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2.
Hypertens Res ; 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31685939

RESUMO

This study aimed to explore the association of systolic blood pressure (SBP) trajectories of pregnant women with the risk of adverse outcomes of pregnant women and their fetuses. A register-based cohort of 63,724 pregnant women and their fetuses from January 2013 to December 2017 was investigated. Demographic characteristics, history of disease and family history of disease for pregnant women and perinatal outcomes were recorded, and blood pressure was measured during the whole pregnancy. SBP trajectories were estimated with latent mixture modeling by Proc Traj in SAS using SBP data from the first antenatal care appointment (8-14 weeks), the highest SBP before admission, the admission SBP and the SBP at 2 h postpartum. A censored normal model (CNORM) was considered appropriate, and model fit was assessed using the Bayesian information criterion (BIC). A logistic regression model was used to examine the association between SBP trajectories and the risk of adverse perinatal outcomes. Four distinct SBP trajectory patterns over the pregnancy period were identified and were labeled as low-stable, moderate-stable, high-decreasing and moderate-increasing. Three maternal and three fetal adverse outcomes were selected as the main outcome measures. After adjusting for confounding factors, compared with pregnant women with the low-stable pattern, those with the high-decreasing pattern had a higher risk of developing poor growth outcomes of fetuses, while those with the moderate-increasing pattern had higher risks of developing both adverse maternal and fetal outcomes. Our study results suggest that pregnant women should pay attention to the control of blood pressure throughout pregnancy.

3.
Kaohsiung J Med Sci ; 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31688986

RESUMO

To screen the key circulating microRNAs (miRNAs) involved in missed abortion (MA) and explore their role in MA process. We examined the miRNA profile from the serum of three MA patients and three early pregnancy induced abortion patients (controls) by next-generation sequencing. We analyzed the target genes of the differentially expressed (DE) miRNAs to analyze the function and pathway enrichment using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, respectively. We validated five candidate miRNAs by real time-qPCR. Integrated miRNA-mRNA-pathway network analysis was performed to show the interaction network of the candidate miRNAs and their target genes of interest with the involved pathways. It was observed that 227 miRNAs were differently expressed between the MA group and the early pregnancy control group, with 58 miRNAs downregulated and 169 miRNAs upregulated in the MA group. Real-time qPCR results revealed that expression of the five candidate miRNAs, namely hsa-miR-22-3p, hsa-miR-145-3p, hsa-miR-107, hsa-miR-361-3p, and hsa-miR-378c, was consistent with the miRNA data obtained by sequencing. Integrated miRNA-mRNA-pathway network analysis illustrated that target genes of the candidate miRNAs were mainly involved in the PI3K-Akt signaling pathway, HIF-1 signaling pathway, and VEGF signaling pathway, which would have potential significance in pregnancy and MA. We are the first to reveal the DE miRNAs involved in MA and illustrate their functional interaction network. These results might provide potential circulating biomarkers and new therapeutic targets for MA.

4.
Bioresour Technol ; 296: 122311, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31678708

RESUMO

Partial nitrification (PN) of ammonia to nitrite is investigated in a lab-scale sequencing batch reactor (SBR) coupled with both a microporous aeration system and a mechanical agitation system at a moderate temperature of (27 ±â€¯1 °C). The SBR has a high actual oxygen transfer efficiency (AOTE) of 2.0% and dynamical efficiency (DE) of 20.0%. Alkalinity consumption declined with the decreasing ratios of HCO3- to NH4+-N in the influent from 2.57, 1.96, 1.91 to 1.66, while the pH of the effluent is constantly maintained at 7.5 ±â€¯0.1. The SBR is successfully operated for 195 days at a nitrogen loading rate (NLR) of up to 2.82 kg·m-3.d-1, achieving a nitrite accumulation rate (NAR) of over 90%. The high-throughput sequencing shows that the ratio of Nitrosomonas, the dominant species, is up to 29.83%.

5.
Adv Healthc Mater ; : e1901299, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31697048

RESUMO

Design of theranostic nanoplatforms represents a major topic for current nanomedicine. Here, the preparation of multifunctional poly(cyclotriphosphazene-co-polyethylenimine) nanospheres (PNSs) labeled with radionuclide 131 I for single photon emission computed tomography (SPECT) imaging-guided radiotherapy of tumors is reported. In this work, PNSs are prepared using hexachlorocyclotriphosphazene as a crosslinker to crosslink branched polyethylenimine (PEI) via a nucleophilic substitution reaction, modified with 3-(4'-hydroxyphenyl) propionic acid-OSu (HPAO) for 131 I labeling, and reacted with 1,3-propane sulfonate (1,3-PS) to render the particles with antifouling property, followed by acetylation of the remaining surface amines and labeling with 131 I. The acquired PNS.NHAc-HPAO(131 I)-PS particles are well characterized. It is shown that the multifunctional PNSs with an average size of 184 ± 29.3 nm exhibit favorable antifouling properties, high 131 I labeling efficiency (76.05 ± 3.75%), and excellent radiostability and colloidal stability. With these properties owned, the developed PNS.NHAc-HPAO(131 I)-PS spheres enable much more efficient SPECT imaging and radiotherapy of a xenografted tumor model in vivo than the PEI counterpart material (PEI.NHAc-HPAO(131 I)-PS). The developed PNSs may be used as a versatile platform for further development of different forms of nanomedicine for various biomedical applications.

6.
Thorac Cancer ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31692283

RESUMO

BACKGROUND: Distinction in the mutational profile between the common histological types, lung adenocarcinoma (LUAD) and squamous cell lung carcinoma (LUSC) has been well-established. However, comprehensive mutation profiles of the predominant histological subtypes within LUAD and LUSC remains elusive. METHODS: We analyzed the mutational profile of 318 Chinese NSCLC patients of adenocarcinoma and squamous cell carcinoma predominant subtypes from seven hospitals using capture-based ultra-deep sequencing of 68 lung cancer-related genes. RESULTS: Of the 318 NSCLC patients, 215 were diagnosed with LUAD and 103 with LUSC. Adenocarcinoma in situ and acinar adenocarcinoma were the most predominant subtypes of LUAD. On the other hand, keratinizing squamous cell carcinoma was the most predominant subtype of LUSC. Among the LUAD subtypes, EGFR sensitizing mutations were most prevalent in the invasive lepidic subtype. More than half of the patients with preinvasive adenocarcinoma in situ, minimally invasive, acinar, micropapillary and papillary subtypes were also EGFR-mutants. Patients with colloidal, invasive mucinous, and fetal subtypes had the least number of EGFR mutations. Moreover, KRAS mutations were prevalent in patients with invasive mucinous, colloid, enteric and solid subtypes. A total of 90% of the LUSC patients harbor mutations in TP53, wherein all patients except five with nonkeratinizing were TP53 mutants. PIK3CA amplifications were most prevalent in keratinizing, followed by basaloid and nonkeratinizing subtypes. CONCLUSION: These data suggest that the mutational profiles among the predominant histological subtypes were very distinct, which provided a reliable tool to improve treatment decisions.

7.
Drug Des Devel Ther ; 13: 3657-3667, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695333

RESUMO

Background: Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM) and also a major cause of end-stage renal disease (ESRD). Olmesartan medoxomil (OM) is an angiotensin II receptor blocker (ARB) and has been shown to exhibit renoprotective effects on a streptozotocin (STZ)-induced diabetic rat model. Yet, whether OM affects DN progression and renal injury in db/db mice, a type 2 diabetic murine model, has not been established. Methods: Wild-type (n = 15) and db/db mice (n = 15) were treated with control saline or OM via oral gavage. The physiological and biochemical parameters were evaluated and histological examinations of kidney specimens were performed. Results: Compared with saline-treated db/db mice, db/db mice administered with OM showed ameliorated diabetic physiological and biochemical parameters. In addition, OM decreased urinary albumin excretion and plasma creatinine level in db/db mice. Moreover, histologically, OM reduced glomerular hypertrophy and injury, and also ameliorated tubular injury, thus suggesting that OM improves renal function and minimizes renal pathological deterioration in db/db mice. Conclusion: Our study reveals a beneficial role of OM in ameliorating DN in db/db mice, which is associated with its renoprotective function.

8.
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.

9.
Math Biosci Eng ; 16(6): 7808-7828, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31698641

RESUMO

Objective: To evaluate the influence of drilling sites for benign lesions in femoral head and neck with curettage, bone-grafting and internal fixation. Methods: Twelve paired formalin-fixed human cadaveric femora were grouped randomly into 2 groups of 6 pairs each, which were group 1 and group 2, and one of each pair of femora was grouped randomly to drill an oval-shaped hole in the anterior femoral neck, and the contralateral femur was assigned to drill an oval-shaped hole in the lateral of the proximal femur. Group 1 femora were simulated the operation of curettage, bone-grafting and internal fixation, and group 2 femora were simulated the operation of curettage. Besides, finite element models corresponding to mechanical testing were simulated according to one of the twelve femora, then finite element analysis were done. Wilcoxon signed-rank test was used for statistical analysis, with a p value < 0.05 indicating statistical significance. Results: The simulated operation of curettage decreased the axial stiffness and torsional stiffness of the intact proximal femur significantly, while there was no statistical difference on the degree of the decline between different drilling sites. Although the simulated operation of bone-grafting and internal fixation in different drilling sites increased the axial stiffness and torsional stiffness, only in the case of implanting bones and internal fixation for the lateral cortical drilled hole increased the axial stiffness greatly and made a statistical difference, even more stiff than the intact proximal femur model. Conclusion: Compared with drilling in the anterior femoral neck, a bigger stability could be obtained after drilling in the lateral proximal femur for benign lesions in femoral head and neck with curettage, bone-grafting and internal fixation.

10.
Harmful Algae ; 89: 101667, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31672232

RESUMO

Colony formation provides excellent advantages for the dominance of Microcystis. However, studies on microenvironments during the process of colony formation are rare, especially regarding intra-colony light usage. This study analyzed the attenuation of light intensity in Microcystis colonies, where most objects followed Lambert-Beer law ( [Formula: see text] ). Intra-colony light limited the maximum thickness of the colony (BMax=4.3×105c-1) and thus affected colony size. Field data showed that the colony size for M. ichthyoblabe was small and limited to approximately 300 µm, while larger colonies were mainly formed by M. aeruginosa and M. wesenbergii respectively. These results imply that the strategies used by morphospecies to allow colonies to tolerate intra-colony light limitation might be different; M. aeruginosa benefited from a reticular growth pattern, and M. wesenbergii colonies were large (500 µm), obtaining a large thickness by lowering cell concentration. The results obtained in this work suggest that M. aeruginosa and M. wesenbergii had more advantages regarding intra-colony light usage, colony size level and bloom formation ability in summer and autumn.

12.
Theranostics ; 9(26): 8206-8220, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31754391

RESUMO

Background: By providing oxygen, nutrients and metastatic conduits, tumour angiogenesis is essential for cancer metastasis. Cancer cell-secreted microRNAs can be packaged into exosomes and are implicated in different aspects of tumour angiogenesis. However, the underlying mechanisms are incompletely understood. Methods: The GEPIA database and in situ hybridization assay were used to analyse expression of miR-205 in ovarian tissues. Immunohistochemistry was performed to examine the relationship between miR-205 and microvessel density. Expression of circulating miR-205 was evaluated by RT-PCR and GEO database analysis. Co-culture and exosome labelling experiments were performed to assess exosomal miR-205 transfer from ovarian cancer (OC) cells to endothelial cells ECs. Exosome uptake assays were employed to define the cellular pathways associated with the endocytic uptake of exosomal miR-205. The role of exosomal miR-205 in angiogenesis was further investigated in vivo and in vitro. Western blotting and rescue experiments were applied to detect regulation of the PTEN-AKT pathway by exosomal miR-205 in ECs. Results: miR-205 was up-regulated in OC tissues, and high expression of miR-205 was associated with metastatic progression in OC patients. Moreover, miR-205 was highly enriched in cancer-adjacent ECs, and up-regulation of miR-205 correlated positively with high microvessel density in OC patients. Importantly, miR-205 was markedly enriched in the serum of OC patients, and a high level of miR-205 in circulating exosomes was associated with OC metastasis. In addition, OC-derived miR-205 was secreted into the extracellular space and efficiently transferred to adjacent ECs in an exosome-dependent manner, and the lipid raft-associated pathway plays an important role in regulating uptake of exosomal miR-205. Exosomal miR-205 from OC cells significantly promoted in vitro angiogenesis and accelerated angiogenesis and tumour growth in a mouse model. Furthermore, we found that exosomal miR-205 induces angiogenesis via the PTEN-AKT pathway. Conclusion: These findings demonstrate an exosome-dependent mechanism by which miR-205 derived from cancer cells regulates tumour angiogenesis and implicate exosomal miR-205 as a potential therapeutic target for OC.

13.
Gene ; : 144243, 2019 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-31743768

RESUMO

BACKGROUND: Circulating microRNAs have become reliable sources of non-invasive biomarkers for cancer diagnosis. miRNA expression analysis in blood circulation for the identification of novel signatures might assist the early detection of nasopharyngeal carcinoma (NPC) patients. METHODS: In the screening stage, the Exiqon miRNA qPCR panel was applied for the selection of candidate miRNAs. Serum samples taken from 208 NPC patients and 238 healthy donors (as normal controls (NCs)) were assigned to into the following three stages (training (30 NPC VS. 30 NCs), testing (138 NPC VS. 166 NCs) and external validation stage (40 NPC VS. 42 NCs)) for further confirmation of differently expressed miRNAs using qRT-PCR. The identified miRNA signatures were further explored in tissue specimens (48 NPC VS. 32 NCs) and serum-derived exosomes samples (32 NPC VS. 32 NCs). RESULTS: Five miRNAs in serum including let-7b-5p, miR-140-3p, miR-192-5p, miR-223-3p and miR-24-3p were found to be significantly up-regulated in NPC patients compared to NCs. The five identified miRNAs were further combined into one panel and the areas under the receiver operating characteristic curve (AUCs) for three independent stages were 0.910 (training), 0.916 (testing) and 0.968 (external validation), respectively. miR-192-5p and miR-24-3p were consistently up-regulated in NPC tissues while let-7b-5p and miR-140-3p were conversely down-regulated. In serum-derived exosomes samples, no expression difference was observed between NPC patients and NCs. CONCLUSION: A five-miRNA signature was identified in serum to be potential biomarkers for NPC detection.

14.
J Exp Clin Cancer Res ; 38(1): 469, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31744516

RESUMO

BACKGROUND: The activation of tumour-associated macrophages (TAMs) contributes to the progression of hepatocellular carcinoma (HCC). SIRT4 acts as a tumour suppressor of tumour growth by regulating cell metabolism, inflammation, and anti-tumourigenesis. However, the involvement of SIRT4 in the activation of TAMs is unknown. Based on previous findings, the expression of SIRT4 in distinct groups of TAMs as well as the effect of SIRT4 silencing on macrophage polarization was investigated. METHODS: The expression of SIRT4 in HCC tissues and peritumour tissues was tested by qRT-PCR, western blotting and histological analysis. A Kaplan-Meier survival curve was generated based on the expression of SIRT4 in the HCC samples. Next, immunofluorescence staining was used to evaluate distinct groups of TAMs in human HCC samples, and the expression of SIRT4 in M1 and M2 TAMs was examined by flow cytometry. A homograft mouse model was used to assess the effect of SIRT4 silencing in TAMs on the development of HCC cells. RESULTS: SIRT4 was significantly downregulated in HCC tumour tissues, and the expression of SIRT4 in peritumour tissues was positively associated with survival in patients. We further found that downregulation of SIRT4 was associated with increased macrophage infiltration and a high ratio of M2/M1 macrophages in HCC peritumour tissues. Using gene interference, we found that SIRT4 silencing in TAMs significantly modulated the alternative activation of macrophages and promoted in vitro and in vivo HCC cell growth. Mechanistically, we revealed that HCM restricted the expression of SIRT4 in macrophages and promoted alternative activation of macrophages via the FAO-PPARδ-STAT3 axis. Furthermore, we also revealed that elevated MCP-1 expression induced by SIRT4 downregulation was responsible for increased TAM infiltration in peritumour tissues. CONCLUSIONS: Overall, our results demonstrate that downregulation of SIRT4 in TAMs modulates the alternative activation of macrophages and promotes HCC development via the FAO-PPARδ-STAT3 axis. These results could provide a new therapeutic target for the treatment of HCC.

15.
Int J Oncol ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31746419

RESUMO

Hepatitis B virus (HBV) x protein (HBx) has been reported as the primary pathogenic factor involved in HBV­related liver cancer; however, the mechanisms underlying how HBx promotes tumor­associated invasion and metastasis remain unclear. Long noncoding RNA activated by transforming growth factor (TGF)­ß (lncRNA­ATB) is a novel oncogenic lncRNA stimulated by TGF­ß, which is closely associated with the invasion and metastasis of liver cancer. In the present study, whether lncRNA­ATB was involved in HBx­mediated hepatocarcinogenesis was investigated. The expression of lncRNA­ATB in 26 primary liver cancer tissues and lentivirus transfected HBx­HepG2 cell lines was detected, and it was revealed that more advanced tumor­node­metastasis staging and increased expression of lncRNA­ATB in liver cancer tissues were significantly associated with HBV infection. It was further demonstrated that the expression levels of lncRNA­ATB and TGF­ß were elevated in HepG2 cells following HBx­vector transfection, which was accompanied with increased autophagy. Conversely, knockdown of lncRNA­ATB or TGF­ß could suppress this effect. Furthermore, such suppression on autophagy in HepG2 cells could be alleviated by the induction of starvation. In addition, the invasive and migration abilities of HBx­HepG2 cells were increased compared with HepG2 cells, while knockdown of lncRNA­ATB or TGF­ß could reduce these abilities. In conclusion, the results of the present study revealed that HBx was closely associated with oncogenic lncRNA­ATB. HBx­induced autophagy could upregulate the expression of TGF­ß and lncRNA­ATB. This may be considered to be a potential mechanism underlying HBV­induced hepatocarcinogenesis.

16.
Acta Diabetol ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31728736

RESUMO

AIMS: This study aimed to explore the level of and changes in the 1,5-anhydroglucitol × glycated hemoglobin A1c/100 (AH index, AHI) associated with different glucose metabolism statuses and to evaluate the islet function and insulin sensitivity of patients with type 2 diabetes (T2DM) with different AHI levels. METHODS: Of the 3562 subjects enrolled in this study, 1697 had T2DM. The disposition index (DI) was the product of islet secretion function and insulin sensitivity-related indexes. RESULTS: The mean AHI level was 1.0 (0.7-1.3) in the general population, while the mean AHI level in the T2DM group was 0.8 (0.5-1.2), which was significantly lower than that in the impaired glucose regulation and normal glucose tolerance group (both 1.2 (0.9-1.5), both P < 0.01). We further divided patients with T2DM into four subgroups according to the quartile of AHI. The results showed that with the increase in AHI level, the homeostasis model assessment of insulin resistance (HOMA-IR) decreased, while HOMA-ß, insulin generation index, insulin sensitivity index, and DI increased (all Pfor trend < 0.01). Multivariate logistic regression showed that the odds ratios for a low DI for increasing levels of AHI were 1.00, 0.22 (0.16-0.29), 0.16 (0.11-0.22), and 0.09 (0.06-0.13), showing a decreasing trend (Pfor trend < 0.05). CONCLUSION: The AHI could reflect the variation in glycemic disorder and the function of islet ß cells. The lower the AHI, the worse the glycemic disorder, as well as the islet ß-cell function.

17.
Biomed Pharmacother ; 121: 109591, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31733576

RESUMO

The present study was done to evaluate the prebiotic effect of Lycium barbarum polysaccharide (LBP), its effect on murine fecal microbiota composition and innate immune response. Results showed that LBP supports the growth of selective probiotic bacteria with a maximum of 8.23 (log10 cfu/mL) and 6.62 (log10 cfu/mL) for Lactobacillus acidophilus and Bifidobacterium longum respectively. In vivo studies revealed that the administrations of LBP to mice resulted in an increase in the abundance of the phyla Proteobacteria and Firmicutes, while reducing the ratio of the phylum Bacteroidetes. At the genus level, the administration of LBP stimulated the emergence of some potential probiotic genera (Akkermansia, Lactobacillus, and Prevotellaceae). The concentrations of TGF-ß and IL-6 in serum and sIgA in the colon content were enriched significantly after LBP administrations in mice. The thymus index and spleen index of mice treated with LBP displayed significant difference compared to the control group (P < 0.05). These findings suggest that LBP is a good source as a potential prebiotic and can enhance the intestinal microbiota and boost beneficial bacteria levels, modulate innate immune response.

18.
Clin Cancer Res ; 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31732519

RESUMO

PURPOSE: Immunogenicity derived from the murine scFv, a major molecular compomemt of chimeric antigen receptors (CARs), may limit the persistence of CAR-T cells, resulting in tumor relapse of complete remission (CR) patients. In this study, we developed a humanized anti-CD19 scFv CAR-T (hCAR-T) to treat patients with relapsed/refractory acute lymphoblastic leukemia (r/r ALL). EXPERIMENTAL DESIGN: In this one-arm, open-labeled study, we infused the T cells modified with hCAR to patients with r/r ALL. Patients were evaluated with long term follow-up for response and safety of the treatment. The study was registered at Clinicaltrials.gov (NCT02349698). RESULTS: Ten patients with r/r ALL were recruited for this study. All were response evaluable and all achieved CR; eight patients remained CR, and six were in CR for over 18 months without further treatment. A long-term persistence of hCAR-T cells was observed in most of the patients. Among these patients, four of them with high tumor burden and rapidly progressive disease (median 58%) experienced grade 3-4 CRS and neurotoxicity. These severe CRSs were successfully controlled by tocilizumab, glucocorticoid and plasma exchange (PE). CONCLUSIONS: T cells expressing the humanized anti-CD19 scFv CAR exhibited sustained therapeutic efficacy in the treatment of r/r ALL. Low replase rate was associated with the long-term persistence of CAR-T cells.

19.
J Med Chem ; 62(22): 10352-10361, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31689116

RESUMO

Described herein is a new approach to mitigate CYP3A4 induction. In this unconventional approach, a fine-tuning of the dihedral angle between the C4 phenyl and the dihydropyrimidine core of the heteroaryldihydropyrimidine (HAP) class of capsid inhibitors successfully altered the structure-activity-relationships (SARs) of the unwanted CYP3A4 induction and the desired HBV capsid inhibition to more favorable values. This eventually led to the discovery of a new capsid inhibitor with significantly reduced CYP3A4 induction, excellent anti-HBV activity, favorable preclinical PK/PD profiles, and no early safety flags.

20.
Redox Biol ; 28: 101365, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31707354

RESUMO

Though succinate accumulation is associated with reactive oxygen species (ROS) production and neuronal injury, which play critical roles in epilepsy, it is unclear whether succinate accumulation contributes to the onset of epilepsy or seizures. We sought to investigate changes in succinate, oxidative stress, and mito-SOX levels, as well as mitophagy and neuronal change, in different status epilepticus (SE) rat models. Our results demonstrate that KA-induced SE was accompanied by increased levels of succinate, oxidative stress, and mito-SOX, as well as mitophagy and neuronal degeneration. The similarly increased levels of succinate, oxidative stress, and mito-SOX were also found in pilocarpine-induced SE. Moreover, the reduction of succinate accumulation by the inhibition of succinate dehydrogenase (SDH), malate/aspartate shuttle (MAS), or purine nucleotide cycle (PNC) served to reduce succinate, oxidative stress, and mito-SOX levels, thereby preventing oxidative stress-related neuronal damage and lessening seizure severity. Interestingly, simulating succinate accumulation with succinic acid dimethyl ester may induce succinate accumulation and increased oxidative stress and mito-SOX levels, as well as behavior and seizures in electroencephalograms similar to those observed in rats exposed to KA. Our results indicate that succinate accumulation may contribute to the increased oxidative stress/mitochondrial ROS levels, neuronal degeneration, and SE induced by KA administration. Furthermore, we found that succinate accumulation was mainly due to the inverse catalysis of SDH from fumarate, which was supplemented by the MAS and PNC pathways. These results reveal new insights into the mechanisms underlying SE and that reducing succinate accumulation may be a clinically useful therapeutic target in SE.

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