Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.004
Filtrar
1.
Nat Commun ; 10(1): 4957, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31673082

RESUMO

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.

2.
Pharmazie ; 74(10): 583-589, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31685081

RESUMO

The compatibility between ticagrelor and selected excipients (mannitol, calcium phosphate tribasic, sodium carboxymethyl starch, hydroxypropyl cellulose and magnesium stearate) was investigated by differential scanning calorimetry. The compatibility was further corroborated by Raman spectroscopy and isothermal stress testing experiments. These results revealed that ticagrelor has high compatibility with mannitol, calcium phosphate tribasic, sodium carboxymethyl starch, hydroxypropyl cellulose and magnesium stearate.

3.
Exp Mol Pathol ; : 104328, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31678237

RESUMO

Isoflurane is a commonly used inhalational anesthetic that can induce neurotoxicity, while Dexmedetomidine (Dex) has significant neuroprotective effects. In our study, we explored the effects of Dex on isoflurane-induced neurotoxicity through the TLR2/NF-κB signaling pathway. Seven-day old neonatal Sprague-Dawley rats pretreated with 25, 50, 75 µg/kg Dex were exposed to 0.75% isoflurane for 6 h. Spatial learning and memory abilities were detected by Morris water maze test. Ultrastructure of hippocampal neurons, neuronal apoptosis, and the levels of TLR2/NF-κB signaling pathway-related factors were determined. Besides, TLR2 agonist Pam3CSK4 or NF-κB inhibitor BAY11-7082 was injected to further validate the involvement of TLR2/NF-κB signaling following Dex treatment. Consequently, we found isoflurane inhalation resulted in increased cell apoptosis, inflammation and TLR2/NF-κB signaling pathway activation, and decreased PSD95 expression and spatial learning and memory abilities. Dex led to decreased inflammation, improved neuronal structure and viability in rats as well as enhanced spatial learning and memory abilities of rats, and it inactivated the TLR2/NF-κB signaling pathway. Additionally, Pam3CSK4 injection reversed the protective effects of Dex on isoflurane-induced neurotoxicity. In conclusion, this study provided evidence that Dex could alleviate isoflurane-induced neurotoxicity through inhibition of the TLR2/NF-κB signaling pathway. The findings may offer novel insights for the clinical usage of anesthetics.

4.
Physiol Genomics ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31682178

RESUMO

Long non-coding RNAs have been implicated in the development and progression of atherosclerosis. However, the expression and mechanism of action of lncRNAs in atherosclerosis are still unclear. We implemented microarray analysis in human advanced atherosclerotic plaques and normal arterial intimae to detect the lncRNA and mRNA expression profile. Gene Ontology functional enrichment and pathway analyses were applied to explore the potential functions and pathways involved in the pathogenesis of atherosclerosis. A total of 236 lncRNAs and 488 mRNAs were selected for further Ingenuity Pathway Analysis. Moreover, qRT-PCR tests of most selected lncRNAs and mRNAs with high fold changes were consistent with the microarray data. We also performed ELISA to investigate the corresponding proteins levels of selected genes and showed that serum levels of SPP1, CD36, ATP6V0D2, CHI3L1, MYH11 and BDNF were differentially expressed in patients with coronary heart disease compared with healthy subjects.These proteins correlated with some biochemical parameters used in the diagnosis of cardiovascular diseases. Furthermore, receiver operating characteristic analysis showed a favorable diagnostic performance.The microarray profiling analysis and validation of differentially-expressed lncRNAs and mRNAs in atherosclerosis not only provide new insights into the pathogenesis of this disease, but may also reveal new biomarkers for its diagnosis and treatment.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31692167

RESUMO

Prion-like trans-cellular spreading of tau in Alzheimer's Disease (AD) is mediated by tau binding to cell surface heparan sulfate (HS). However, the structural determinants for tau-HS interaction are not well understood. Microarray and SPR assays of structurally-defined HS oligosaccharides show that a rare 3-O-sulfation(3-O-S) of HS significantly enhances tau binding. In Hs3st1-/- (HS 3-O-sulfotransferase-1 knockout) cells, reduced 3-O-S levels of HS diminished both cell surface binding and internalization of tau. In cell culture, the addition of 3-O-S HS 12-mer reduced both tau cell surface binding and cellular uptake. NMR titration mapped 3-O-S binding sites to microtubule binding repeat 2 (R2) and proline-rich region 2 (PRR2) of tau. Tau is only the 7th protein currently known to recognize HS 3-O-sulfation. Our work demonstrates that this rare 3-O-sulfation enhances tau-HS binding and likely the trans-cellular spread of tau, providing a novel target for disease modifying treatment of AD and other tauopathy.

6.
Cancer Med ; 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31697452

RESUMO

BACKGROUND: It remains controversial if radical prostatectomy or definitive radiation therapy produces equivalent outcomes in high-risk localized prostate cancer. METHODS: We queried The Surveillance, Epidemiology, and End Results (SEER) database for those who received upfront surgery or who were recommended for surgery but instead received radiation. Inverse probability of treatment weighing was used to adjust for covariate imbalance and the weighted Cox proportional hazards model was used to estimate the effects of treatment groups on survival. A meta-analysis was performed to pool estimates from published studies. RESULTS: Among eligible 62 533 patients, 59 540 had upfront surgery and 2993 patients had upfront radiotherapy. EBRT + BT was associated with a superior cancer-specific survival (CSS) compared with surgery or EBRT alone (HR, 0.55, 95% CI, 0.3-1.0; HR, 0.49, 95% CI, 0.24-0.98, respectively), whereas EBRT was associated with an inferior overall survival (OS) compared with surgery (HR, 1.46, 95% CI, 1.16-1.8). Radiotherapy (EBRT ± BT) was inferior to surgery by OS (HR, 1.63, 95% CI, 1.13-2.34) in patients ≤ 65 years, and was superior to surgery by CSS in patients > 65 years (HR, 0.69, 95% CI, 0.49-0.97). The meta-analysis showed consistent results. CONCLUSION: EBRT + BT was associated with a significantly better prostate CSS compared with surgery or EBRT. EBRT alone was inferior to surgery by OS.

7.
Stem Cell Res Ther ; 10(1): 315, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31685031

RESUMO

Hepatocyte nuclear factor-1 alpha (HNF-1α) is a transcription factor expressed predominantly in the liver among other organs. Structurally, it contains POU-homeodomain that binds to DNA and form proteins that help in maintaining cellular homeostasis, controlling metabolism, and differentiating cell lineages. Scientific research over the period of three decades has reported it as an important player in various liver malignancies such as hepatocellular cancers (HCCs), hepatocellular adenoma (HA), and a more specific HNF-1α-inactivated human hepatocellular adenoma (H-HCAs). Abundant clinical and rodent data have noted the downregulation of HNF-1α in parallel with liver malignancies. It is also interesting to notice that the co-occurrence of mutated HNF-1α expression and hepatic carcinomas transpires typically along with metabolic repercussion. Moreover, scientific data implies that HNF-1α exerts its effects on cell stemness and hence can indirectly impact liver malignancies and metabolic functioning. The effects of HNF-1α on cell stemness present a future opportunity to explore a possible and potential breakthrough. Although the mechanism through which inactivated HNF-1α leads to hepatic malignancies remain largely obscure, several key signal molecules or pathways, including TNF-α, SHP-1, CDH17, SIRT, and MIA-2, have been reported to take part in the regulations of HNF-1α. It can be concluded from the present scientific data that HNF-1α has a great potential to serve as a target for liver malignancies and cell stemness.

8.
Mol Immunol ; 116: 180-190, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31704501

RESUMO

Infectious pancreatic necrosis virus (IPNV) and infectious hematopoietic necrosis virus (IHNV) are two common viral pathogens that cause severe economic losses in all salmonid species in culture, but especially in rainbow trout. Although vaccines against both diseases have been commercialized in some countries, no such vaccines are available for them in China. In this study, a recombinant virus was constructed using the IHNV U genogroup Blk94 virus as a backbone vector to express the antigenic gene, VP2, from IPNV via the reverse genetics system. The resulting recombinant virus (rBlk94-VP2) showed stable biological characteristics as confirmed by virus growth kinetic analyses, pathogenicity analyses, indirect immunofluorescence assays and western blotting. Rainbow trout were immunized with rBlk94-VP2 and then challenged with the IPNV ChRtm213 strain and the IHNV Sn1203 strain on day 45 post-vaccination. A significantly higher survival rate against IHNV was obtained in the rBlk94-VP2 group on day 45 post-vaccination (86%) compared with the PBS mock immunized group (2%). Additionally, IPNV loads decreased significantly in the rBlk94-VP2 immunized group in the liver (28.6-fold to 36.5-fold), anterior kidney (21.7-fold to 44.2-fold), and spleen (14.9-fold to 22.7-fold), as compared with the PBS mock control group. The mRNA transcripts for several innate and adaptive immune-related proteins (IFN-γ, IFN-1, Mx-1, CD4, CD8, IgM, and IgT) were also significantly upregulated after rBlk94-VP2 vaccination, and neutralizing antibodies against both IHNV and IPNV were induced on day 45 post-vaccination. Collectively, our results suggest that this recombinant virus could be developed as a vaccine vector to protect rainbow trout against two or more diseases, and our approach lays the foundations for developing live vaccines for rainbow trout.

9.
Appl Opt ; 58(29): 8075-8082, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31674363

RESUMO

The optical parameters (extinction or backscatter coefficients) of multi-wavelength beams can be used for the retrieval of the aerosol particle size distribution (APSD). An improved algorithm for APSD and aerosol microphysical parameters (AMPs) is studied and discussed by using only multi-wavelength extinction coefficients data. The regularized algorithm and prior value are combined for the retrieval of APSD and AMPs. The regularization algorithm, based on minimum discrepancy principle and averaging procedure, is used for the retrieval of fine-mode APSD and an averaging procedure that can achieve stable outputs is proposed. The 1% averaging result near the minimum of the discrepancy is selected and verified. Based on the inversion results of fine mode from the regularization algorithm, the lognormal distribution with a prior value (model radius) is applied to reconstruct the coarse mode of APSDs through fitting the data. The comprehensive application of the regularization algorithm and averaging process improves the stability of the inversion in the fine mode, and the use of the prior value broadens the inversion radius range of APSD. The complex refractive index need not be assumed for this method. The inversion error for different types of aerosols is analyzed and studied. The reliability of the algorithm is tested and verified by many typical APSDs and the measured APSDs by particle size spectrometer in different pollution days. The algorithm sensitivity analysis is also provided and discussed. The algorithm can obtain reliable inversion of APSD and AMPs with large radius range.

10.
Mol Ther Nucleic Acids ; 18: 485-495, 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31670198

RESUMO

Long non-coding RNAs (lncRNAs) have been widely highlighted due to their involvement in various types of cancers, including glioma; however, the exact mechanism and function by which they operate in regard to spinal cord glioma remain poorly understood. LOC101928963 was screened out for its differential expression in spinal cord glioma by microarray analysis. Therefore, this study was conducted to investigate the modulatory effects of LOC101928963 on spinal cord glioma by binding to phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1). The expression of LOC101928963 and LOC101928963 was characterized in spinal cord glioma tissues, and their interaction was examined by dual-luciferase reporter gene assay. Cells with LOC101928963 that exhibited elevated or suppressed levels of PMAIP1 were established to substantiate the mechanism between LOC101928963 and PMAIP1. qRT-PCR and western blot methods were subsequently applied to determine the expression of cell-proliferation- and apoptosis-related genes in response to the alterations of LOC101928963 and PMAIP1. Glioma cell proliferation and apoptosis were assessed by MTT assay and flow cytometry. Decreased cell apoptosis and PMAIP1 expression, as well as overexpressed LOC101928963, were exhibited among spinal cord glioma tissues. LOC101928963 overexpression was observed to promote cell proliferation and cell-cycle entry and inhibit the process of apoptosis. PMAIP1, a target of LOC101928963, displayed a downregulated level following the elevation of LOC101928963. The present results strongly emphasize the neutralization effect of PMAIP1 overexpression on spinal cord glioma progression induced by the overexpression of LOC101928963. The data obtained during the study highlighted the inhibitory role of LOC101928963 silencing in spinal cord glioma through the increase in PMAIP1, which suggests a potential target in the treatment of spinal cord glioma.

11.
Mol Ther Nucleic Acids ; 18: 533-545, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31671346

RESUMO

Long noncoding RNAs (lncRNAs) have emerged as key regulators of cell differentiation and development. However, potential roles for lncRNAs in chondrogenic differentiation have remained poorly understood. Here we identify lncRNA ADAMTS9 antisense RNA 2, ADAMTS9-AS2, which controls the chondrogenic differentiation by acting as a competing endogenous RNA (ceRNA) in human mesenchymal stem cells (hMSCs). We screen out ADAMTS9-AS2 of undifferentiated and differentiated cells during chondrogenic differentiation by microarrays. Suppression or overexpression of lncRNA ADAMTS9-AS2 correlates with inhibition and promotion of hMSC chondrogenic differentiation, respectively. We find that ADAMTS9-AS2 can sponge miR-942-5p to regulate the expression of Scrg1, a transcription factor promoting chondrogenic gene expression. Finally, we confirm the function of ADAMTS9-AS2 to cartilage repair in the absence of transforming growth factor ß (TGF-ß) in vivo. In conclusion, ADAMTS9-AS2 plays an important role in chondrogenic differentiation as a ceRNA, so that it can be regarded as a therapy target for cartilage repair.

12.
J Am Chem Soc ; 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31682419

RESUMO

Hedgehog (Hh) autoprocessing converts Hh precursor protein to cholesterylated Hh ligand for downstream signaling. A conserved active-site aspartate residue, D46, plays a key catalytic role in Hh autoprocessing by serving as a general base to activate substrate cholesterol. Here we report that a charge-altering Asp-to-His mutant (D46H) expands native cholesterylation activity and retains active-site conformation. Native activity toward cholesterol was established for D46H in vitro using a continuous FRET-based autoprocessing assay and in cellulo with stable expression in human 293T cells. The catalytic efficiency of cholesterylation with D46H is similar to that with wild type (WT), with kmax/KM = 2.1 × 103 and 3.7 × 103 M-1 s-1, respectively, and an identical pKa = 5.8 is obtained for both residues by NMR. To our knowledge this is the first example where a general base substitution of an Asp for His preserves both the structure and activity as a general base. Surprisingly, D46H exhibits increased catalytic efficiency toward non-native substrates, especially coprostanol (>200-fold) and epicoprostanol (>300-fold). Expanded substrate tolerance is likely due to stabilization by H46 of the negatively charged tetrahedral intermediate using electrostatic interactions, which are less constrained by geometry than H-bond stabilization by D46. In addition to providing fundamental insights into Hh autoprocessing, our findings have important implications for protein engineering and enzyme design.

13.
Theranostics ; 9(24): 7403-7416, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695776

RESUMO

Bone marrow mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) have been widely used for treating myocardial infarction (MI). However, low retention and short-lived therapeutic effects are still significant challenges. This study aimed to determine whether incorporation of MSC-derived sEVs in alginate hydrogel increases their retention in the heart thereby improving therapeutic effects. Methods: The optimal sodium alginate hydrogel incorporating sEVs system was determined by its release ability of sEVs and rheology of hydrogel. Ex vivo fluorescence imaging was utilized to evaluate the retention of sEVs in the heart. Immunoregulation and effects of sEVs on angiogenesis were analyzed by immunofluorescence staining. Echocardiography and Masson's trichrome staining were used to estimate cardiac function and infarct size. Results: The delivery of sEVs incorporated in alginate hydrogel (sEVs-Gel) enhanced their retention in the heart. Compared with sEVs only treatment (sEVs), sEVs-Gel treatment significantly decreased cardiac cell apoptosis and promoted the polarization of macrophages at day 3 after MI. sEVs-Gel treatment also increased scar thickness and angiogenesis at four weeks post-infarction. Measurement of cardiac function and infarct size were significantly better in the sEVs-Gel group than in the group treated with sEVs only. Conclusion: Delivery of sEVs incorporated in alginate hydrogel provides a novel approach of cell-free therapy and optimizes the therapeutic effect of sEVs for MI.

14.
Math Biosci Eng ; 16(6): 7911-7920, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31698646

RESUMO

For the accuracy of Specific Absorption Rate (SAR) measurement, there is a need to have the measuring instrument, the E-field probe, calibrated on a regular basis, however, the conventional calibration approach can be complicated for an encapsulated dosimestic E-field probe. This paper proposed a new method to obtain the conversion factor of the E-field probe in the simulant tissue. The novelty of this proposal is that it can simplify the procedure of the conversion factor analysis, by employing the liquid waveguide with known E-filed as a component of the reference field to compare with the measured E-field of the dosimestic probe immersed in the equivalent-tissue liquid. Also, this paper evaluated the uncertainty of calibration for this method.

15.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(5): 646-657, 2019 Oct 30.
Artigo em Chinês | MEDLINE | ID: mdl-31699195

RESUMO

Objective To summarize the characteristics of Chinese coccidioidomycosis cases, improve the diagnosis and treatment of this disease and prevent misdiagnosis as well as therapeutic error.Methods Search in databases including Medline,Wanfang,and CNKI using "Coccidioidomycosis" and "China" as index words yielded 23 articles that reported a total of 32 Chinese coccidioidomycosis cases.In addition,one patient with disseminated coccidioidomycos was treated in our center in April 2016.The demographic data,site of infection,clinical manifestations,past medical history,exposure history,imaging and laboratory findings,and pathological features of these 33 patients were analyzed.Results Among these 33 patients,7(21.2%)had visited an epidemic area and 6(18.2%)were immunocompromised.The disease involved the respiratory system,skin,bone,central nervous system,cornea,and stomach in 24,6,3,2,1,and 1 patients,respectively.Eight patients (24.2%) had multiple system involvement,and three of them died.The imaging findings included pulmonary nodules(n=14),mediastinal lymphadenopathy(n=5),solid shadow(n=4),cavity(n=4),pleural effusion(n=3),multiple plaques(n=2)and masses(n=2).Coccidiolys cysts were detected in the affected tissues(n=28)or in pus,exudate or pleural smear(n=3);in addition,coccidioides mycelium and spores were found in the sputum,pus,and tissue cultures in 4 cases,among whom only 2 cases were confirmed by serological examination.The treatments included triazoles(n=20),systemic or local administration of amphotericin B(n=13),surgical resection of the lesion(n=8),and intravenous gamma globulin(n=1).Five patients died,among whom three had underlying diseases that caused immunosuppression and one was an infant.The prognoses were relatively good in the remaining patients.Conclusions Early diagnosis and proper treatment can achieve good prognosis in coccidioidomycosis patients.Multi-system involvement and immunosuppression are risk factors for poor prognosis of coccidioidomycosis.For these patients,adequate and full-course medication may prevent rapid disease progression.

16.
Clin Ther ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31699438

RESUMO

PURPOSE: Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma that can be either aggressive or indolent. Although MCL usually responds well to initial treatment with chemotherapy-based regimens, the disease often relapses or becomes refractory within a few years. Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor with minimal off-target activity. WIthout head-to-head clinical trial data, estimation of the comparative efficacy and safety of new therapeutic entities provides valuable information for patients, clinicians, and health care payers. The objective of this analysis was to compare the efficacy and safety of acalabrutinib versus other targeted therapies employed for the treatment of relapsed/refractory MCL by using matching-adjusted indirect comparisons. METHODS: Individual data from 124 patients treated with acalabrutinib in the Phase II ACE-LY-004 trial were adjusted to match average baseline characteristics of populations from studies using alternative targeted treatment regimens for relapsed/refractory MCL (for monotherapy: ibrutinib, bortezomib, lenalidomide, and temsirolimus; for combination therapies: ibrutinib + rituximab, bendamustine + rituximab, and lenalidomide + rituximab). Patient populations were matched on age, sex, race, Eastern Cooperative Oncology Group performance status, Simplified MCL International Prognostic Index score, tumor bulk, lactate dehydrogenase concentration, extranodal disease, bone marrow involvement, and number of previous treatment regimens. Outcomes assessed included overall response rate (ORR), complete response (CR) rate, overall survival (OS), progression-free survival (PFS), and adverse events. FINDINGS: After matching, acalabrutinib was associated with significant increases in ORR and CR rate (estimated treatment difference [95% CI]) versus ibrutinib (ORR, 9.3% [0.3-18.3]; CR, 14.9% [5.4-24.3]), bortezomib (ORR, 50.6% [40.2-61.0]; CR, 18.8% [9.1-28.5]), lenalidomide (ORR, 38.1% [27.1-49.1]; CR, 43.5% [34.8-52.3]), and temsirolimus (ORR, 40.7% [31.0-50.4]; CR, 27.1% [19.2-35.0]). PFS (hazard ratio [95% CI]) with acalabrutinib was significantly increased versus bortezomib (0.36 [0.26-0.51]), lenalidomide (0.65 [0.48-0.89]), lenalidomide + rituximab (0.57 [0.35-0.93]), and temsirolimus (0.33 [0.24-0.45]). Acalabrutinib was associated with significantly increased OS (hazard ratio) versus bortezomib (0.36 [0.22-0.61]) and temsirolimus (0.32 [0.23-0.44]). The overall safety profile of acalabrutinib was similar or better compared with the monotherapies; however, infection risk increased versus bendamustine + rituximab, and anemia increased risk versus lenalidomide + rituximab and ibrutinib + rituximab. IMPLICATIONS: This comparison of targeted therapies used in the treatment of relapsed/refractory MCL showed that acalabrutinib has the potential to provide increased response rates, with trends for increased PFS and OS, and an improved safety profile.

17.
Int Heart J ; 60(5): 1231, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564710

RESUMO

An error appeared in the article entitled "Polysaccharides from Enteromorpha Prolifera Ameliorate Acute Myocardial Infarction in Vitro and in Vivo via Up-Regulating HIF-1α" by Zongqiu Wang, Zhihua Zhang, Jing Zhao, Chunming Yong, and Yongjun Mao (Vol. 60, No. 4, 964-973, 2019).The second affiliation of the authors on the bottom of page 964 should be replaced by "2Department of Vascular Surgery, The Affiliated Central Hospital of Qingdao University, Qingdao, China".

18.
J Cell Physiol ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31566734

RESUMO

Neonatal pneumonia is a high neonatal mortality disease. We studied the function and mechanism of long noncoding RNA myocardial infarction-associated transcript 2 (lncRNA MIAT2) on lipopolysaccharide (LPS)-induced inflammation in WI-38 cells. Cell Counting Kit-8 and apoptosis assay were respectively used to detect the functions of LPS, MIAT2, and microRNA-15 (miR-15) on viability and apoptosis. MIAT2 and miR-15 expressions were changed by cell transfection. Moreover, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot, and enzyme-linked immunosorbent assay were used to detect the expressions of interleukin (IL)-6 and monocyte chemoattractant protein-1 (MCP-1). The levels of Bax, cleaved-caspase-3, and cell pathways-related proteins were tested by western blot. Besides, the levels of miR-15 and MIAT2 were tested by RT-qPCR. We found that LPS declined cell viability and heightened apoptosis and levels of Bax, cleaved-caspase-3, IL-6, and MCP-1. MIAT2 was negatively regulated by LPS and it alleviated LPS-induced damage. Furthermore, MIAT2 reversely regulated miR-15 and miR-15 mimic could reverse the effects of MIAT2. Finally, MIAT2 restrained the p38MAPK and NF-κB pathways by downregulating miR-15. In conclusion, MIAT2 alleviated LPS-induced inflammation damage in WI-38 cells by sponging miR-15 via p38MAPK and NF-κB pathways.

19.
Med Chem ; 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31584376

RESUMO

BACKGROUND: Molecular characterization of insulin resistance, a growing health issue worldwide, will help to develop novel strategies and accurate biomarkers for disease diagnosis and treatment. OBJECTIVE: Integrative analysis of gene expression profiling and gene regulatory network was exploited to identify potential biomarkers early in the development of insulin resistance. METHODS: RNA was isolated from livers of animals at three weeks of age, and whole-genome expression profiling were performed and analyzed with Agilent mouse 4×44K microarrays. Differentially expressed genes were subsequently validated by qRT-PCR. Functional characterizations of genes and their interactions were performed by Gene Ontology (GO) analysis and gene regulatory network (GRN) analysis. RESULTS: A total of 197 genes were found to be differentially expressed by fold change ≥2 and P < 0.05 in BKS-db +/+ mice relative to sex and age-matched controls. Functional analysis suggested that these differentially expressed genes were enriched in the regulation of phosphorylation and generation of precursor metabolites which are closely associated with insulin resistance. Then a gene regulatory network associated with insulin resistance (IRGRN) was constructed by integration of these differentially expressed genes and known human protein-protein interaction network. Principal component analysis demonstrated that 67 genes in IRGRN could clearly distinguish insulin resistance from the non-disease state. Some of these candidate genes were further experimentally validated by qRT-PCR, highlighting the predictive role as biomarkers for insulin resistance. CONCLUSIONS: Our study provides new insight into the pathogenesis and treatment of insulin resistance and also reveals potential novel molecular targets and diagnostic biomarkers for insulin resistance.

20.
Nature ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31569198

RESUMO

Organoboron reagents are important synthetic intermediates that play a key role in the construction of natural products, pharmaceuticals, and organic materials.1 The discovery of simpler, milder and more efficient approaches to organoborons opens a route to diverse substances.2-5 Here we show a general method of directed C-H activation for site-selective C-H borylation of arenes and heteroarenes avoiding the use of metal catalysts. C7 and C4-borylated indoles are produced by a mild approach with broad functional group compatibility. The mechanism involves BBr3 as both reagent and catalyst and is established with DFT calculations. Downstream transformation of the formed boron species to natural products and drug scaffolds highlights the potential utility of this strategy.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA