Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 198
Filtrar
1.
J Cell Mol Med ; 25(20): 9851-9862, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34523794

RESUMO

Adiponectin is an adipocyte-derived hormone, which is closely associated with the development of Alzheimer's disease (AD) and has potential preventive and therapeutic significance. In the present study, we explored the relationship between adiponectin and circadian rhythm disorder in AD, the effect of adiponectin on the abnormal expression of Bmal1 mRNA/protein induced by amyloid-ß protein 31-35 (Aß31-35), and the underlying mechanism of action. We found that adiponectin-knockout mice exhibited amyloid-ß deposition, circadian rhythm disorders and abnormal expression of Bmal1. Adiponectin ameliorated the abnormal expression of the Bmal1 mRNA/protein caused by Aß31-35 by inhibiting the activity of glycogen synthase kinase 3ß (GSK3ß). These results suggest that adiponectin deficiency could induce circadian rhythm disorders and abnormal expression of the Bmal1 mRNA/protein, whilst exogenous administration of adiponectin may improve Aß31-35-induced abnormal expression of Bmal1 by inhibiting the activity of GSK3ß, thus providing a novel idea for the treatment of AD.

2.
Acta Biochim Biophys Sin (Shanghai) ; 53(10): 1354-1366, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34532739

RESUMO

An increase in cardiomyocyte apoptosis is the main contributor to the observed high morbidity of cardiac disease during aging. Mitochondria play important roles in cardiac apoptosis, and dynamin-related protein 1 (Drp1) is the critical factor that participates in mitochondrial fission and induces mitophagy to maintain mitochondria quality. However, whether Drp1 is involved in the increase of apoptosis in aging heart remains unclear. The purpose of this study was to determine whether Drp1 participates in inducing the apoptosis through regulating mitophagy in aging myocardium. To explore the effect of mitophagy and apoptosis in aging heart, we detected the expression of COX IV and the co-localization of COX IV and LC3 II, which reflect mitophagy, and measured adenosine triphosphate and reactive oxygen species contents, which reflect mitochondrial injury. Cell apoptosis was detected by measuring the activity of caspase-3 and the expression of cleaved caspase-3 and further confirmed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. The results showed an increase in apoptosis and a decrease in mitophagy in aging cardiomyocytes, and apoptosis was ameliorated after the induction of mitophagy by carbonyl cyanide m-chlorophenyl hydrazone (a mitophagy activator) in D-galactose (D-gal)-induced senescence H9c2 cells. To clarify the role of Drp1 in apoptosis, we knocked down Drp1 by transfecting si-Drp1, or overexpressed Drp1 in senescent cells, and then detected mitophagy, mitochondrial injury, and apoptosis. The data showed that downregulated Drp1 induces mitochondrial damage and apoptosis. In addition, to explore the regulatory relationship between Drp1 and phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy, we detected the expressions of PINK1 and Parkin after the overexpression of Drp1 in the D-gal group cells and found that Drp1-mediated mitophagy inhibited the PINK1/Parkin pathway in senescent cells. Our results demonstrated that insufficient Drp1 induces cardiomyocyte apoptosis by inhibiting mitophagy, and Drp1 affects the PINK1/Parkin pathway of mitophagy in the aging heart.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34382407

RESUMO

All-solid-state lithium batteries (ASSLBs) are regarded as the next-generation energy storage devices due to their superior safety and potential high energy density. In ASSLBs, a composite solid electrolyte is the most competitive candidate. The interface between the cathode and composite electrolyte and the interface between ceramic and polymers are important factors affecting the performance of solid-state batteries. The interface between the superionic conductor and polymer electrolyte (polyvinylidene fluoride) was modified by in situ synthesis of a pyrochlore-type La2Sn2O7 (LSO) ceramic layer on the surface of Li6.4La3Zr1.4Ta0.6O12 (LLZTO). The synthesis of LSO consumes La in LLZTO, increases the concentration of lithium ions in LLZTO, and significantly improves the conductivity of the composite electrolyte (LLZTO@LSO-CSE). Compared with the pristine sample (3.15 × 10-5 S cm-1), the conductivity of LLZTO@0.9%LSO-CSE was improved by an order of magnitude (as high as 1.30 × 10-4 S cm-1). At the same time, the lithium-ion transference number of LLZTO@0.9%LSO-CSE and LLZTO@1.5%LSO-CSE was 0.42 and 0.44, respectively (LLZTO@0%LSO-CSE was 0.36). Meanwhile, the pyrochlore structure of LSO has the characteristics of fast energy storage and conversion, so the full cell LiFePO4|LLZTO@LSO-CSE|Li showed superior rate capability and cycling stability. As anticipated, the discharge capacities of LiFePO4|LLZTO@0.9%LSO-CSE|Li were 141.4 mA h g-1 (1 C) and 128.1 mA h g-1 (2 C), respectively. However, the discharge capacities of pristine batteries without LLZTO modification were 122.5 mA h g-1 (1 C) and 88.7 mA h g-1 (2 C). After 400 cycles, the discharge capacity of the LiFePO4|LLZTO@0.9%LSO-CSE|Li remained at 110.6 mA h g-1, the Coulomb efficiency was 99.4%, and the capacity retention rate was 72% compared to 75.5 mA h g-1, 98, and 49% for the pristine one, respectively. In addition, the transfer printing (TP) technology was used to improve the interface between the cathode and the solid-state electrolyte, which immensely increased the energy density (without aluminum foil). Compared with the original interface impedance of 379 Ω, the interface impedance was significantly reduced to 213 Ω. This uniquely developed LLZTO@LSO-CSE combined with the TP technology can provide an effective approach for the development of all-solid-state batteries.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34409847

RESUMO

AIMS: Hyperhomocysteinemia (HHcy) has been considered as a risk factor for cardiovascular disease (CVD), Alzheimer's disease (AD), nonalcoholic fatty liver (NAFL) and many other pathological conditions. Vitamin B6, Vitamin B12, and folate have been used to treat HHcy in clinic. However, at present clinical therapies of HHcy display unsatisfactory effects. Here, we would like to explore a new mechanism involved in Hcy metabolic disorders and a novel target for HHcy treatment. The key enzymes involved in Hcy metabolism deserve more insightful investigation. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating the intracellular Hcy metabolism. Until now, the effect of post-translational modification on bioactivity of MTHFR still remains unclear. This study aimed to explore the relationship between MTHFR S-sulfhydration and its bioactivity, and identify the contribution of elevated Hcy level on MTHFR bioactivity. RESULTS: By both in vivo and in vitro studies, we observed the following results: (1) The bioactivity of MTHFR was positively associated with its S-sulfhydration level; (2) MTHFR was modified at Cys32, Cys130, Cys131, Cys193, and Cys306 by S-sulfhydration under physiological conditions; (3) Hydrogen sulfide (H2S) deficiency caused the decrease of MTHFR S-sulfhydration level and bioactivity in HHcy, which resulted in further aggravation of HHcy; (4) H2S donors reversed the decreased bioactivity of MTHFR in HHcy, thus reduced the excessive Hcy level. Innovation and Conclusion: Our study suggested that H2S could improve MTHFR bioactivity by S-sulfhydration, which might provide a candidate therapeutic strategy for HHcy.

5.
J Cell Mol Med ; 25(17): 8464-8478, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34322993

RESUMO

Cardiomyocytes autophagy is essential for maintaining cardiac function. Our previous studies have found that ß1 -adrenergic receptor autoantibody (ß1 -AA) induced the decreased myocardial autophagic flux, which resulted in cardiomyocyte death and cardiac dysfunction. And other studies demonstrated that ß1 -AA induced the decrease of AMPK phosphorylation, the key hub of autophagy pathway, while adiponectin up-regulated autophagic flux mediated by AMPK. However, it is not clear whether adiponectin improves the inhibition of myocardial autophagic flux induced by ß1 -AA by up-regulating the level of AMPK phosphorylation. In this study, it has been confirmed that ß1 -AA induced the decrease of AMPK phosphorylation level in both vivo and vitro. Moreover, pretreatment of cardiomyocytes with AMPK inhibitor Compound C could further reduce the autophagic flux induced by ß1 -AA. Adiponectin deficiency could aggravate the decrease of myocardial AMPK phosphorylation level, autophagic flux and cardiac function induced by ß1 -AA. Further, exogenous adiponectin could reverse the decline of AMPK phosphorylation level and autophagic flux induced by ß1 -AA and even reduce cardiomyocyte death. While pretreated with the Compound C, the adiponectin treatment did not improve the decreased autophagosome formation, but still improved the decreased autophagosome clearance induced by ß1 -AA in cardiomyocytes. This study is the first time to confirm that ß1 -AA could inhibit myocardial autophagic flux by down-regulating AMPK phosphorylation level. Adiponectin could improve the inhibition of myocardial autophagic flux induced by ß1 -AA partly dependent on AMPK, so as to provide an experimental basis for the treatment of patients with ß1 -AA-positive cardiac dysfunction.

6.
Biochem Biophys Res Commun ; 570: 8-14, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34271438

RESUMO

Large conductance calcium-activated potassium channel (BK channel) is widely expressed in skeletal muscle, myocardium, smooth muscle and other muscle tissues. Mutation, abnormal expression and altered activity of BK channel are linked to muscle-related diseases such as dyskinesia, epilepsy and erectile dysfunction. In order to compare the effects of BK channel on different muscle tissues, we constructed BK channel gene knockout rats||||||| (BK-/- rats). HE staining, open field and grip strength tests, ultrasound, blood pressure measurement and vascular tension test were utilized to explore the effects of BK channel deletion on the structure and function changes in skeletal muscle, myocardium, and vascular smooth muscle (VSM). It was found that compared with wild-type rats, the BK-/- rats showed decreased skeletal muscle fiber area, grip, movement distance and speed at 2 and 12 months of ages. At heart, the muscle fiber area, cardiac systolic/diastolic function and heart rate decreased in BK-/- rats. The wall of the left ventricle became thin. However, the vascular wall of BK-/- rats thickened, the pulse wave velocity was increased, and the VSM contraction was enhanced. Unexpectedly, both systolic and diastolic blood pressure were reduced in BK-/- rats, while pulse pressure difference was increased. These results suggest that BK channel may have different effects on different types of muscle tissue, and it should be noted that different parts of muscle tissue may have different effects when BK channel-related drugs are used.

7.
J Tradit Chin Med ; 41(3): 479-485, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34114407

RESUMO

OBJECTIVE: To evaluate the efficacy of herb-partitioned moxibustion (HPM) at Qihai (CV6), Tianshu (ST25) and Shangjuxu (ST37) acupoints in relieving symptoms and the immune regulation of HPM on the toll-like receptors 4 (TLR4) signaling pathway in ulcerative colitis (UC) patients. METHODS: A randomized, single-blind study was conducted 63 patients to receive HPM or sham HPM treatment. The efficacy outcomes included scores of the Mayo, Baron, inflammatory bowel disease questionnaire (IBDQ), self-rating depression scale (SDS), self-rating anxiety scale (SAS). HE staining was used to observe the histopathological changes of the colon. The expression of inflammatory cytokines and TLR4 signaling pathway related molecules were determined by enzyme-linked immunosorbent assay and immunohistochemistry. RESULTS: Baron, SDS, SAS scores were significantly decreased in moxibustion group (P < 0.05), IBDQ score was significantly greater in the moxibustion group than in the sham moxibustion group (P < 0.05). Histopathology of mucosal biopsies showed that both two groups improved in mucosa after treatment. The expression levels of tumor necrosis factor-α, interleukin-2, interleukin-12, interferon-γ, and TLR4, lipopolysaccharide, myeloid differentiation factor 88, interleukin receptor associated kinase, tumor necrosis factor receptor associated factor 6 and nuclear factor kappa-B p65 were significantly lower in the moxibustion group than in the sham moxibustion group (P < 0.05). CONCLUSION: This study showed that HPM at Qihai?(CV6),?Tianshu?(ST25) and?Shangjuxu (ST37) acupoints is effective to relieve symptoms, anxiety, depression and improving life quality in UC patients, which may be related to the immune regulation of HPM on TLR4 signaling pathway.

8.
J Neuroinflammation ; 18(1): 135, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127024

RESUMO

Inflammatory bowel disease (IBD), which mainly includes ulcerative colitis (UC) and Crohn's disease (CD), is a group of chronic bowel diseases that are characterized by abdominal pain, diarrhea, and bloody stools. IBD is strongly associated with depression, and its patients have a higher incidence of depression than the general population. Depression also adversely affects the quality of life and disease prognosis of patients with IBD. The tryptophan-kynurenine metabolic pathway degrades more than 90% of tryptophan (TRP) throughout the body, with indoleamine 2,3-dioxygenase (IDO), the key metabolic enzyme, being activated in the inflammatory environment. A series of metabolites of the pathway are neurologically active, among which kynerunic acid (KYNA) and quinolinic acid (QUIN) are molecules of great interest in recent studies on the mechanisms of inflammation-induced depression. In this review, the relationship between depression in IBD and the tryptophan-kynurenine metabolic pathway is overviewed in the light of recent publications.

9.
Pestic Biochem Physiol ; 175: 104832, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33993957

RESUMO

Phytophthora infestans is the pathogen causing potato late blight, one of the most serious diseases of potato. Myxobacteria have become a valuable biological control resource due to their preponderant abilities to produce various secondary metabolites with novel structure and remarkable biological activity. In this study, Myxococcus xanthus strain B25-I-1, which exhibited strong antagonistic activity against P. infestans, was isolated from soil sample and identified by 16S rRNA sequence analysis. The strain exhibited antagonistic activity against several species of fungus and bacteria. Analysis of the biocontrol mechanism showed that the active extract produced by strain B25-I-1 had strong inhibitory effects on mycelium and the asexual and sexual reproductive structures of P. infestans. Furthermore, these active extract decreased the content of soluble proteins and activity of the protective enzymes (PPO, POD, PAL, and SOD), increased the oxidative damage and the permeability of the cell membrane in P. infestans. All of these mechanisms might be the biocontrol mechanism of B25-I-1 against P. infestans. The active extract of strain B25-I-1 was separated by TLC and HPLC, and the components with antibiotic activity were detected by HPLC-MS. It was found that the antagonistic components of B25-I-1 contained methyl (2R)-2-azido-3-hydroxyl-2-methylpropanoate and N-(3-Amino-2-hydroxypropyl)-N-methylsulfuric diamide. The active extract significantly inhibited the infection on detached potato leaves by P. infestans, and these substances did not cause damage to the potato leaves. In conclusion, M. xanthus B25-I-1 produced active extract against P. infestans and might potentially be a candidate to develop into biological pesticides for the control of potato late blight. This study adds to the literature on the isolation and identification of active extracts from myxobacteria, and B25-I-1 in particular, for cures or treatments to potato late blight.


Assuntos
Myxococcus xanthus , Phytophthora infestans , Solanum tuberosum , Phytophthora infestans/genética , Doenças das Plantas , RNA Ribossômico 16S
10.
Biochem Biophys Res Commun ; 548: 182-188, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33647794

RESUMO

Intermittent hypoxia (IH), a main characteristic of obstructive sleep apnea (OSA) syndrome, is an independent risk factor of cardiovascular complications. However, the mechanism has not been fully elucidated. Growing evidence has revealed alterations of extracellular vesicle (EV) contents, mostly miRNAs, playing a pathogenic role in cardiovascular complications. In current study, we attempt to compare the disparity of myocardial EV miRNA components after IH or normoxia treatment and determine whether EVs from IH-treated cardiomyocytes could affect endothelial function. 63 differentially expressed miRNAs were identified in EVs from IH-exposed cardiomyocytes by miRNA chip assay. Among them, 16 miRNAs with homologous sequence in mouse and human were verified by qPCR assay and 11 miRNAs were proved with the same tendency as miRNA chip assay. KEGG predicted that the function of differentially expressed miRNA was enriched to Akt signaling pathway. Notably, EVs from IH-exposed cardiomyocytes dramatically impaired endothelial-dependent relaxation and inhibited Akt/eNOS expression in endothelial cells. This study provides the first evidence that IH significantly alters myocardial EV miRNA composition and reveals a novel role of myocardial EVs in endothelial function under IH status, which will help to understand the OSA- or IH-related endothelial dysfunction from a new scope.


Assuntos
Células Endoteliais/metabolismo , Vesículas Extracelulares/metabolismo , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Hipóxia Celular/genética , Vesículas Extracelulares/ultraestrutura , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miocárdio/metabolismo , Reprodutibilidade dos Testes
11.
Zhongguo Zhen Jiu ; 41(1): 17-22, 2021 Jan 12.
Artigo em Chinês | MEDLINE | ID: mdl-33559436

RESUMO

OBJECTIVE: To observe the effect of acupuncture-moxibustion on negative emotions and plasma tryptophan (Trip)-kynurenine (Kyn) metabolism in the patients with Crohn's disease (CD) at the mild and moderate active stage. METHODS: A total of 66 CD patients were randomized into an observation group (33 cases, 1 case dropped off) and a control group (33 cases, 2 cases dropped off). In the observation group, acupuncture was applied in combination with moxibustion. In the control group, the sham-acupuncture was used in combination with sham-moxibustion. In both of the observation group and the control group, acupuncture was applied to Zhongwan (CV 12), Shangjuxu (ST 37), Sanyinjiao (SP 6), Gongsun (SP 4), Hegu (LI 4), Quchi (LI 11), Taixi (KI 3) and Taichong (LR 3), and moxibustion was applied to Tianshu (ST 25) and Zusanli (ST 36). The treatment was given once every two days, 3 times a week, totally for 12 weeks. Separately, before and after treatment, the score of the hospital anxiety-depression scale (HADS) and the score of intestinal core symptoms (degree of abdominal pain and frequency of diarrhea) were observed in the patients of the two groups. The concentration of plasma indoleamine 2,3-dioxygenase 1 (IDO1) and the ratios of Kyn/Trp, QuinA/Kyn, KynA/Kyn and KynA/QuinA were compared between the two groups. RESULTS: Compared with before treatment, the scores of HADS-A and HADS-D in the observation group and the score of HADS-A in the control group were all reduced after treatment (P<0.01, P<0.05). The scores of abdominal pain degree in the two groups and score of diarrhea frequency in the observation group were all reduced after treatment (P<0.001). After treatment, the reducing ranges of the score of HADS-A and the scores of abdominal pain degree and diarrhea frequency in the observation group were all larger than the control group (P<0.01, P<0.05). Compared with before treatment, the plasma IDO1 concentration in the two groups and the ratios of plasma Kyn/Trp and QuinA/Kyn in the observation group were all reduced after treatment (P<0.001, P<0.05, P<0.01), the ratios of plasma KynA/Kyn and KynA/QuinA were increased after treatment in the observation group (P<0.05, P<0.01). After treatment, the changes in IDO1 concentration and the ratios of plasma QuinA/Kyn and KynA/QuinA in the observation were larger than the control group (P≤0.01, P<0.05). In the observation group, the difference in the ratio of plasma KynA/Kyn before and after treatment was negatively related to the improvement value of HADS-D (r =-0.67, P<0.05). After treatment, plasma IDO1 concentration was positively related to HADS-A in the observation group (r =0.65, P<0.05). CONCLUSION: Acupuncture and moxibustion relieve the negative emotions of anxiety and depression in CD patients at mild and moderate active stage, which is probably related to the regulation of plasma Trp-Kyn metabolic pathway.


Assuntos
Terapia por Acupuntura , Doença de Crohn , Moxibustão , Pontos de Acupuntura , Doença de Crohn/terapia , Emoções , Humanos , Plasma , Resultado do Tratamento , Triptofano
12.
Clin Exp Pharmacol Physiol ; 48(6): 846-854, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33565091

RESUMO

Cardiac dysfunction is involved in disorders of energy metabolism. High-titre autoantibodies against the ß1 -adrenoceptor (ß1 -AAs) have been reported to exist in patients with cardiac dysfunction; however, the mechanism by which ß1 -AAs affect cardiac function is unknown. This study aimed to determine whether ß1 -AAs disturb myocardium energy metabolism and cause cardiac dysfunction. ß1 -AA monoclonal antibodies (ß1 -AAmAbs) were successfully pre-synthesized by hybridoma clones and used in all experiments. ß1 -AAmAbs impaired cardiac function and induced a myocardial metabolic disturbance, as evidenced by decreased left ventricular ejection fraction and fractional shortening. In addition, ß1 -AAmAbs decreased the adenosine triphosphate level and increased cardiac energy consumption (rate-pressure product). We further showed that the effects of ß1 -AAmAbs on heart tissue might involve the mitochondria and metabolic pathways via the ß1 -adrenoceptor based on an immunoprecipitation and mass spectrometry. Additionally, we found that ß1 -AAmAbs impaired myocardial mitochondrial structure, decreased the membrane potential, and induced insufficient mitophagy. In conclusion, ß1 -AAmAb-induced cardiac dysfunction is partly due to a disturbance in myocardial energy metabolism.

13.
Free Radic Biol Med ; 164: 20-33, 2021 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-33418108

RESUMO

Sp1-CSE-H2S pathway plays an important role in homocysteine-metabolism, whose disorder can result in hyperhomocysteinemia. H2S deficiency in hyperhomocysteinemia has been reported, while the underlying mechanism and whether it in turn affects the progress of hyperhomocysteinemia are unclear. This study focused on the post-translational modification of Sp1/CSE and revealed four major findings: (1) Homocysteine-accumulation augmented CSE's nitration, inhibited its bio-activity, thus caused H2S deficiency. (2) H2S deficiency inhibited the S-sulfhydration of Sp1, down-regulated CSE and decreased H2S further, which in turn weakened CSE's own S-sulfhydration. (3) CSE was S-sulfhydrated at Cys84, Cys109, Cys172, Cys229, Cys252, Cys307 and Cys310, among which the S-sulfhydration of Cys172 and Cys310 didn't affect its enzymatic activity, while the S-sulfhydration of Cys84, Cys109, Cys229, Cys252 and Cys307 was necessary for its bio-activity. (4) H2S deficiency trapped homocysteine-metabolism into a vicious cycle, which could be broken by either blocking nitration or restoring S-sulfhydration. This study detected a new mechanism that caused severe hyperhomocysteinemia, thereby provided new therapeutic strategies for hyperhomocysteinemia.


Assuntos
Sulfeto de Hidrogênio , Hiper-Homocisteinemia , Cistationina gama-Liase/genética , Humanos , Sulfeto de Hidrogênio/metabolismo , Hiper-Homocisteinemia/genética , Processamento de Proteína Pós-Traducional , Fator de Transcrição Sp1
14.
World J Gastroenterol ; 26(39): 5997-6014, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33132650

RESUMO

BACKGROUND: Autophagy is an evolutionarily conserved biological process in eukaryotic cells that involves lysosomal-mediated degradation and recycling of related cellular components. Recent studies have shown that autophagy plays an important role in the pathogenesis of Crohn's disease (CD). Herbal cake-partitioned moxibustion (HM) has been historically practiced to treat CD. However, the mechanism by which HM regulates colonic autophagy in CD remains unclear. AIM: To observe whether HM can alleviate CD by regulating colonic autophagy and to elucidate the underlying mechanism. METHODS: Rats were randomly divided into a normal control (NC) group, a CD group, an HM group, an insulin + CD (I + CD) group, an insulin + HM (I + HM) group, a rapamycin + CD (RA + CD) group, and a rapamycin + HM (RA + HM) group. 2,4,6-trinitrobenzenesulfonic acid was administered to establish a CD model. The morphology of the colonic mucosa was observed by hematoxylin-eosin staining, and the formation of autophagosomes was observed by electron microscopy. The expression of autophagy marker microtubule-associated protein 1 light chain 3 beta (LC3B) was observed by immunofluorescence staining. Insulin and rapamycin were used to inhibit and activate colonic autophagy, respectively. The mRNA expression levels of phosphatidylinositol 3-kinase class I (PI3KC1), Akt1, LC3B, sequestosome 1 (p62), and mammalian target of rapamycin (mTOR) were evaluated by RT-qPCR. The protein expression levels of interleukin 18 (IL-18), tumor necrosis factor-α (TNF-α), nuclear factor κB/p65 (NF-κB p65), LC3B, p62, coiled-coil myosin-like BCL2-interacting protein (Beclin-1), p-mTOR, PI3KC1, class III phosphatidylinositol 3-kinase (PI3KC3/Vps34), and p-Akt were evaluated by Western blot analysis. RESULTS: Compared with the NC group, the CD group showed severe damage to colon tissues and higher expression levels of IL-18 and NF-κB p65 in colon tissues (P < 0.01 for both). Compared with the CD group, the HM group showed significantly lower levels of these proteins (P IL-18 < 0.01 and P p65 < 0.05). There were no significant differences in the expression of TNF-α protein in colon tissue among the rat groups. Typical autophagic vesicles were found in both the CD and HM groups. The expression of the autophagy proteins LC3B and Beclin-1 was upregulated (P < 0.01 for both) in the colon tissues of rats in the CD group compared with the NC group, while the protein expression of p62 and p-mTOR was downregulated (P < 0.01 for both). However, these expression trends were significantly reversed in the HM group compared with the CD group (P LC3B < 0.01, P Beclin-1 < 0.05, P p62 < 0.05, and P m-TOR < 0.05). Compared with those in the RA + CD group, the mRNA expression levels of PI3KC1, Akt1, mTOR, and p62 in the RA + HM group were significantly higher (P PI3KC1 < 0.01 and P Akt1, mTOR, and p62 < 0.05), while those of LC3B were significantly lower (P < 0.05). Compared with the RA + CD group, the RA + HM group exhibited significantly higher PI3KC1, p-Akt1, and p-mTOR protein levels (P PI3KC1 < 0.01, P p-Akt1 < 0.05, and P p-mTOR < 0.01), a higher p62 protein level (P = 0.057), and significantly lower LC3B and Vps34 protein levels (P < 0.01 for both) in colon tissue. CONCLUSION: HM can activate PI3KC1/Akt1/mTOR signaling while inhibiting the PI3KC3 (Vps34)-Beclin-1 protein complex in the colon tissues of CD rats, thereby inhibiting overactivated autophagy and thus exerting a therapeutic effect.


Assuntos
Fenômenos Biológicos , Doença de Crohn , Moxibustão , Animais , Autofagia , Colo , Doença de Crohn/terapia , Fosfatidilinositol 3-Quinases , Ratos
15.
Acta Biochim Biophys Sin (Shanghai) ; 52(12): 1373-1381, 2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33231607

RESUMO

Exposure to adverse factors in utero may lead to adaptive changes in cardiac structure and metabolism, which increases the risk of chronic cardiovascular disease later in life. Studies showed that the angiotensin II type 1 receptor autoantibodies (AT1-AAs) are able to cross the placenta into the circulation of pregnant rodents' embryo, which adversely affects embryogenesis. However, the effects of AT1-AA exposure on the fetal heart in utero are still unknown. In this study, we investigated whether intrauterine AT1-AA exposure has adverse effects on fetal heart structure, function and metabolism. AT1-AA-positive pregnant mouse models were successfully established by passive immunity, evidenced by increased AT1-AA content. Morphological and ultrasonic results showed that the fetal mice on embryonic day 18 (E18) of AT1-AA group have loose and disordered myocardial structure, and decreased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), compared with control groups. The myocardium of AT1-AA group fetal mice on E18 exhibited increased expression of the key molecules in the glycolytic pathway, pyruvate and lactic acid content and ATP production, suggesting that the glycolysis rate was enhanced. Furthermore, the enhanced effect of glycolysis caused by AT1-AA is mainly through the PPARß/δ pathway. These data confirmed that fetus exposure to AT1-AA in utero developed left ventricular dysfunction, myocardial structural arrangement disorders, and enhanced glycolysis on E18. Our results support AT1-AA being a potentially harmful factor for cardiovascular disease in fetal mice.


Assuntos
Autoanticorpos/toxicidade , Cardiomiopatias/etiologia , Feto/imunologia , Feto/fisiopatologia , Glicólise/imunologia , Receptor Tipo 1 de Angiotensina/imunologia , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Cardiomiopatias/patologia , Modelos Animais de Doenças , Feminino , Camundongos Endogâmicos BALB C , PPAR gama/metabolismo , PPAR beta/metabolismo , Placenta/fisiologia , Gravidez , Segundo Trimestre da Gravidez , Volume Sistólico/imunologia , Função Ventricular Esquerda/imunologia
16.
Gastroenterol Res Pract ; 2020: 8186106, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33014041

RESUMO

Background: Electroacupuncture (EA) has been confirmed effectiveness in the treatment of irritable bowel syndrome (IBS), and P2X3 receptors in the peripheral and central neurons participate in the acupuncture-mediated relief of the visceral pain in IBS. Objective: To reveal the neurobiological mechanism that P2X3 receptor of colonic primary sensory neurons in the dorsal root ganglia of the lumbosacral segment is involved in the alleviation of visceral hypersensitivity by EA in an IBS rat model. Methods: The IBS chronic visceral pain rat model was established according to the method of Al-Chaer et al. EA at the bilateral He-Mu points, including ST25 and ST37, was conducted for intervention. The behavioral studies, histopathology of colon, electrophysiology, immunofluorescence histochemistry, and real-time polymerase chain reaction assays were used to observe the role of P2X3 receptor in the colon and related DRG in relieving visceral hypersensitivity by EA. Results: EA significantly reduced the behavior scores of the IBS rats under different levels (20, 40, 60, 80 mmHg) of colorectal distention stimulation and downregulated the expression levels of P2X3 receptor protein and mRNA in colon and related DRG of the IBS rats. EA also regulated the electrical properties of the membranes, including the resting membrane potential, rheobase, and action potential of colon-associated DRG neurons in the IBS rats. Conclusion: EA can regulate the P2X3 receptor protein and mRNA expression levels in the colon and related DRG of IBS rats with visceral pain and then regulate the excitatory properties of DRG neurons.

17.
Trials ; 21(1): 844, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046128

RESUMO

BACKGROUND: Traditional Chinese medicine (TCM) has a long history of use in breast cancer, but lacking systematic evidence to support its clinical benefits. In this study, we evaluated the prophylactic and therapeutic effects of moxibustion combined with decoctions for treating chemotherapy-induced myelosuppression (CIM) in early-stage breast cancer patients. METHODS: This is a randomized controlled clinical trial single-blinded for TCM decoction but not moxibustion. Patients are equally divided into the control group without decoction and moxibustion treatment (control), the decoction+moxibustion group (MD), and the placebo+moxibustion group (MP), according to the following stratification factors: age (below 40s, 40s, 50s, and 60s or above), chemotherapy regimen (anthracyclines, taxanes, anthracyclines+taxane, and others), and chemotherapy strategy (adjuvant and neoadjuvant). The TCM decoction is Wenshen Shengbai Decoction. The anticipated sample size is 462 cases (154 cases in each group). All participants are expected to treat with chemotherapy and recombinant human granulocyte colony-stimulating factor (rhG-CSF). The primary outcomes include the proportion of patients with relief of leukopenia and/or neutropenia, the myelosuppression-associated serious adverse event including grade 3-4 leukopenia and/or neutropenia, and febrile neutropenia, and the dose of rhG-CSF. The secondary outcomes include chemotherapy adherence, stratified analysis, adverse reactions, quality of life by EORTC Breast-Cancer-Specific Quality of Life Questionnaire including EORTC QLQ-C30 (V3.0) and QLQ-BR23, TCM Constitution, and 3-year disease-free survival and overall survival. Baseline information including age, surgical approach, chemotherapy regimen and strategy, pathological stage, and molecular subtype will be recorded. DISCUSSION: This will be the first randomized controlled trial to evaluate the efficacy of moxibustion combined with TCM decoction in treating CIM in early-stage breast cancer patients, aiming to standardize the TCM decoction and moxibustion method, thus providing evidence for its clinical benefit. TRIAL REGISTRATION: chictr.org.cn ChiCTR-INR-16009557 . Registered on 23 October 2016.


Assuntos
Neoplasias da Mama , Moxibustão , Antibióticos Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Medicina Tradicional Chinesa , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
18.
Mol Cell Endocrinol ; 518: 111022, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32871226

RESUMO

Blood glucose is of great importance to development and metabolic homeostasis in fetuses. Stimulation of harmful factors during gestation induces pathoglycemia. Angiotensin II type 1 receptor autoantibody (AT1-AA), a newly discovered gestational harmful factor, has been shown to induce intrauterine growth restriction in fetuses and glucose disorders in adults. However, whether and how AT1-AA influences the blood glucose level of fetuses during gestation is not yet clear. The purpose of the current study was to observe the fetal blood glucose level of AT1-AA-positive pregnant rats during late pregnancy and to determine the roles that hepatic glucose transporters play in this process. We established AT1-AA-positive pregnant rats by injecting AT1-AA into the caudal veins of rats in the 2nd trimester of gestation. Although the fetal blood glucose level in the 3rd trimester of gestation decreased, hepatic glucose uptake increased detected. Through separating membrane and cytosolic proteins, we demonstrated that both the expression and membrane transport ratio of glucose transporter 1 (GLUT1), which is responsible for glucose transport in fetal hepatocytes, were upregulated, accompanied by increased expression of N-glycosyltransferase STT3A, which contributes to the N-glycosylation of GLUT1. In vitro, we identified that AT1-AA increased glucose uptake, the expression and membrane transport ratio of GLUT1 and the expression of STT3A in HepG2 cell lines via separating membrane and cytosolic proteins and immunofluorescence, resulting in the decreased glucose content in the medium. The GLUT1 inhibitor WZB117 reversed the decreases in glucose content in the medium, the increases in glucose uptake, the increases in the expression and membrane transport ratio of GLUT1 caused by AT1-AA. The N-glycosyltransferase inhibitor NGI as well as si-STT3A reversed the AT1-AA-induced upregulation of the STT3A-GLUT1-glucose uptake effect. This study demonstrates that AT1-AA lowers the blood glucose level of fetuses via the STT3A-GLUT1-glucose uptake axis in liver.

19.
BMC Cardiovasc Disord ; 20(1): 337, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32664860

RESUMO

BACKGROUND: High blood glucose impairs voltage-gated K+ (Kv) channel-mediated vasodilation in rat coronary artery smooth muscle cells (CSMCs) via oxidative stress. Advanced glycation end product (AGE) and receptor for AGE (RAGE) axis has been found to impair coronary dilation by reducing Kv channel activity in diabetic rat small coronary arteries (RSCAs). However, its underlying mechanism remain unclear. Here, we used isolated arteries and primary CSMCs to investigate the effect of AGE incubation on Kv channel-mediated coronary dilation and the possible involvement of peroxisome proliferators-activated receptor (PPAR) -γ pathway. METHODS: The RSCAs and primary CSMCs were isolated, cultured, and treated with bovine serum albumin (BSA), AGE-BSA, alagrebrium (ALA, AGE cross-linking breaker), pioglitazone (PIO, PPAR-γ activator) and/or GW9662 (PPAR-γ inhibitor). The groups were accordingly divided as control, BSA, AGE, AGE + ALA, AGE + PIO, or AGE + PIO + GW9662. Kv channel-mediated dilation was analyzed using wire myograph. Histology and immunohistochemistry of RSCAs were performed. Western blot was used to detect the protein expression of RAGE, major Kv channel subunits expressed in CSMCs (Kv1.2 and Kv1.5), PPAR-γ, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2 (NOX-2). RESULTS: AGE markedly reduced Forskolin-induced Kv channel-mediated dilation of RSCAs by engaging with RAGE, and ALA or PIO significantly reversed the functional loss of Kv channel. In both RSCAs and CSMCs, AGE reduced Kv1.2/1.5 expression, increased RAGE and NOX-2 expression, and inhibited PPAR-γ expression, while ALA or PIO treatment partially reversed the inhibiting effects of AGE on Kv1.2/1.5 expression, accompanied by the downregulation of RAGE and decreased oxidative stress. Meanwhile, silencing of RAGE with siRNA remarkably alleviated the AGE-induced downregulation of Kv1.2/1.5 expression in CSMCs. CONCLUSION: AGE reduces the Kv channel expression in CSMCs and further impairs the Kv channel-mediated dilation in RSCAs. The AGE/RAGE axis may enhance oxidative stress by inhibiting the downstream PPAR-γ pathway, thus playing a critical role in the dysfunction of Kv channels.


Assuntos
Produtos Finais de Glicação Avançada/farmacologia , Canal de Potássio Kv1.2/metabolismo , Canal de Potássio Kv1.5/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , PPAR gama/metabolismo , Soroalbumina Bovina/farmacologia , Vasodilatação/efeitos dos fármacos , Anilidas/farmacologia , Animais , Células Cultivadas , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Canal de Potássio Kv1.2/genética , Canal de Potássio Kv1.5/genética , Masculino , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/efeitos dos fármacos , Pioglitazona/farmacologia , Ratos Sprague-Dawley , Transdução de Sinais
20.
Artigo em Inglês | MEDLINE | ID: mdl-32617101

RESUMO

Objective: To explore whether the effect of electroacupuncture (EA) on visceral hypersensitivity (VH) in rats with irritable bowel syndrome (IBS) is related to the changes of astrocyte activation in the medial thalamus (MT) and anterior cingulate cortex (ACC). Method: Male Sprague-Dawley rats were randomly divided into the normal control (NC) group, model control (MC) group, electroacupuncture (EA) group, and fluorocitrate (FCA) group. A model of visceral hypersensitivity was established by neonatal colorectal irritation. In the EA group, needles were inserted into the skin at the Tianshu (ST25) and Shangjuxu (ST37) acupoints, once a day for 7 days. The FCA group received intrathecal injection of FCA on the 1st, 4th, and 7th days. Visceral hypersensitivity was evaluated by the abdominal withdrawal reflex (AWR), and glial fibrillary acidic protein (GFAP) mRNA and protein levels in the MT and ACC were detected by real-time PCR, immunohistochemistry, and western blots. Results: The AWR score in the MC group was significantly higher than in the NC group, and EA and FCA reduced the AWR score of VH rats. GFAP mRNA and protein levels in the MT and ACC of rats in the MC group were significantly increased compared with the NC group. After either electroacupuncture or fluorocitrate, GFAP mRNA and protein levels in the MT and ACC were both clearly reduced. Conclusion: Electroacupuncture alleviates IBS visceral hypersensitivity by inhibiting the activation of astrocytes in the MT and ACC.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...