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1.
Artif Cells Nanomed Biotechnol ; 48(1): 362-376, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31899965

RESUMO

Microvascular disturbance, excessive inflammation and gliosis are key pathophysiologic changes in relation to functional status following the traumatic spinal cord injury (SCI). Continuous release of vascular endothelial growth factor (VEGF) to the lesion site was proved be able to promote the vascular remodelling, whereas the effects on reduction of inflammation and gliosis remain unclear. Currently, aiming at exploring the synergistic roles of VEGF and neurotrophin-3 (NT-3) on angiogenesis, anti-inflammation and neural repair, we developed a technique to co-deliver VEGF165 and NT-3 locally with a homotopic graft of tissue-engineered acellular spinal cord scaffold (ASCS) in a hemisected (3 mm in length) SCI model. As the potential in secretion of growth factors (GFs), bone mesenchymal stem cells (BMSCs) were introduced with the aim to enhance the VEGF/NT-3 release. Our data demonstrate that sustained VEGF/NT-3 release from ASCS significantly increases the local levels of VEGF/NT-3 and angiogenesis, regardless of whether it is in combination with BMSCs transplantation that exhibits positive effects on anti-inflammation, axonal outgrowth and locomotor recovery. This study verifies that co-delivery of VEGF/NT-3 reduces inflammation and gliosis in the hemisected spinal cord, promotes axonal outgrowth and results in better locomotor recovery, while the BMSCs transplantation facilitates these functions limitedly.

2.
Drug Dev Ind Pharm ; : 1-10, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31878816

RESUMO

Flurbiprofen (FP) is one of the most potent nonsteroidal anti-inflammatory drugs with very low bioavailability of approximately 12% following transdermal administration, compared to that after oral administration. This study aimed to deliver FP as a microemulsion (ME) gel by transdermal administration. Galangal essential oil (GEO) was extracted from Rhizoma Alpiniae Officinarum and identified by GC-MS. The most abundant constituent was determined to be 1,8-cineole (52.06%). Compared to azone, GEO was proved to exert significantly higher (p < .01) penetration enhancement effect and significantly (p < .001) lower skin cell toxicity. The formulation (FP-GEO-ME gel) was prepared using GEO as an oil phase and a penetration enhancer. Compared to that of FP solution, the enhancement ratio (ER) of FP-GEO-ME gel was 4.06. In addition, more than 25% 1,8-cineole permeated through the rat skin. In vivo pharmacokinetic studies revealed that the AUC0-t of FP after transdermal administration of FP-GEO-ME gel was higher by approximately 4.56-fold than that of marketed FP cataplasms. The relative bioavailability of FP and 1,8-cineole after transdermal administration compared to oral administration of FP-GEO-ME were determined to be 96.58% and 85.49%, respectively. FP-GEO-ME gel significantly inhibited carrageenan-induced hind-paw edema and decreased PGE2 levels in rat serum. GEO-ME gel also exhibited significant anti-inflammatory effects at 2 h after the therapy (p < .05). The synergistic effects of FP and GEO were expected for the application of FP-GEO-ME gel. In conclusion, GEO-ME gel may be a promising formulation for transdermal administration of anti-inflammatory hydrophobic drugs, such as FP.

3.
Ann Hepatol ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31836423

RESUMO

In laparoscopic cholecystectomy (LC), the treatment of iatrogenic biliary tract injury has been given much attention. However, most accidental right hepatic artery (RHA) injuries are treated with simple clipping. The reason is that the RHA has difficulty in revascularization, and it is generally considered that RHA injury does not cause serious consequences. However, some studies suggest that some cases of RHA ligation can cause a series of pathological changes correlated to arterial ischemia, such as liver abscess, bile tumor, liver atrophy and anastomotic stenosis. Theoretically, RHA blood flow should be restored when possible, in order to avoid the complications of right hepatic ischemia. The present study involved two patients, including one male and one female patient. Both patients were admitted to the hospital with the diagnosis of chronic cholecystitis and gallbladder stone, and developed ischemia of the right half hepatic after accidental transection of the RHA. Both patients underwent continuous end-end anastomosis of the RHA with 6-0 Prolene suture. After the blood vessel anastomosis, the right half liver quickly recovered to its original bright red. No adverse complications were observed in follow-ups at three and six months after the operation. Laparoscopic repair of the RHA is technically feasible. Reconstruction of the RHA can prevent complications associated with right hepatic ischemia.

4.
Onco Targets Ther ; 12: 10727-10737, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31839712

RESUMO

Background: Emerging proof suggests that microRNA (miRNA) malfunction is correlated to the generation and development of multiple malignancies. It has been proven that miRNA (miR)-139 represses a variety of malignancies. However, the understanding of its impact on ovarian cancer (OC) is insufficient. We aimed to investigate the expression and function of miR-139 in OC. Methods: The expression of mir-139 was detected and recorded, and the relationship of mir-139 remaining OC cells was explored. At the same time, we studied the correlation between ATP7A and mir-139 by the luciferase reporter test, Western blot, and quantitative real-time reverse transcription PCR. Results: The expression of miR-139 was remarkably downregulated in OC specimens. Furthermore, excessive miR-139 expression noticeably inhibited the migration, colony generation, proliferation, and invasion of OC cells. In addition, excessive miR-139 expression remarkably repressed the death and the expression of proteins related to cell death in OC cells, as well as inhibited the shedding of exosomes. According to the luciferase reporter test, Western blot, and quantitative real-time reverse transcription PCR, miR-139 directly targeted ATP7A. Furthermore, the expression of ATP7A was found to be negatively related to miR-139 levels in OC specimens. It was revealed via a rescue experiment that excessive ATP7A expression counteracted the repressive effect of miR-139 in OC cells. Conclusion: It was revealed via an in vivo study that miR-139 remarkably inhibited the growth of malignancies by downregulating ATP7A in nude mice. miR-139 represses the development of malignancies in OC by directly targeting ATP7A, offering an innovative approach for molecular therapy of OC.

5.
Front Physiol ; 10: 1430, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824338

RESUMO

A 10-week feeding trial was conducted to investigate the effects of dietary bile acids (BA) on growth, glucose and lipid metabolism, liver histopathology, and the underlying regulation mechanism on AKT/FOXO1 (forkhead box O1) and cAMP/AMPK/SREBP1 (sterol regulatory element-binding protein 1) pathway in largemouth bass (Micropterus salmoides) fed with a high starch diet. Six experimental diets were prepared with BA levels at 0 (B0), 80 (B80), 160 (B160), 240 (B240), 300 (B300), and 600 (B600) mg/kg in a basal diet with 18.7% starch. Each diet was fed to six replicates with 30 fish (6.17 ± 0.03 g) in each tank. The highest weight gain rate (WGR) was observed in B300 group and the optimal level of BA was estimated at 475 mg/kg by a monistic cubic equation regression analysis. Dietary BA inclusion decreased hepatosomatic index (HSI) and hepatic lipid content significantly. The fish in B300 group clearly showed alleviated hepatic fibrosis, but more steatohepatitis symptoms diagnosed with various histopathological and immunofluorescence analysis. 10 out of 12 samples were observed hepatic fibrosis in B0 group while only two fibrosis samples in B300 group. The promoted liver histopathology by dietary BA was related to improved glucose and lipid metabolism. Dietary BA inhibited the expression of G6Pase by activating AKT and reducing FOXO1 transcription, which improved the regulation ability of gluconeogenesis, activated cAMP/AMPK and repressed SREBP1 transcription to inhibit hepatic lipogenesis, which prevented hepatic lipid accumulation. In conclusion, dietary BA enhanced the growth and alleviated liver fibrosis induced by a high starch diet to steatohepatitis/recovery symptom via improving glucose and lipid metabolism, which regulated by AKT/FOXO1 and cAMP/AMPK/SREBP1 pathway in largemouth bass.

6.
Cell Res ; 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31811276

RESUMO

Coagulation balance is maintained through fine-tuned interactions among clotting factors, whose physiological concentrations vary substantially. In particular, the concentrations of coagulation proteases (pM to nM) are much lower than their natural inactivator antithrombin (AT, ~ 3 µM), suggesting the existence of other coordinators. In the current study, we found that transferrin (normal plasma concentration ~40 µM) interacts with fibrinogen, thrombin, factor XIIa (FXIIa), and AT with different affinity to maintain coagulation balance. Normally, transferrin is sequestered by binding with fibrinogen (normal plasma concentration ~10 µM) at a molar ratio of 4:1. In atherosclerosis, abnormally up-regulated transferrin interacts with and potentiates thrombin/FXIIa and blocks AT's inactivation effect on coagulation proteases by binding to AT, thus inducing hypercoagulability. In the mouse model, transferrin overexpression aggravated atherosclerosis, whereas transferrin inhibition via shRNA knockdown or treatment with anti-transferrin antibody or designed peptides interfering with transferrin-thrombin/FXIIa interactions alleviated atherosclerosis. Collectively, these findings identify that transferrin is an important clotting regulator and an adjuster in the maintenance of coagulation balance and modifies the coagulation cascade.

7.
Int J Biol Sci ; 15(13): 2783-2797, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31853218

RESUMO

Endometriosis (EMS) is the most common gynecological disease in women of reproductive age, and it is associated with chronic pelvic pain, dyspareunia and infertility. As a consequence of genetic, immune and environmental factors, endometriotic lesions have high cyclooxygenase (COX)-2 and COX-2-derived prostaglandin E2 (PGE2) biosynthesis compared with the normal endometrium. The transcription of the PTGS2 gene for COX-2 is associated with multiple intracellular signals, which converge to cause the activation of mitogen-activated protein kinases (MAPKs). COX-2 expression can be regulated by several factors, such as estrogen, hypoxia, proinflammatory cytokines, environmental pollutants, metabolites and metabolic enzymes, and platelets. High concentrations of COX-2 lead to high cell proliferation, a low level of apoptosis, high invasion, angiogenesis, EMS-related pain and infertility. COX-2-derived PGE2 performs a crucial function in EMS development by binding to EP2 and EP4 receptors. These basic findings have contributed to COX-2-targeted treatment in EMS, including COX-2 inhibitors, hormone drugs and glycyrrhizin. In this review, we summarize the most recent basic research in detail and provide a short summary of COX-2-targeted treatment.

8.
BMC Microbiol ; 19(1): 297, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842748

RESUMO

BACKGROUND: Siberian sturgeon (Acipenser baeri Brandt) and Beluga sturgeon (Huso huso) are two important commercial fish in China, and the feeding habits of them are very different. Diets and feeding habits are two significant factors to affect the gastrointestinal microbiota in fish. The intestinal microbiota has been reported to play a key role in nutrition and immunity. However, it is rarely reported about the relationship between the intestinal microbiota and feeding habits/diets on different Acipenseridae fish. This study is to comparative analysis of gut microbial community in Siberian sturgeon and Beluga sturgeon fed with the same diet/Beluga sturgeon fed with different diets in order to determine the effects of different feeding habits/diets on the fish intestinal microbiota. RESULTS: According to the experimental objectives, BL and BH groups were Beluga sturgeon (Huso huso) fed with low fishmeal diet and high fishmeal diet, respectively. SH group represented Siberian sturgeon (Acipenser baeri Brandt) fed with the same diet as BH group. After 16 weeks feeding trial, the intestinal microbiota was examined by 16S rRNA high-throughput sequencing technology. On the phylum level, Proteobacteria and Bacteroidetes were significantly higher in BL group than BH group, and Cyanobacteria showed the opposite trend. Compared with BH group, Proteobacteria and Firmicutes were significantly increased in SH group, whereas Cyanobacteria were clearly decreased. At the genus level, Pseudomonas and Citrobacter in BL group were significantly higher comparing with BH group, while Bacillus, Luteibacter, Staphylococcus and Oceanobacillus was lower in BH group than SH group. CONCLUSIONS: Alpha and beta diversities indicated that the intestinal microflora were significant difference between Siberian sturgeon and Beluga sturgeon when they fed with the same diet. Meanwhile, Beluga sturgeon fed with low fishmeal diet can increase the species diversity of intestinal microbiota than it fed high fishmeal diet. Therefore, feeding habits clearly affected the gastrointestinal microbiota of sturgeons. Moreover, the impact of changes in food on the gut microbiota of sturgeons should be taken into consideration during the process of sturgeon aquaculture.

9.
Reproduction ; 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31869309

RESUMO

Immune cells and cytokines have important roles in the pathogenesis of endometriosis. However, the production and role of cytokines of T helper type 1 (Th1) and Th2 cells in the progress of endometriosis have remained to be fully elucidated. The present study reported that interferon (IFN)-γ levels and the percentage of IFN-γ+CD4+ cells was significantly increased in the peritoneal fluid (PF) at the early stage and maintained at a higher level at the advanced stage of endometriosis; furthermore, interleukin (IL)-10 and IL-10+CD4+ cells were elevated in the advanced stage of endometriosis. In addition, IL-2 levels in the PF at the advanced stage of endometriosis were elevated and negatively associated with IFN-γ expression. In a co-culture system of ectopic endometrial stromal cells (ESCs) and macrophages, elevated IL-2 was observed, and treatment with cytokines IL-2 and transforming growth factor-ß led to upregulation of the ratio of IL-2+ macrophages. IL-27-overexpressing ESCs and macrophages were able to induce a higher ratio of IL-10+CD4+ T cells. Blocking of IL-2 with anti-IL-2 neutralizing antibody led to upregulation of the ratio of IFN-γ+CD4+ T cells in the co-culture system in vitro. Recombinant human IL-10 and IFN-γ promoted the viability, invasiveness and transcription levels of matrix metalloproteinase (MMP)2, MMP9 and prostaglandin-endoperoxide synthase 2 of ESCs, particularly combined treatment with IL-10 and IFN-γ. These results suggest that IL-2 and IL-27 synergistically promote the growth and invasion of ESCs by modulating the balance of IFN-γ and IL-10, and contribute to the progress of endometriosis.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31846559

RESUMO

Preparation of native S-palmitoylated (S-palm) membrane proteins represents one of the unsolved challenges in chemical protein synthesis. Herein, we reported the first chemical synthesis of S-palm membrane proteins by reversible backbone modification assisted Ser/Thr Ligation (RBM GABA -assisted STL). This method involves two critical steps: (1) Synthesis of S-palm peptides by a new γ-aminobutyric acid group-based RBM (RBM GABA ) strategy, (2) Ligation of the S-palm RBM-modified peptides to give the desired S-palm product by STL. The utility of RBM GABA -assisted STL method was demonstrated by the synthesis of rabbit S-palm sarcolipin (SLN) and the S-palm matrix-2 (M2) ion channel. The synthesis of S-palm membrane proteins highlights the importance of developing non-NCL methods for chemical protein synthesis.

12.
Dig Dis Sci ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31701262

RESUMO

BACKGROUND: DnaJ/Hsp40 homolog, subfamily B, member 6 (DNAJB6) is significantly down-regulated in esophageal squamous cell carcinoma (ESCC), while its complicated molecular mechanisms are still unknown. AIMS: To investigate the relationship between DNAJB6 and ESCC. METHODS: The expression of DNAJB6 was detected in ESCC patient by Western blot and immunohistochemistry. To overexpress DNAJB6a by lentivirus infection, colony-forming, CCK-8, transwell, mouse xenograft assays were utilized to verify the proliferous, invasive, and migratory role of DNAJB6a in ESCC cells. The MDA and GSH assays determine whether DNAJB6a participates in cell redox reaction. The variation of AKT and GPX4 was detected by Western blot. RESULTS: The correlation between DNAJB6 level and lymph node metastasis in ESCC patient was negative. Overexpressing DNAJB6a shows tumor-suppressive effects in vitro and in vivo. In addition, DNAJB6a overexpression was accompanied together with a remarkable reduction in the protein levels of GPX4 and phosphorylated AKT (p-AKT). CONCLUSION: DNAJB6 plays an important anti-oncogenic role in ESCC evolvement via ferroptosis.

13.
Org Lett ; 21(23): 9497-9501, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31718192

RESUMO

The reaction of hydrazides with triphosgene in the presence of triethylamine is a facile method to construct various oxadiazolones. Utilizing this reaction, a new class of colorimetric and fluorogenic phosgene chemosensors were developed with the BODIPY as fluorophore, five BODIPY-based hydrazides, which exhibited highly effective reactions with phosgene. The mechanism was updated. Finally, the test paper with a hydrazide was fabricated for facile, selective, and visual detection of phosgene gas.

14.
Front Oncol ; 9: 1160, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781487

RESUMO

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive solid malignant tumors worldwide. Increasing investigations demonstrate that long non-coding RNAs (lncRNAs) expression is abnormally dysregulated in cancers. It is crucial to identify and predict the prognosis of patients for the selection of further therapeutic treatment. Methods: PDAC lncRNAs abundance profiles were used to establish a signature that could better predict the prognosis of PDAC patients. The least absolute shrinkage and selection operator (LASSO) Cox regression model was applied to establish a multi-lncRNA signature in the TCGA training cohort (N = 107). The signature was then validated in a TCGA validation cohort (N = 70) and another independent Fudan cohort (N = 46). Results: A five-lncRNA signature was constructed and it was significantly related to the overall survival (OS), either in the training or validation cohorts. Through the subgroup and Cox regression analyses, the signature was proven to be independent of other clinic-pathologic parameters. Receiver operating characteristic curve (ROC) analysis also indicated that our signature had a better predictive capacity of PDAC prognosis. Furthermore, ClueGO and CluePedia analyses showed that a number of cancer-related and drug response pathways were enriched in high risk groups. Conclusions: Identifying the five-lncRNA signature (RP11-159F24.5, RP11-744N12.2, RP11-388M20.1, RP11-356C4.5, CTC-459F4.9) may provide insight into personalized prognosis prediction and new therapies for PDAC patients.

15.
Sci Rep ; 9(1): 17646, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31776475

RESUMO

Inflammatory bowel disease (IBD) is a persistent and chronic disease that is characterized by destructive gastrointestinal (GI) inflammation. Researchers are trying to identify and develop new and more effective treatments with no side effects. Acute and chronic mouse models of IBD were established using dextran sulfate sodium (DSS) solution. To evaluate the efficacy and mechanism, umbilical cord mesenchymal stem cells (UCMSCs) were obtained from Kunming (KM) mice and humans. In the chronic IBD study, the survival rates of the normal control, model, mouse UCMSC (mUCMSC) and human UCMSC (hUCMSC) groups were 100%, 40%, 86.7%, and 100%, respectively. The histopathological scores of the normal control, intraperitoneal injection, intravenous treatment, and model groups were 0.5 ± 0.30, 5.9 ± 1.10, 8.7 ± 1.39, and 8.8 ± 1.33 (p = 0.021). UCMSCs promoted the expression of the intestinal tight junction protein occludin, downregulated the protein expression of the autophagy marker LC3A/B in colon tissue, and upregulated the expression of VEGF-A and VEGFR-1 at the injured site. This study provides an experimental model for elucidating the therapeutic effects of UCMSCs in IBD. We provide a theoretical basis and method for the clinical treatment of IBD using UCMSCs.

16.
Cancer Sci ; 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31777993

RESUMO

Chemotherapy for non-small cell lung cancer (NSCLC) is far from satisfactory, mainly due to poor targeting of antitumor drugs and self-adaptations of the tumors. Angiogenesis, vasculogenic mimicry (VM) channels, migration, and invasion are the main ways for tumors to get nutrition. Herein, RPV-modified Epirubicin and dioscin co-delivery liposomes were successfully prepared. These liposomes exhibited ideal physicochemical properties, enhanced tumor targeting and accumulation in tumor sites, and inhibited VM channels formation, tumor angiogenesis, migration and invasion. The liposomes also down-regulated VM-related and angiogenesis-related proteins in vitro. Furthermore, when tested in vivo, the targeted co-delivery liposomes increased the selective accumulation of drugs in tumor sites and exhibited extended stability in blood circulation. In conclusion, the RPV-modified Epirubicin and dioscin co-delivery liposomes exhibited strong antitumor efficacy in vivo and could thus be considered a promising strategy for NSCLC treatment.

17.
Med Sci Monit ; 25: 8807-8813, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31749446

RESUMO

BACKGROUND Developmental dislocation of the hip (DDH) results in osteoarthritis in infants and children. This study aimed to investigate the effects of a single approach to arthroscopic reduction and debridement on clinical outcome in 12 infants with DDH. MATERIAL AND METHODS Twelve infants with irreducible DDH underwent single approach arthroscopic reduction and debridement followed by the use of a frog-leg position plaster cast with fixed flexion and abduction of the hips combined with external fixation for 6-8 weeks. Magnetic resonance imaging (MRI) or plain X-ray images were analyzed. Intra-articular obstructive factors for reduction were evaluated. The safety angle, medialization rate of the femoral head, and the acetabular angle were measured before and after arthroscopic reduction. RESULTS Imaging showed that the signs of DDH were significantly improved following arthroscopic reduction. Obstructive factors included hypertrophy of the round ligament, fibrous tissue and fat in the acetabular base, arthrocapsular constriction, and varus deformity of the hip. The safety angle was significantly increased following arthroscopic reduction (53.5°) compared with the safety angle before treatment (18.5°) (p<0.05). Medialization of the femoral head was significantly increased (127%) compared with that before treatment (72%) (p<0.05). Arthroscopic reduction significantly reduced the acetabular angle (25°) compared with that before treatment (37.5°) (p<0.05). CONCLUSIONS Single approach arthroscopic reduction and debridement was an effective method for treating DDH that significantly improved the medialization rate of the femoral head, acetabular angle, and the outcome of external fixation when a plaster cast was used with fixed flexion and abduction of the hips.

18.
Zhongguo Zhen Jiu ; 39(11): 1160-3, 2019 Nov 12.
Artigo em Chinês | MEDLINE | ID: mdl-31724349

RESUMO

OBJECTIVE: To observe the effect of acupuncture at Renying (ST 9) on morning blood pressure, daytime peak blood pressure and 24-hour blood pressure load in patients with ischemic stroke complicated with essential hypertension. METHODS: A total of 80 patients (3 cases dropped off) were randomized into an observation group (39 cases) and a control group (38 cases). Xingnao Kaiqiao acupuncture and nifedipine were given in the control group. On the basis of treatment in the control group, acupuncture at Renying (ST 9) was applied in the observation group, once a day, 6 times a week for 4 weeks. The changes of morning blood pressure, daytime peak blood pressure and blood pressure load were observed before and after treatment in the two groups. RESULTS: Compared before treatment, morning blood pressure, daytime peak blood pressure and blood pressure load after treatment were reduced in the two groups (all P<0.05). The change of morning systolic pressure in the observation group was not significant as compared with that in the control group (P>0.05); the changes of morning diastolic pressure, daytime peak blood pressure and blood pressure load in the observation group were larger than those in the control group (all P<0.05). CONCLUSION: On the basis of Xingnao Kaiqiao acupuncture and nifedipine, acupuncture at Renying (ST 9) can effectively reduce morning blood pressure, daytime peak blood pressure and blood pressure load in patients with ischemic stroke complicated with essential hypertension.


Assuntos
Terapia por Acupuntura , Isquemia Encefálica , Hipertensão Essencial , Acidente Vascular Cerebral , Pontos de Acupuntura , Terapia por Acupuntura/métodos , Pressão Sanguínea , Hipertensão Essencial/terapia , Humanos , Resultado do Tratamento
19.
J Cell Mol Med ; 2019 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-31733099

RESUMO

It has been found that long noncoding RNA HOTAIR, microRNA-130a (miR-130a) and insulin-like growth factor 1 (IGF1) expression are associated with ovarian cancer, thus, we hypothesised that the HOTAIR/miR-130a/IGF1 axis might associate with endocrine disorders and biological behaviours of ovarian granulosa cells in rat models of polycystic ovary syndrome (PCOS). PCOS rat models were established by injection of dehydro-isoandrosterone, followed by treatment of si-HOTAIR, oe-HOTAIR, miR-130a mimics or miR-130a inhibitors. Serum hormonal levels were determined to evaluate endocrine conditions. The effect of HOTAIR and miR-130a on activities of isolated ovarian granulosa cells was assessed, as well as the involvement of IGF1.In the ovarian tissues and granulosa cells of PCOS rat models, highly expressed HOTAIR and IGF1 and poorly expressed miR-130a were identified. In response to oe-HOTAIR, serum levels of E2 , T and LH were increased and serum levels of FSH were reduced; the proliferation of granulosa cells was reduced and apoptosis was promoted; notably, expression of miR-130a was reduced while expression of IGF1 was increased. The treatment of si-HOTAIR reversed the situation. Furthermore, the binding of HOTAIR to miR-130a and targeting relationship of miR-130a and IGF1 were confirmed. LncRNA HOTAIR up-regulates the expression of IGF1 and aggravates the endocrine disorders and granulosa cell apoptosis through competitive binding to miR-130a in rat models of PCOS. Based on our finding, we predict that competitive binding of HOTAIR to miR-130a may act as a novel target for the molecular treatment of PCOS.

20.
Nat Metab ; 1(11): 1157-1167, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31742248

RESUMO

Catecholamines stimulate the first step of lipolysis by PKA-dependent release of the lipid droplet-associated protein ABHD5 from perilipin to co-activate the lipase ATGL. Here, we unmask a yet unrecognized proteolytic and cardioprotective function of ABHD5. ABHD5 acts in vivo and in vitro as a serine protease cleaving HDAC4. Through the production of an N-terminal polypeptide of HDAC4 (HDAC4-NT), ABHD5 inhibits MEF2-dependent gene expression and thereby controls glucose handling. ABHD5-deficiency leads to neutral lipid storage disease in mice. Cardiac-specific gene therapy of HDAC4-NT does not protect from intra-cardiomyocyte lipid accumulation but strikingly from heart failure, thereby challenging the concept of lipotoxicity-induced heart failure. ABHD5 levels are reduced in failing human hearts and murine transgenic ABHD5 expression protects from pressure-overload induced heart failure. These findings represent a conceptual advance by connecting lipid with glucose metabolism through HDAC4 proteolysis and enable new translational approaches to treat cardiometabolic disease.

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