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1.
Cell Mol Immunol ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34522020

RESUMO

Invariant natural killer T (iNKT) cells are highly conserved innate-like T lymphocytes that originate from CD4+CD8+ double-positive (DP) thymocytes. Here, we report that serine/arginine splicing factor 1 (SRSF1) intrinsically regulates iNKT cell development by directly targeting Myb and balancing the abundance of short and long isoforms. Conditional ablation of SRSF1 in DP cells led to a substantially diminished iNKT cell pool due to defects in proliferation, survival, and TCRα rearrangement. The transition from stage 0 to stage 1 of iNKT cells was substantially blocked, and the iNKT2 subset was notably diminished in SRSF1-deficient mice. SRSF1 deficiency resulted in aberrant expression of a series of regulators that are tightly correlated with iNKT cell development and iNKT2 differentiation, including Myb, PLZF, Gata3, ICOS, and CD5. In particular, we found that SRSF1 directly binds and regulates pre-mRNA alternative splicing of Myb and that the expression of the short isoform of Myb is substantially reduced in SRSF1-deficient DP and iNKT cells. Strikingly, ectopic expression of the Myb short isoform partially rectified the defects caused by ablation of SRSF1. Furthermore, we confirmed that the SRSF1-deficient mice exhibited resistance to acute liver injury upon α-GalCer and Con A induction. Our findings thus uncovered a previously unknown role of SRSF1 as an essential post-transcriptional regulator in iNKT cell development and functional differentiation, providing new clinical insights into iNKT-correlated disease.

2.
J Steroid Biochem Mol Biol ; 214: 105991, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34487832

RESUMO

BACKGROUND: Valproate (VPA) is an antiepileptic drug (AEDs) with an ideal effect against epilepsy as well as other neuropsychiatric diseases. There is considerable evidence that women taking VPA are prone to reproductive endocrine disorders. However, few studies have been published about VPA effects on human ovarian granulosa cells. METHODS: By treating human ovarian granulosa cell line KGN with VPA, the cell viability and progesterone production function were evaluated. RNA-sequencing was applied to uncover the global gene expression upon VPA treatment. RESULTS: We revealed that VPA dose-dependently repressed the viability of KGN. VPA treatment at 600 µM inhibited the progesterone production. The mRNA and protein expression of CYP11A1 and STAR, two key enzymes in the biosynthesis of progesterone, were both suppressed. Gene set enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis of the transcriptome revealed classical functions of VPA as a neuromodulator and regulator of histone acetylation modifications. In addition to this, VPA commonly affected many steroid metabolism related genes in follicle cells, such as promoting the expression of vitamin D receptor (VDR). CONCLUSION: Our findings suggest that VPA caused steroids metabolism pathways disturbance related with ovarian function and inhibited progesterone biosynthesis by inhibiting the expression of steroidogenesis genes. Our research may provide theoretical basis for the better use of VPA and the possible ways to counteract its side effects.

3.
Autophagy ; : 1-19, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34524943

RESUMO

Epidemiological and clinical studies have shown that exposure to particulate matter (PM) is associated with an increased incidence of lung cancer and metastasis. However, the underlying mechanism remains unclear. Here, we demonstrated the central role of PM-induced neutrophil recruitment in promoting lung cancer metastasis. We found that reactive oxygen species (ROS)-mediated alveolar epithelial macroautophagy/autophagy was essential for initiating neutrophil chemotaxis and pre-metastatic niche formation in the lungs in response to PM exposure. During PM-induced autophagy, the E3 ubiquitin ligase TRIM37 was degraded and protected TRAF6 from proteasomal degradation in lung epithelial cells, which promoted the NFKB-dependent production of chemokines to recruit neutrophils. Importantly, ROS blockade, autophagy inhibition or TRAF6 knockdown abolished PM-induced neutrophil recruitment and lung metastasis enhancement. Our study indicates that host lung epithelial cells and neutrophils coordinate to promote cancer metastasis to the lungs in response to PM exposure and provides ideal therapeutic targets for metastatic progression.Abbreviations: ACTA2/α-SMA: actin alpha 2, smooth muscle, aorta; ATII: alveolar type II; Cho-Traf6 siRNA: 5'-cholesterol-Traf6 siRNA; EMT: epithelial-mesenchymal transition; HBE: human bronchial epithelial; HCQ: hydroxychloroquine; MAPK: mitogen-activated protein kinase; NAC: N-acetyl-L-cysteine; NFKB: nuclear factor of kappa light polypeptide gene enhancer in B cells; NS: normal saline; PM: particulate matter; ROS: reactive oxygen species; TRAF6: TNF receptor-associated factor 6; TRIM37: tripartite motif-containing 37.

4.
J Cell Sci ; 134(2)2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34432034

RESUMO

Silicosis is characterized by silica exposure-induced lung interstitial fibrosis and formation of silicotic nodules, resulting in lung stiffening. The acetylation of microtubules mediated by α-tubulin N-acetyltransferase 1 (α-TAT1) is a posttranslational modification that promotes microtubule stability in response to mechanical stimulation. α-TAT1 and downstream acetylated α-tubulin (Ac-α-Tub) are decreased in silicosis, promoting the epithelial-mesenchymal transition (EMT); however, the underlying mechanisms are unknown. We found that silica, matrix stiffening or their combination triggered Ac-α-Tub downregulation in alveolar epithelial cells, followed by DNA damage and replication stress. α-TAT1 elevated Ac-α-Tub to limit replication stress and the EMT via trafficking of p53-binding protein 1 (53BP1, also known as TP53BP1). The results provide evidence that α-TAT1 and Ac-α-Tub inhibit the EMT and silicosis fibrosis by preventing 53BP1 mislocalization and relieving DNA damage. This study provides insight into how the cell cycle is regulated during the EMT and why the decrease in α-TAT1 and Ac-α-Tub promotes silicosis fibrosis. This article has an associated First Person interview with the first authors of the paper.


Assuntos
Transição Epitelial-Mesenquimal , Tubulina (Proteína) , Acetilação , Dano ao DNA , Transição Epitelial-Mesenquimal/genética , Humanos , Processamento de Proteína Pós-Traducional , Dióxido de Silício/toxicidade , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo
5.
Zhongguo Zhong Yao Za Zhi ; 46(11): 2881-2888, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34296589

RESUMO

In this study, patients with prehypertensive liver-fire hyperactivity syndrome(LFHS) were selected as the research objects. The plasma samples of healthy volunteers and patients with prehypertensive LFHS were analyzed by non-targeted metabolomics based on UPLC-Q-Exactive MS. The differential biomarkers and metabolic pathways were screened out by multivariate statistics and metabolic pathway analysis, which revealed the characteristics of metabolic patterns of the syndrome. Thirty-three potential biomarkers such as androsterone and lysophosphatidylcholine and 16 related metabolic pathways such as steroid hormone metabolism and lipid metabolism were identified, and a partial least squares-discriminant analysis(PLS-DA) model of traditional Chinese medicine(TCM) syndromes was preliminarily constructed: Y =-0.070X_(13)-0.006X_8+ 0.040X_5-0.152X_1+0.131X_(10)+0.036X_(11)+0.043X_(23)+0.076X_(16)+0.132X_(20)+0.081X_(19)-0.101X_(31)+0.082X_(15)-0.038X_9+0.079X_(24). The predictive value of the model was 88.1%, and the explanatory power was 88.4%. In this study, the characteristic metabolic pattern of the prehypertensive LFHS was distinguished and revealed by metabolomics. The constructed PLS-DA model is expected to provide an objective basis for the identification of TCM syndromes in prehypertension, and inspiration for exploring the biological basis of TCM syndromes at small-molecular and overall levels.


Assuntos
Fígado , Metabolômica , Biomarcadores , Cromatografia Líquida de Alta Pressão , Humanos , Síndrome , Tecnologia
6.
Bioorg Chem ; 115: 105172, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34303898

RESUMO

Two series of tetrahydrocarbazole derivatives have been designed and synthesized based on ZG02, a promising candidate developed in our previous studies. The newly prepared compounds were screened for glucose consumption activity in HepG2 cell lines. Aza-tetrahydrocarbazole compound 12b showed the most potent hypoglycemic activity with a 45% increase in glucose consumption when compared to the solvent control, which had approximately 1.2-fold higher activity than the positive control compounds (metformin and ZG02). An investigation of the potential mechanism indicated that 12b may exhibit hypoglycemic activity via activation of the AMPK pathway. Metabolic stability assays revealed that 12b showed good stability profiles in both artificial gastrointestinal fluids and blood plasma from SD rats. An oral glucose tolerance test (OGTT) was performed and the results further confirmed that 12b was a potent hypoglycemic agent.

7.
Toxicol Mech Methods ; 31(9): 655-666, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34225584

RESUMO

Pulmonary fibrosis induced by silica dust is an irreversible, chronic, and fibroproliferative lung disease with no effective treatment at present. BMSCs-derived exosomes (BMSCs-Exo) possess similar functions to their parent cells. In this study, we investigated the therapeutic potential and underlying molecular mechanism for BMSCs-Exo in the treatment of silica-induced pulmonary fibrosis. The rat model of experimental silicosis pulmonary fibrosis was induced with 1.0 mL of one-off infusing silica suspension using the non-exposed intratracheal instillation (50 mg/mL/rat). In vivo transplantation of BMSCs-Exo effectively alleviated silica-induced pulmonary fibrosis, including a reduction in collagen accumulation, inhibition of TGF-ß1, and decreased HYP content. Treatment of BMSCs-Exo increased the expression of epithelial marker proteins including E-cadherin (E-cad) and cytokeratin19 (CK19) and reduced the expression of fibrosis marker proteins including α-Smooth muscle actin (α-SMA) after exposure to silica suspension. Furthermore, we found that BMSCs-Exo inhibited the expression of Wnt/ß-catenin pathway components (P-GSK3ß, ß-catenin, Cyclin D1) in pulmonary fibrosis tissue. BMSCs-Exo is involved in the alleviation of silica-induced pulmonary fibrosis by reducing the level of profibrotic factor TGF-ß1 and inhibiting the progression of epithelial-mesenchymal transition (EMT). Additionally, attenuation of the Wnt/ß-catenin signaling pathway closely related to EMT may be one of the mechanisms involved in anti-fibrotic effects of exosomes.

8.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073283

RESUMO

Infection induces the production of proinflammatory cytokines and chemokines such as interleukin-8 (IL-8) and IL-6. Although they facilitate local antiviral immunity, their excessive release leads to life-threatening cytokine release syndrome, exemplified by the severe cases of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this study, we investigated the roles of the integrated stress response (ISR) and activator protein-1 (AP-1) family proteins in regulating coronavirus-induced IL-8 and IL-6 upregulation. The mRNA expression of IL-8 and IL-6 was significantly induced in cells infected with infectious bronchitis virus (IBV), a gammacoronavirus, and porcine epidemic diarrhea virus, an alphacoronavirus. Overexpression of a constitutively active phosphomimetic mutant of eukaryotic translation initiation factor 2α (eIF2α), chemical inhibition of its dephosphorylation, or overexpression of its upstream double-stranded RNA-dependent protein kinase (PKR) significantly enhanced IL-8 mRNA expression in IBV-infected cells. Overexpression of the AP-1 protein cJUN or its upstream kinase also increased the IBV-induced IL-8 mRNA expression, which was synergistically enhanced by overexpression of cFOS. Taken together, this study demonstrated the important regulatory roles of ISR and AP-1 proteins in IL-8 production during coronavirus infection, highlighting the complex interactions between cellular stress pathways and the innate immune response.


Assuntos
Infecções por Coronavirus/metabolismo , Estresse do Retículo Endoplasmático/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Interleucina-8/metabolismo , Resposta a Proteínas não Dobradas/genética , Alphacoronavirus/metabolismo , Alphacoronavirus/patogenicidade , Animais , Linhagem Celular , Chlorocebus aethiops , Infecções por Coronavirus/genética , Gammacoronavirus/metabolismo , Gammacoronavirus/patogenicidade , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Vírus da Bronquite Infecciosa/metabolismo , Vírus da Bronquite Infecciosa/patogenicidade , Interleucina-8/genética , Fosforilação , Vírus da Diarreia Epidêmica Suína/metabolismo , Vírus da Diarreia Epidêmica Suína/patogenicidade , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Transdução de Sinais/genética , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Regulação para Cima , Células Vero , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
9.
Medicine (Baltimore) ; 100(1): e24208, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429812

RESUMO

OBJECTIVE: To explore the influence of the education of lifestyle in the type 2 diabetes mellitus (T2DM) patients with microalbuminuria as a part of the enhanced multifactorial intervention. METHODS: This study will be conducted from May 2021 to August 2022 at Ningbo No.6 hospital. The experiment was granted through the Research Ethics Committee of Ningbo No.6 hospital (539D035). The patients will be included if they are between 18 and 65 years old and are diagnosed with T2DM with microalbuminuria and the patients who have signed the written informed consent. While the patients will be excluded if they have serious physical comorbidities and patients who are unwilling to offer the informed consent to take part in this experiment. We measure the clinical examination (fasting blood-glucose, glycosylated hemoglobin and routine urine test) timely. Detail of daily dietary intake and lifestyle factors are also recorded. RESULTS: Table 1 reflects the comparison of the biochemical and clinical variables and the lifestyle factors. CONCLUSION: Lifestyle education is effective in facilitating the control of T2DM and reducing microalbuminuria. TRIAL REGISTRATION NUMBER: researchregistry6348.


Assuntos
Diabetes Mellitus Tipo 2/terapia , Educação de Pacientes como Assunto , Assunção de Riscos , Albuminúria/complicações , Diabetes Mellitus Tipo 2/complicações , Humanos
10.
Cell Mol Life Sci ; 78(2): 531-544, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32780149

RESUMO

Currently, a novel coronavirus (SARS-CoV-2, also called 2019-nCoV) has triggered pandemic Coronavirus Disease 2019 (COVID-19), an acute infectious respiratory disease that first became epidemic in Wuhan (China) and is now spreading worldwide. Although 2019-nCoV and SARS-CoV are very similar viruses genomically and structurally, the huge number of severe cases and deaths now being caused by 2019-nCoV infections has understandably prompted intense research on the receptor used by it to enter human cells. Angiotensin converting enzyme 2 (ACE2), a functional receptor for SARS-CoV, now appears likely to mediate 2019-nCoV entry into human cells. In this review, we describe the roles performed by ACE2 as an enzymatic catalyst and as a receptor for this novel coronavirus. We also summarize the latest research pertaining to the changes noted in ACE2 expression after viral binding, and the relationships relating to virus transmission and population susceptibility to it. Lastly, we speculate on the pathogenesis of COVID-19 and provide a useful reference for drug development against this aggressive virus.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , COVID-19/virologia , SARS-CoV-2/fisiologia , Animais , Humanos , Pandemias , SARS-CoV-2/metabolismo , Internalização do Vírus
12.
J Cell Sci ; 134(2)2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33310909

RESUMO

Silicosis is characterized by silica exposure-induced lung interstitial fibrosis and formation of silicotic nodules, resulting in lung stiffening. The acetylation of microtubules mediated by α-tubulin N-acetyltransferase 1 (α-TAT1) is a posttranslational modification that promotes microtubule stability in response to mechanical stimulation. α-TAT1 and downstream acetylated α-tubulin (Ac-α-Tub) are decreased in silicosis, promoting the epithelial-mesenchymal transition (EMT); however, the underlying mechanisms are unknown. We found that silica, matrix stiffening or their combination triggered Ac-α-Tub downregulation in alveolar epithelial cells, followed by DNA damage and replication stress. α-TAT1 elevated Ac-α-Tub to limit replication stress and the EMT via trafficking of p53-binding protein 1 (53BP1, also known as TP53BP1). The results provide evidence that α-TAT1 and Ac-α-Tub inhibit the EMT and silicosis fibrosis by preventing 53BP1 mislocalization and relieving DNA damage. This study provides insight into how the cell cycle is regulated during the EMT and why the decrease in α-TAT1 and Ac-α-Tub promotes silicosis fibrosis.This article has an associated First Person interview with the first authors of the paper.


Assuntos
Transição Epitelial-Mesenquimal , Tubulina (Proteína) , Acetilação , Dano ao DNA , Transição Epitelial-Mesenquimal/genética , Processamento de Proteína Pós-Traducional , Dióxido de Silício/toxicidade , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo
13.
BMC Plant Biol ; 20(1): 558, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33302868

RESUMO

BACKGROUND: Previous studies have shown that ABFs (abscisic acid-responsive transcription factors) are important ABA-signaling components that participate in abiotic stress response. However, little is known about the function of ABFs in Triticum aestivum. In addition, although various ABFs have been identified in other species, the phylogenetic relationship between ABF transcription factors has not been systemically investigated in land plants. RESULTS: In this study, we systemically collected ABFs from land plants and analyzed the phylogenetic relationship of these ABF genes. The ABF genes are present in all the land plants we investigated, including moss, lycophyte, monocots, and eudicots. Furthermore, these ABF genes are phylogenetically divided into seven subgroups, differentiations that are supported by variation in the gene structure, protein properties, and motif patterns. We further demonstrated that the expression of ABF genes varies among different tissues and developmental stages, and are induced by one or more environmental stresses. Furthermore, we found that three wheat ABFs (TaABF1, TaABF2, and TaABF3) were significantly induced by drought stress. Compared with wild-type (WT) plants, transgenic Arabidopsis plants overexpressing TaABF3 displayed enhanced drought tolerance. CONCLUSIONS: These results provide important ground work for understanding the phylogenetic relationships between plant ABF genes. Our results also indicate that TaABFs may participate in regulating plant response to abiotic stresses.

14.
Front Immunol ; 11: 603157, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33178229

RESUMO

Immune checkpoint inhibitors (ICIs) have brought impressive clinical benefits in a variety of malignancies over the past years, which dramatically revolutionized the cancer treatment paradigm. Monotherapy or in combination with chemotherapy of ICIs targeting programmed death 1/programmed death ligand 1 (PD-L1) has emerged as an alternative treatment for patients with advanced non-small-cell lung cancer (NSCLC). However, constrained by primary or acquired resistance, most patients obtain limited benefits from ICIs and occasionally suffer from severe immune-related adverse events. Moreover, owing to the complexity of the tumor microenvironment and the technical limitations, clinical application of PD-L1 and tumor mutation burden as biomarkers shows many deficiencies. Thus, additional predictive biomarkers are required to further advance the precision of proper patient selection, avoiding the exposure of potential non-responders to unnecessary immunotoxicity. Nowadays, an increasing number of investigations are focusing on peripheral blood as a noninvasive alternative to tissue biopsy in predicting and monitoring treatment outcomes. Herein, we summarize the emerging blood-based biomarkers that could predict the clinical response to checkpoint immunotherapy, specifically in patients with NSCLC.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Tomada de Decisão Clínica , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Valor Preditivo dos Testes , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais , Resultado do Tratamento , Microambiente Tumoral
15.
J Virol ; 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33239458

RESUMO

Coronaviruses have evolved a variety of strategies to optimize cellular microenvironment for efficient replication. In this study, we report the induction of AP-1 transcription factors by coronavirus infection based on genome-wide analyses of differentially expressed genes in cells infected with avian coronavirus infectious bronchitis virus (IBV). Most members of the AP-1 transcription factors were subsequently found to be upregulated during the course of IBV and porcine epidemic diarrhea virus (PEDV) infection of cultured cells as well as in IBV-infected chicken embryos. Further characterization of the induction kinetics and functional roles of cFOS in IBV replication demonstrated that upregulation of cFOS at early to intermediate phases of IBV replication cycles suppresses IBV-induced apoptosis and promotes viral replication. Blockage of nuclear translocation of cFOS by peptide inhibitor NLSP suppressed IBV replication and apoptosis, ruling out the involvement of the cytoplasmic functions of cFOS in the replication of IBV. Furthermore, knockdown of ERK1/2 and inhibition of JNK and p38 kinase activities reduced cFOS upregulation and IBV replication. This study reveals an important function of cFOS in the regulation of coronavirus-induced apoptosis, facilitating viral replication.IMPORTANCE The ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by a newly emerged zoonotic coronavirus (SARS-CoV-2), highlights the importance of coronaviruses as human and animal pathogens and our knowledge gaps in understanding the cellular mechanisms, especially mechanisms shared among human and animal coronaviruses, exploited by coronaviruses for optimal replication and enhanced pathogenicity. This study reveals that upregulation of cFOS, along with other AP-1 transcription factors, as a cell-survival strategy is such a mechanism utilized by coronaviruses during their replication cycles. Through induction and regulation of apoptosis of the infected cells at early to intermediate phases of the replication cycles, subtle but appreciable differences in coronavirus replication efficiency were observed when the expression levels of cFOS were manipulated in the infected cells. As the AP-1 transcription factors are multi-functional, further studies of their regulatory roles in proinflammatory responses may provide new insights into the pathogenesis and virus-host interactions during coronavirus infection.

16.
Int J Med Sci ; 17(18): 2947-2953, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33173415

RESUMO

Background: Ultrasound is emerging as an effective method for measuring muscle mass in elderly people. It has been applied in numerous studies to obtain measurement of lower limbs. The study aims to explore the relationship between sarcopenia and ultrasound measurements of biceps brachii. Methods: Participants (n=179) aged over 60 years were enrolled from the first affiliated hospital of Zhejiang University. The muscle thickness (MT), cross-sectional area (CSA) and fat thickness (FT) of these participants were recorded. Spearman test and partial correlation test was used to determine the correlation between indicators. Mann-Whitney U test was performed to compare ultrasonic parameters between sarcopenia group and non-sarcopenia group. The binary logistic regression analysis was employed to detect the potential indicators and prediction equation of sarcopenia. Receiver operating characteristic (ROC) curve analysis was performed for the accuracy of equation. Results: The prevalence of sarcopenia were 16.3% and 10.8% respectively in men and women. CSA was significantly lower in sarcopenia group than non-sarcopenia group in women (P<0.05). CSA was positively correlated with skeletal muscle mass index (SMI) and grip strength (men: r=0.460, 0.433; women: r=0.267, 0.392). After controlling of age and BMI, these correlations disappeared. Binary logistic regression analysis showed that age (OR=1.149, 95%CI: 1.060-1.246; P=0.001) and CSA (OR=0.465, 95%CI: 0.225-0.963; P=0.039) was significant indicators associated with sarcopenia. Area Under Curve was 0.822 (95%CI: 0.725-0.919, P<0.001) for the prediction equation composed of age, gender and CSA for sarcopenia. Conclusion: CSA of the biceps brachii measured with ultrasound is an important indicator associated with sarcopenia.

17.
Toxicol Appl Pharmacol ; 408: 115255, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33007385

RESUMO

Silicosis is a major public health concern with various contributing factors. The renin-angiotensin system (RAS)is a critical regulator in the pathogenesis of this disease. We focused on two key RAS enzymes, angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2), to elucidate the activation of the ACE-angiotensin II (Ang II)-angiotensin II receptor 1 (AT1) axis and the inhibition of the ACE2-angiotensin-(1-7) [Ang-(1-7)]-Mas receptor axis in C57BL/6mice following SiO2 treatment. Silica exposure caused nodule formation, pulmonary interstitial fibrosis, epithelial-mesenchymal transition (EMT), abnormal deposition of extracellular matrix, and impaired lung function in mice. These effects were attenuated by the inhibition of ACE (captopril), blockade of the AT1(losartan), or systemic knockdown of the Ace gene. These effects were exacerbated by the inhibition of ACE2 (MLN-4760), blockade of the Mas (A779), or knockdown of the Ace2 gene. N-Acetyl-Seryl-Asparyl-Lysyl-Proline (Ac-SDKP), an anti-fibrotic peptide, ameliorated the silica-exposure-induced pathological changes by targeting the RAS system by activating the protective ACE2-Ang-(1-7)-Mas axis and inhibiting the deleterious ACE-Ang II-AT1 axis, thereby exerting a protective effect. This was confirmed in mouse lung type II epithelial cells (MLE-12) pretreated with Ang II and/or gene silencing separately targeting Ace and Ace2.The effects of Ac-SDKP were similar to those produced by Ace gene silencing and were partly attenuated by Ace2 deficiency. These findings suggested that RAS plays critical roles in the pathomechanism of silicosis fibrosis and that Ac-SDKP regulates lung RAS to inhibit EMT in silicotic mice and MLE-12 cells.


Assuntos
Transição Epitelial-Mesenquimal , Pulmão/metabolismo , Oligopeptídeos , Sistema Renina-Angiotensina , Silicose/metabolismo , Angiotensina I/antagonistas & inibidores , Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/genética , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Captopril/farmacologia , Linhagem Celular , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose , Losartan/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/antagonistas & inibidores , Peptidil Dipeptidase A , Sistema Renina-Angiotensina/efeitos dos fármacos , Silicose/patologia , Silicose/fisiopatologia
18.
Toxicol Res (Camb) ; 9(4): 509-518, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32905263

RESUMO

In our previous study, we found that subchronic exposure of chlorpyrifos (CPF) can cause reproductive damage in male rats. However, the mechanisms underlying the reproductive effects of CPF are not well understood. DNA methylation is essential for epigenetic gene regulation in development and disease. Therefore, we aim to compare DNA methylation profiles between controls and CPF-treated rats in order to identify the epigenetic mechanism of male reproductive toxicity induced by CPF. Methylated DNA immunoprecipitation with high-throughput sequencing (MeDIP-seq) was used to investigate the genome-wide DNA methylation pattern in testes of control and CPF-treated rats for 90 days. We identified 27 019 differentially methylated regions (DMRs) (14 150 upmethylated and 12 869 downmethylated) between CPF-exposed and control groups. The DMR-related genes are mainly involved in 113 pathways predicted by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The result showed that high methylation gene PIK3CD may play a key role in epigenetic regulation of multiple pathways, such as Ras signaling pathway, AGE-RAGE signaling pathway in diabetic complications, HIF-1 signaling pathway, VEGF signaling pathway, and glioma and Fc epsilon RI signaling pathway in rats exposed to CPF. Our study provides significant explanations for the epigenetic mechanism of male reproductive toxicology induced by CPF.

19.
Angew Chem Int Ed Engl ; 59(49): 22054-22062, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32705778

RESUMO

The direct depletion of lactate accumulated in the tumor microenvironment holds promise for cancer therapy but remains challenging. Herein, we report a one-pot synthesis of openwork@ dendritic mesoporous silica nanoparticles (ODMSNs) to address this problem. ODMSNs self-assembled through a time-resolved lamellar growth mechanism feature an openworked core and a dendritic shell, both constructed by silica nanosheets of ≈3 nm. With a large pore size, high surface area and pore volume, ODMSNs exhibited a high loading capacity (>0.7 g g-1 ) of lactate oxidase (LOX) and enabled intratumoral lactate depletion by >99.9 %, leading to anti-angiogenesis, down-regulation of vascular endothelial growth factor, and increased tumor hypoxia. The latter event facilitates the activation of a co-delivered prodrug for enhancing anti-tumor and anti-metastasis efficacy. This study provides an innovative nano-delivery system and demonstrates the first example of direct lactate-depletion-enabled chemotherapy.


Assuntos
Inibidores da Angiogênese/farmacologia , Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Ácido Láctico/metabolismo , Neovascularização Patológica/tratamento farmacológico , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dendrímeros/química , Sistemas de Liberação de Medicamentos , Feminino , Hipóxia/tratamento farmacológico , Camundongos , Oxigenases de Função Mista/metabolismo , Nanopartículas/química , Tamanho da Partícula , Porosidade , Dióxido de Silício/química , Propriedades de Superfície , Microambiente Tumoral/efeitos dos fármacos
20.
Sci Total Environ ; 740: 139810, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32563865

RESUMO

Maize (Zea mays L.)/soybean (Glycine max L.) intercropping has been widely practiced in China, because of its effectiveness in improving crop yield and nitrogen utilization efficiency. However, the responses of indigenous arbuscular mycorrhizal fungal (AMF) diversity and communities in rhizosphere soil and roots to intercropping systems with different nitrogen application rates remain unclear. In this study, a field experiment was conducted with split-plot design, and AMF communities in crop rhizosphere soil and roots in monoculture and intercropping systems treated with different levels of nitrogen fertilization were investigated using Illumina MiSeq sequencing. Nitrogen fertilization significantly decreased the AMF alpha-diversity in maize rhizosphere soil, and no significant differences were observed between monocultured and intercropped maize. The Shannon index of soybean rhizosphere soil was significantly higher in intercropping treatments than in monoculture treatments for the corresponding nitrogen levels. The AMF diversity in the roots of maize showed different trends to those in the soil. The dominant genera in the present study were Glomus_f_Glomeraceae, Paraglomus, and Gigaspora, which occupied 55.52%, 9.18%, and 8.20% of the rhizosphere soil and 65.35%, 5.32%, and 17.16% of the roots, respectively. Our study showed that the abundance of the dominant genus, Glomus_f_Glomeraceae in maize soil and roots significantly increased in intercropping treatments compared with monoculture treatments, and it also increased with the increase in nitrogen application levels. In soybean soil and roots, the abundance of Glomus_f_Glomeraceae decreased with the increase in nitrogen application levels. The results of the redundancy and correlations analyses indicated that the changes in the AMF diversity and community in intercropping areas were significantly associated with alterations of the soil total nitrogen and alkali-hydrolysable nitrogen due to the interactions between maize and soybeans in intercropping systems with different nitrogen fertilizer application rates.


Assuntos
Micorrizas/química , Zea mays , Agricultura , China , Nitrogênio/análise , Raízes de Plantas/química , Rizosfera , Solo , Microbiologia do Solo , Soja
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