mitochondria. More mitophagosomes and higher expression of autophagy-related proteins were detected. Increased levels of proteins PINK1 and Parkin indicate that PINK1/Parkin-mediated mitophagy was activated in diabetic SMG. Consistently, high glucose (HG) induced mitochondrial dysfunction and PINK1/Parkin-mediated mitophagy in cultivated SMG-C6 cells. HG also increased reactive oxygen species (ROS) and lessened activation of antioxidants in SMG-C6 cells. In addition, HG lowered ERK1/2 phosphorylation and HG-induced mitophagy was decreased after ERK1/2 was activated by LM22B-10. Altogether, these data suggest that ROS played a crucial role in diabetes-induced mitochondrial dysfunction and PINK1/Parkin-mediated mitophagy and ERK1/2 was required in HG-induced mitophagy in SMG.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Mitofagia/efeitos dos fármacos , Proteínas Quinases/metabolismo , Glândulas Salivares/citologia , Ubiquitina-Proteína Ligases/metabolismo , Xerostomia/complicações , Animais , Linhagem Celular , Glucose/toxicidade , Camundongos , Camundongos Endogâmicos NOD , Mitocôndrias/metabolismo , Mitofagia/fisiologia , Proteínas Quinases/genética , Ratos , Glândulas Salivares/efeitos dos fármacos , Ubiquitina-Proteína Ligases/genética
13.
J Mol Histol ; 51(1): 33-46, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31865502

RESUMO

IgG4-related sialadenitis (IgG4-RS) is a chronic fibro-inflammatory disease characterized by swelling of salivary glands and varying degrees of xerostomia. Tight junctions (TJs) play an essential role in maintaining secretory function by regulating the paracellular flow of ions and water. However, whether TJs are altered and contribute to the hyposecretion in IgG4-RS is not fully understood. Here, a total of 399 differentially expressed proteins were identified in IgG4-RS submandibular glands (SMGs) and enriched in the regulation of actin cytoskeleton and the salivary secretion. Real-time PCR results showed that the mRNA levels of claudin-3, -4, -6, -7, -8, -10, -12, occludin, and ZO-1 were significantly lower, whereas claudin-1 and -5 were higher in IgG4-RS SMGs. Immunohistochemical and immunofluorescence staining revealed that claudin-1, -3, -4, occludin, and ZO-1 were mainly distributed at apicolateral membranes in acini and ducts of SMGs from controls, whereas claudin-1 protein intensity at apicolateral membrane was elevated, while the staining of claudin-3, -4, and ZO-1 were reduced in IgG4-RS SMGs. Occludin was dispersed into cytoplasm of acini and ducts in SMGs of patients. Among them, claudin-3 and ZO-1 protein levels were positively correlated with saliva flow rate. Furthermore, the decreased fluorescence intensity of F-actin at peri-apicolateral membranes and the loss of ZO-1 staining at the same location were observed in acinar and ductal cells of IgG4-RS SMGs, which might be responsible for disorganization of TJ complex. Taken together, these findings indicate that the integrity of TJ complex of SMGs is impaired and might contribute to hyposalivation of IgG4-RS patients.


Assuntos
Imunoglobulina G/metabolismo , Glândulas Salivares/metabolismo , Sialadenite/metabolismo , Proteínas de Junções Íntimas/biossíntese , Junções Íntimas/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Glândulas Salivares/patologia , Sialadenite/patologia , Junções Íntimas/patologia
14.
J Cancer ; 10(25): 6233-6243, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31772656

RESUMO

Objectives: Intro-arterial chemotherapy combined with radiotherapy (IACRT) for the treatment of head and neck cancer (HNC) underwent a revival in recent years. Although many clinical trials have reported favorable outcomes, the effect of IACRT for HNC is still controversial. Therefore, this study was designed to evaluate the efficacy and safety of IACRT for HNC. Methods: The relevant articles published before August 2019 were searched from PubMed, Embase, Cochrane Library, Web of Science and PMC databases. Data were extracted and the combined complete response (CR), overall survival (OS) and toxicity incidence with 95% credible interval (CI) were examined from eligible studies. Results: Thirty-four studies comprising 1890 patients were included. IACRT achieved high CR (0.81, 95% CI: 0.76-0.86, P < 0.001), 3-year OS (0.75, 95% CI: 0.68-0.82, P < 0.001) and 5-year OS (0.68, 95% CI: 0.61-0.75, P < 0.001). The 3-year OS rate of stage III cancer (0.75, 95% CI: 0.53-0.97, P< 0.001) was higher than stage IV (0.52, 95% CI: 0.37-0.66, P = 0.025). Meanwhile, the 5-year OS of T3 cancer (0.87, 95% CI: 0.73-1.01, P = 0.028) was higher than T4 (0.53, 95% CI: 0.42-0.63, P = 0.286). Additionally, oral diseases, mucositis, leukopenia and dermatitis were the major toxicities of IACRT, which were all reversible. Conclusion: IACRT is an efficient and safe modality for HNC, which could achieve favorable cancer response and higher survival rate with acceptable toxicities, even for advanced HNC.

15.
Antioxid Redox Signal ; 31(1): 75-91, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30829051

RESUMO

Aims: Vascular calcification is associated with cardiovascular death in patients with chronic kidney disease (CKD). Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) plays an important role in various cardiovascular diseases. However, its role in vascular calcification remains unknown. Results: Adenine-induced rat CKD model was used to induce arterial medial calcification. The level of PGC-1α decreased in abdominal aorta of CKD rats. Overexpression of PGC-1α significantly ameliorated calcium deposition in rat abdominal aorta, isolated carotid rings, and cultured vascular smooth muscle cells (VSMCs). Mitochondrial reactive oxygen species (mtROS) increased in calcifying aorta and VSMCs. Upregulation of PGC-1α inhibited, whereas PGC-1α depletion promoted ß-glycerophosphate-induced mtROS production and calcium deposition. Moreover, PGC-1α increased superoxide dismutase 1 (SOD1) and SOD2 contents in vivo and in vitro, whereas SOD2 deletion eliminated PGC-1α-mediated mtROS change and promoted calcium deposition. Mechanistically, sirtuin 3 (SIRT3) expression declined in calcifying aorta and VSMCs, while PGC-1α overexpression restored SIRT3 expression. Inhibition of SIRT3 by 3-TYP or siRNA (small interfering RNA) reduced PGC-1α-induced upregulation of SOD1 and SOD2, and abolished the protective effect of PGC-1α on calcification of VSMCs. Importantly, PGC-1α was reduced in calcified femoral arteries in CKD patients. In phosphate-induced human umbilical arterial calcification, upregulation of PGC-1α attenuated calcium nodule formation, while this protective effect was abolished by SIRT3 inhibitor. Innovation: We showed for the first time that PGC-1α is an important endogenous regulator against vascular calcification. Induction of PGC-1α could be a potential strategy to treat vascular calcification in CKD patients. Conclusions: PGC-1α protected against vascular calcification by SIRT3-mediated mtROS reduction.


Assuntos
Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Insuficiência Renal Crônica/metabolismo , Sirtuína 3/metabolismo , Calcificação Vascular/metabolismo , Adenina/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Animais , Aorta Abdominal/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Estresse Oxidativo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Ratos , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/complicações , Calcificação Vascular/genética
16.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 37(1): 87-91, 2019 Feb 01.
Artigo em Chinês | MEDLINE | ID: mdl-30854826

RESUMO

OBJECTIVE: This study aimed to evaluate the risk factors of radiation-induced caries by using a multiple linear regression equation and to provide the basis for the effective prevention of radioactive caries. METHODS: A total of 166 patients with head and neck cancer who underwent radiotherapy were selected as subjects. The number of decayed, missing or filled surfaces were recorded. Questionnaire contents included age, sex, radiation dose, and radiotherapy techniques. Multiple stepwise regression analyses were performed to identify the risk factors of radiation-induced caries. RESULTS: Multiple stepwise regression analyses indicated that the main risk factors of radiation-induced caries were plaque index, radiotherapy techniques, time after radiotherapy, and radiotherapy dose. CONCLUSIONS: The awareness of dental care and caries treatment should be improved to reduce the occurrence of radiation-induced caries in patients with head and neck cancer. In addition, intensity modulated radiation therapy should be employed to decrease the radiation exposure dose received by teeth.


Assuntos
Cárie Dentária , Neoplasias de Cabeça e Pescoço , Lesões por Radiação , Cárie Dentária/epidemiologia , Cárie Dentária/etiologia , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Lesões por Radiação/epidemiologia , Fatores de Risco , Dente
17.
Hepatology ; 69(6): 2364-2380, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30661248

RESUMO

To understand the mechanism(s) of age-dependent outcomes of hepatitis B virus (HBV) infection in humans, we previously established an age-related HBV mouse model in which 6-week-old (N6W) C3H/HeN mice exhibited virus tolerance whereas 12-week-old (N12W) counterparts presented virus clearance. By investigating the hepatic myeloid cell dynamics in mice of these two ages, we aim to identify factors associated with HBV clearance. C3H/HeN mice were transfected with an HBV plasmid by hydrodynamic injection. Serum HBV markers were monitored weekly. Hepatic leucocyte populations and their cytokine/chemokine productions were examined at baseline, day 3 (D3), day 7 (D7), and day 14 after injection. C-C chemokine receptor type 2 (CCR2) antagonist and clodronate (CLD) were respectively administered to N12W and N6W mice to study the roles of lymphocyte antigen 6 complex, locus C (Ly6C)+ monocytes and Kupffer cells (KCs) in viral clearance. N12W mice had a significantly higher number of TNF-α-secreting Ly6C+ monocytes and fewer IL-10-secreting KCs at D3 in the liver than their younger N6W counterparts after HBV transfection. In addition, the elevated number of interferon-γ+ TNF-α+ CD8+ T cells at D7 was only seen in the older cohort. The enhanced Ly6C+ monocyte induction in N12W mice resulted from elevated C-C motif chemokine ligand 2 (CCL2) secretion by hepatocytes. CCR2 antagonist administration hampered Ly6C+ monocyte recruitment and degree of KC reduction and delayed HBV clearance in N12W animals. Depletion of KCs by CLD liposomes enhanced Ly6C+ monocyte recruitment and accelerated HBV clearance in N6W mice. Conclusions: Ly6C+ monocytes and KCs may, respectively, represent the resistance and tolerance arms of host defenses. These two cell types play an essential role in determining HBV clearance/tolerance. Manipulation of these cells is a promising avenue for immunotherapy of HBV-related liver diseases.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/genética , Hepatite B/imunologia , Imunoterapia/métodos , Monócitos/imunologia , Animais , Células Cultivadas , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Hepatite B/fisiopatologia , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Hepatócitos/imunologia , Humanos , Macrófagos do Fígado/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Distribuição Aleatória , Valores de Referência , Transfecção
18.
Biochem Biophys Res Commun ; 508(4): 1195-1201, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30554658

RESUMO

Phosphoinositide 3-kinase (PI3K)/Akt plays a pivotal role in the vascular response. The present study is to determine whether PI3K/Akt pathway in vascular smooth muscle cells is involved in nitroglycerin (NTG) tolerance and the underlying mechanism. Nitrate tolerance of porcine coronary arteries in vitro was induced by incubation of NTG (10-5 M) for 24 h. Nitrate tolerance in vivo was obtained by subcutaneous injection of mice with NTG (20 mg kg-1, tid, 3 days) and the aortas were used. Protein levels of total and phosphorylated Akt, forkhead box protein O1 (FoxO1), and cGMP-dependent protein kinase (PKG) were determined by western blot analysis. Isometric vessel tension was recorded by organ chamber technique. PKG mRNA was determined by real-time PCR. The cellular translocation of FoxO1 was observed by immunofluorescence. Reactive oxygen species (ROS) level was measured by DHE staining. The vascular relaxation to NTG was significantly inhibited in in vivo and in vitro NTG tolerant arteries. Meanwhile, the protein level of phosphorylated Akt at Ser473 was increased in the tolerant arteries. The attenuated relaxation and the augmented Akt-p were ameliorated by LY294002, a specific inhibitor of PI3K. The protein and mRNA expression of PKG were significantly down-regulated in NTG tolerant arteries, which were reversed by LY294002. The level of phosphorylated FoxO1 at Ser256 and its translocation from the nucleus to the cytosol were both increased in NTG tolerance and were also inhibited by LY294002. ROS production was significantly increased in NTG tolerant arteries, which was not be affected by LY294002 but inhibited by N-acetyl-L-cysteine. In conclusion, the present study suggests that PI3K/Akt in vascular smooth muscle is involved in the development of NTG tolerance via inhibiting PKG transcription and the effect is mediated by FoxO1.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/genética , Proteína Forkhead Box O1/metabolismo , Nitroglicerina/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Animais , Cromonas/farmacologia , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Inibidores da Fosfodiesterase 5/farmacologia , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Suínos , Vasodilatação/efeitos dos fármacos
19.
J Cell Physiol ; 234(6): 9515-9524, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30387129

RESUMO

Parasympathectomy leads to retrogressive alteration and dysfunction of the submandibular gland (SMG) within 1 month, but its long-term effect is unclear. Excessive secretion is observed in half of the patients 4-6 months after SMG transplantation, which completely denervates the gland. Here, we investigated the long-term effect of parasympathectomy on the secretion of SMGs in minipigs. The results showed that the resting salivary secretion of SMGs decreased by 82.9% of that in control at 2 months after denervation, but increased by 156% at 6 months. Although experiencing an atrophic period, the denervated glands regained their normal morphology by 6 months. The expression of the function-related proteins, including muscarinic acetylcholine receptor (mAChR) 3, aquaporin 5 (AQP5), tight junction protein claudin-3, and claudin-4 was decreased at 2 months after denervation. Meanwhile, the protein expression of stem cell markers, including sex-determining region Y-box 2 and octamer-binding transcription factor 4, and the number of Ki67+ cells were significantly increased. However, at 6 months after denervation, the expression of mAChR3, AQP5, claudin-1, claudin-3, and claudin-4 was significantly raised, and the membrane distribution of these proteins was increased accordingly. The autonomic axonal area of the glands was reduced at 2 months after denervation but returned to the control level at 6 months, suggesting that reinnervation took place in the long term. In summary, parasympathectomy increases resting secretion of the SMGs in the long term with a possible mechanism involving improved transepithelial fluid transport. This finding may provide a new strategy for xerostomia treatment.


Assuntos
Parassimpatectomia , Glândula Submandibular/cirurgia , Animais , Transporte Biológico , Líquidos Corporais/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Células-Tronco/metabolismo , Glândula Submandibular/inervação , Suínos , Porco Miniatura , Fatores de Tempo , Fatores de Transcrição/metabolismo
20.
Zhongguo Zhong Yao Za Zhi ; 43(21): 4220-4225, 2018 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-30583621

RESUMO

Psammosilene tunicoides is one of the main ingredients of the "Yunnan Baiyao". P. tunicoides is an endangered species included in the secondary protection list in China Plant Red Data Book as well as the endemic species in Southwest China. Its natural resources could not meet the needs of pharmaceutical production. Construction of core collection of P. tunicoides will lay the foundation for germplasm improvement and molecular breeding. The sequence variation of the key enzymes gene locus (ß-AS) were carried out to survey the population structure and population history of the species. Among the 11 populations across its geographical range, 36 haplotypes were identified. The levels of haplotype diversity (Hd=0.905) were high, while the levels of population differentiation (GST=0.280) were low. Analysisof molecular variance (AMOVA) indicated that a significantly greater proportion of total genetic variationpartitioned among populations thanwithin populations (values of 77.43% and 22.57%, respectively). These results in combination with the star-like phylogenetic network analysis indicate that Hap1 as an ancestral haplotypewas shared in four populations, Hap2, Hap4, Hap15 and Hap16 are occurred in two populations, the remains as private haplotype only distributed in single population. The strategy of core collection was constructed in order to maximumpreserve genetic diversity of P. tunicoides.


Assuntos
Caryophyllaceae/genética , Variação Genética , China , Genética Populacional , Haplótipos , Filogenia , Plantas Medicinais/genética
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