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1.
Mol Genet Genomic Med ; : e949, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31482657

RESUMO

BACKGROUND: Biallelic variants of the CASQ2 are known to cause the autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disease that predisposes young individuals to syncope and sudden cardiac death. To date, only about 24 CASQ2 variants have been reported in association with CPVT pathogenesis; furthermore, studies in Asians, especially in the Chinese population, are relatively rare. The aim of this study was to detect CASQ2 variants in Chinese patients with CPVT. METHODS: We used targeted next-generation sequencing (NGS) to identify CASQ2 variants in Chinese patients with CPVT. A screening process was performed to prioritize rare variants of potential functional significance. Sanger sequencing was conducted to conform the candidate variants and determine the parental origin. RESULTS: We identified seven different CASQ2 variants, of which three (c.1074_1075delinsC, c.1175_1178delACAG, and c.838+1G>A) have not been previously reported. The variants exhibited autosomal recessive inheritance, and were detected in four unrelated Chinese families with CPVT. They included a nonsense variant c.97C>T (p.R33*) and a missense variant c.748C>T (p.R250C) in Family 1 with three CPVT patients; two heterozygous frameshift variants, c.1074_1075delinsC (p.G359Afs*12) and c.1175_1178delACAG (p.D392Vfs*84), in Family 2 with one CPVT patient; one pathogenic homozygous variant c.98G>A (p.R33Q) of CASQ2 in the CPVT patient of Family 3; and two heterozygous splicing variants, (c.532+1G>A) and (c.838+1G>A), in Family 4 with one CPVT patient. CONCLUSION: To our knowledge, this is the first systematic study of Chinese children with CASQ2 variants. Our work further expands the genetic spectrum of CASQ2-associated CPVT.

2.
Bioorg Chem ; 92: 103226, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31491566

RESUMO

Six new compounds, including a new compound with an unusual 2, 4, 6-cycloheptatrien ketone skeleton (1), two new diphenylpropanoid ethers (2, 3), a new protostane-type triterpenoid (4), two new norsesquiterpene (5a, 5b), and two new natural products (6, 7), together with eleven known compounds (8-18) were isolated from the aqueous extract of Alismatis Rhizoma (AR). Their structures were elucidated by a combination of 1D and 2D NMR (1H and 13C NMR, COSY, HSQC, HMBC, and NOESY), HRESIMS spectroscopic data, experimental and calculated electronic circular dichroism (ECD) spectra. Some of the compounds were evaluated for their inhibitory effects on nitric oxide (NO) production in LPS-induced RAW 264.7 cells. Two protostane-type triterpenoids, compounds 4 and 17, exhibited potent inhibitory activities with the IC50 values of 39.3 and 63.9 µM compared with indomethacin. In the meanwhile, their anti-inflammatory effects were also confirmed by acute inflammation model induced by CuSO4 in zebrafish.

3.
J Emerg Med ; 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31514988

RESUMO

BACKGROUND: Acute pain is the most common complaint in Emergency Department (ED) admissions, and options for analgesia are limited. Nitrous oxide/oxygen possesses many properties showing it may be an ideal analgesic in the ED. OBJECTIVES: The aim of this study is to evaluate the safety and analgesic effect of the fixed nitrous oxide/oxygen mixture for trauma patients in the ED. METHODS: We enrolled 60 patients in this double-blind, randomized study. The treatment group received conventional pain treatment plus a mixture of 65% nitrous oxide/oxygen. The control group received the conventional pain treatment plus oxygen. Primary outcome was the reduction in pain intensity at 5 and 15 min after the start of intervention. Secondary outcomes include adverse events, physiological parameters, and satisfaction from both patients and health care professionals. RESULTS: Initial pain scores for the nitrous oxide/oxygen group (6.0 [5.0-8.0]) and the oxygen group (6.75 [5.0-9.0]) were comparable (p = 0.57). The mean numerical rating scale scores at 5 min were 3.4 ± 1.8 and 7.0 ± 1.8 for nitrous oxide/oxygen and oxygen, respectively (p < 0.01). The mean pain intensity at 15 min in the treatment group was 3.0 ± 1.9, compared with 6.3 ± 2.2 in the control group (p < 0.01). Both patients' (8.0 [7.0-9.0] vs. 4.0 [2.0-6.0], p < 0.01) and physicians' (8.5 [8.0-9.0] vs. 4.0 [3.0-6.0], p < 0.01) satisfaction scores in the treatment group were significantly higher than the oxygen group. No serious adverse events were observed. CONCLUSIONS: This study gives supporting evidence for the safety and effectiveness of using self-administered nitrous oxide/oxygen mixture in the ED for moderate-to-severe traumatic pain.

4.
J Org Chem ; 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31499002

RESUMO

Two-fold unsymmetrical C-Si bond bifunctionalization of 2,6-di(trimethylsilyl) benzyl alcohols has been achieved in one pot via sequential [1,4]-Csp2 to O-silyl migration. The hydroxyl group functions as an "on-off-on" switch to control two successive silyl migrations, and 4,7-dimethyl-o-phenanthroline ligand favors cleavage of the endo-cyclic C-Si bond. Diverse Csp3/Csp3 or Csp2/Csp3 electrophiles can be installed at the 2- and 6-positions. This approach was used to chemoselectively functionalize the three C-Si bonds of 2,4,6-tri(trimethylsilyl) benzyl alcohol, transforming it into isochroman derivatives. The approach even works as a five-component reaction to construct complex symmetric structures.

5.
J Pain ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31494272

RESUMO

Orofacial pain is characterized by its easy spread to adjacent areas, thus presenting with primary hyperalgesia (hypersensitivity at the site of injury) and secondary hyperalgesia (extra-territorial hypersensitivity outside the injured zone). However, the mechanisms behind the secondary hyperalgesia are poorly understood. In the present study, we used a mouse model of partial transection of the infraorbital nerve (pT-ION) to study whether calcium channel subunit α2δ1 (Cavα2δ1) and its downstream signaling contributes to the development of secondary hyperalgesia in the orofacial area. pT-ION caused primary (V2 skin) and secondary (V3 skin) hyperalgesia, which was reversed by the Cavα2δ1 antagonist gabapentin and by the expression of Cavα2δ1-targeting interfering RNA in trigeminal ganglion (TG)-V3 neurons. pT-ION induced increased expression of PKC and TRPA1, which was reversed by Cavα2δ1-targeting interfering RNA, and PKC inhibition reversed the upregulation of TRPA1 and gap junction (GJ) proteins induced by pT-ION. Cavα2δ1 overexpression in TG-V2 neurons induced the upregulation of PKC, TRPA1, and the GJ proteins in the TG and trigeminal subnucleus caudalis and induced hypersensitivity in the V3 skin area, which was reversed by TRPA1, GJ, or PKC blockade. Thus, we conclude that Cavα2δ1 contributes to the development of secondary hyperalgesia through its downstream PKC-TRPA1/GJ signaling pathways. Perspective: This study demonstrates that the activation of Cavα2δ1 and the downstream PKC-TRPA1/GJ signaling pathway contributes greatly to trigeminal nerve injury-induced secondary mechanical and cold hyperalgesia. This suggests that inhibitors of Cavα2δ1, TRPA1, or GJs might be effective treatments for nerve injury-induced spreading of orofacial pain.

6.
Int J Biol Macromol ; 139: 342-351, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31377292

RESUMO

Oligosaccharides from green algae Ulva lactuca (ULO) and Enteromorpha prolifera (EPO) were used for investigation of anti-ageing effects and the underlying mechanism in SAMP8 mice. The structural properties of ULO and EPO were analyzed by fourier-transform infrared spectroscopy, gas chromatography-mass spectrometry, and agarose gel electrophoresis. These oligosaccharides enhanced the glutathione, superoxide dismutase, catalase, and telomerase levels and total antioxidant capicity, and decreased the levels of malondialdehyde and advanced glycation end products. After ULO and EPO treatment, the levels of inflammatory factors, including IFN-γ, TNF-α, and IL-6, decreased; the BDNF and ChAT levels increased; and hippocampal neurons were protected. Downregulation of the p53 and FOXO1 genes and upregulation of the Sirt1 gene indicated that ULO and EPO have potential therapeutic effects in the prevention of ageing in SAMP8 mice. By 16S rRNA gene high-throughput sequencing, the abundance of Desulfovibrio was discovered to be markedly different in mice treated with ULO and EPO. The abundances of Verrucomicrobiaceae, Odoribacteraceae, Mogibacteriaceae, Planococcaceae, and Coriobacteriaceae were positively correlated with age-related indicators. These results demonstrated that oligosaccharides from U. lactuca and E. prolifera are ideal candidate compounds that can be used in functional foods and pharmaceuticals to prevent ageing.

7.
J Microbiol Biotechnol ; 29(8): 1230-1239, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31370111

RESUMO

Scutellaria baicalensis Georgi has been widely used in China for treatment of various diseases. This study investigated the effect of Scutellaria baicalensis Georgi extracts (SBE) against Coxsackievirus B3 (CVB3)-induced myocarditis in vitro and in vivo. In vitro, Hela cells and primary myocardial cells were infected with CVB3 and treated with SBE (50-800 µg/ml) and ribavirin (200 µM) for 48 h and then determined by CCK8 assay. Real-time PCR and western blotting assays were performed. In vivo, a myocarditis model was induced in male BALB/c mice by injecting CVB3 suspension intraperitoneally for three times, followed by treatment with SBE (400 and 200 mg/kg) and ribavirin (100 mg/kg) for 28 days. SBE ameliorated the cytotoxicity of CVB3 in Hela cells, especially at 400 µg/ml (39.93% vs 65.67%, p < 0.05) without influencing cell growth and also significantly reduced CVB3 replication in primary myocardial cells. The levels of AKT, ERK, and p38 were increased after CVB3 infection. SBE could downregulate the expressions of AKT and p38. In vivo, the mortality rate from CVB3 reached to 66.67%, while 10.00% and 23.33% of this came after 400 and 200 mg/kg SBE treatment, respectively (p < 0.05). The CVB3 replication was obviously reduced after SBE administration from day 5. Similarly, the levels of AKT, ERK, and p38 mRNAs and proteins were increased, and SBE suppressed the expression of AKT and p38. Our study indicates that SBE is a promising potent antiviral agent against CVB3-induced myocarditis by inhibition of virus replication via depressing AKT and p38 expressions.

8.
Cell Death Dis ; 10(9): 624, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31423010

RESUMO

Recent findings demonstrate that aberrant downregulation of the iron-exporter protein, ferroportin (FPN1), is associated with poor prognosis and osteoclast differentiation in multiple myeloma (MM). Here, we show that FPN1 was downregulated in MM and that clustered regularly interspaced short palindromic repeat (CRISPR)-mediated FPN1 knockout promoted MM cell growth and survival. Using a microRNA target-scan algorithm, we identified miR-17-5p as an FPN1 regulator that promoted cell proliferation and cell cycle progression, and inhibited apoptosis-both in vitro and in vivo. miR-17-5p inhibited retarded tumor growth in a MM xenograft model. Moreover, restoring FPN1 expression at least partially abrogated the biological effects of miR-17-5p in MM cells. The cellular iron concentration regulated the expression of the iron-regulatory protein (IRP) via the 5'-untranslated region of IRP messenger RNA and modulated the post-transcriptional stability of FPN1. Bioinformatics analysis with subsequent chromatin immunoprecipitation-polymerase chain reaction and luciferase activity experiments revealed that the transcription factor Nrf2 drove FPN1 transcription through promoter binding and suppressed miR-17-5p (which also increased FPN1 expression). Nrf2-mediated FPN1 downregulation promoted intracellular iron accumulation and reactive oxygen species. Our study links FPN1 transcriptional and post-transcriptional regulation with MM cell growth and survival, and validates the prognostic value of FPN1 and its utility as a novel therapeutic target in MM.

9.
J Am Chem Soc ; 141(34): 13635-13642, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31362505

RESUMO

We use canonical variational theory (CVT) with small-curvature tunneling (SCT) contributions to investigate quantum effects on the H2 diffusion process in the pure-silica zeolite RHO. At low temperature we find an inverse kinetic isotopic sieving effect in that the heavier isotopic species diffuses faster than the lighter one. Three quantum effects contribute to this kinetic isotope effect (KIE). The first one is quantum mechanical tunneling; this-on its own-would lead to a normal kinetic isotopic sieving effect, in which lighter diprotium diffuses faster than dideuterium. The second factor, which we find to dominate in the present case, is zero-point energy (ZPE). Deuterium has a lower ZPE, which leads to a smaller effective barrier for tunneling because the transition state has a larger ZPE than the precursor stable state; this results in an inverse KIE. The third factor, the thermal vibrational energy (computed from the quantized vibrational partition function), also favors a normal KIE, but it is outweighed by the ZPE effect. The vibrations of the zeolite host framework are found to play an important role at low temperatures, and our calculations consider up to 7296 degrees of freedom at the equilibrium structure and the saddle point and up to 221 degrees of freedom along the reaction path. The importance of quantum considerations on the dynamics is elucidated by comparison to a purely classical treatment.

10.
J Cell Physiol ; 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31389030

RESUMO

miR-222 participates in many cardiovascular diseases, but its effect on cardiac remodeling induced by diabetes is unclear. This study evaluated the functional role of miR-222 in cardiac fibrosis in diabetic mice. Streptozotocin (STZ) was used to establish a type 1 diabetic mouse model. After 10 weeks of STZ injection, mice were intravenously injected with Ad-miR-222 to induce the overexpression of miR-222. miR-222 overexpression reduced cardiac fibrosis and improved cardiac function in diabetic mice. Mechanistically, miR-222 inhibited the endothelium to mesenchymal transition (EndMT) in diabetic mouse hearts. Mouse heart fibroblasts and endothelial cells were isolated and cultured with high glucose (HG). An miR-222 mimic did not affect HG-induced fibroblast activation and function but did suppress the HG-induced EndMT process. The antagonism of miR-222 by antagomir inhibited HG-induced EndMT. miR-222 regulated the promoter region of ß-catenin, thus negatively regulating the Wnt/ß-catenin pathway, which was confirmed by ß-catenin siRNA. Taken together, our results indicated that miR-222 inhibited cardiac fibrosis in diabetic mice via negatively regulating Wnt/ß-catenin-mediated EndMT.

11.
Theranostics ; 9(18): 5122-5133, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31410205

RESUMO

Controlling bilirubin to a low level is necessary in physiology because of its severe neurotoxicity. Therefore, it is of great interest to understand the regulatory mechanisms for bilirubin homeostasis. In this study, we uncover a critical role for circadian clock in regulation of bilirubin detoxification and homeostasis. Methods: The mRNA and protein levels of Bmal1 (a core clock gene), metabolic enzymes and transporters were measured by qPCR and Western blotting, respectively. Luciferase reporter, mobility shift and chromatin immunoprecipitation were used to investigate transcriptional gene regulation. Experimental hyperbilirubinemia was induced by injection of bilirubin or phenylhydrazine. Unconjugated bilirubin (UCB) and conjugated bilirubin were assessed by ELISA. Results: We first demonstrated diurnal variations in plasma UCB levels and in main bilirubin-detoxifying genes Ugt1a1 and Mrp2. Of note, the circadian UCB levels were antiphase to the circadian expressions of Ugt1a1 and Mrp2. Bmal1 ablation abrogated the circadian rhythms of UCB and bilirubin-induced hepatotoxicity in mice. Bmal1 ablation also decreased mRNA and protein expressions of both Ugt1a1 and Mrp2 in mouse livers, and blunted their circadian rhythms. A combination of luciferase reporter, mobility shift, and chromatin immunoprecipitation assays revealed that Bmal1 trans-activated Ugt1a1 and Mrp2 through specific binding to the E-boxes in the promoter region. Further, Bmal1 ablation caused a loss of circadian time-dependency in bilirubin clearance and sensitized mice to chemical induced-hyperbilirubinemia. Moreover, bilirubin stimulated Bmal1 expression through antagonism of Rev-erbα, constituting a feedback mechanism in bilirubin detoxification. Conclusion: These data supported a dual role for circadian clock in regulation of bilirubin detoxification, generating circadian variations in bilirubin level via direct transactivation of detoxifying genes Ugt1a1 and Mrp2, and defending the body against hyperbilirubinemia via Rev-erbα antagonism. Thereby, our study provided a potential mechanism for management of bilirubin related diseases.

12.
Acta Ophthalmol ; 2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31421015

RESUMO

PURPOSE: To study the characteristics of choroid thickness (CT) of the optic disc and macula in children with type 1 diabetes mellitus (T1DM) without visual impairment and diabetic retinopathy (DR) and analyse associated factors. METHODS: A square area of 6 × 6 mm around the centre of the optic disc and macula was scanned. The indices analysed mainly included CT at the macular centre (1 mm), and temporal, superior, nasal or inferior aspect of the inner ring (1-3 mm) and outer ring of (3-6 mm) optic disc and macula. Independent risk factors were analysed using multifactor linear regression. RESULTS: A total of 44 children with T1DM and 48 healthy subjects were enrolled. The diabetic group showed significant increase in the inferior inner ring of parapapillary CT (100.99 ± 30.42 µm versus 89.41 ± 34.00 µm, p = 0.04) and nasal outer ring of parapapillary CT (157.02 ± 47.35 µm versus 131.15 ± 35.17 µm, p = 0.01) as compared to those values in the healthy controls. Spherical equivalent refraction and family history of hypertension are independent factors of both peripappillary choroid thickness (PPCT) and macular choroid thickness (PMCT). Spherical equivalent refraction (p = 0.01) and serum cholesterol (p = 0.03) were independent factors of the inferior inner ring of parapapillary CT, whereas family history of hypertension was an independent factor of the nasal outer ring of parapapillary CT (p = 0.001). CONCLUSION: In children with diabetes without DR or visual impairment, the CT increase in nasal outer ring of parapapillary (PPNO) and the inferior inner ring of parapapillary (PPII) may be the characteristic pre-DR alteration at the early stage of DM. For children with higher serum cholesterol and family history of hypertension, the change of the nasal outer ring of parapapillary CT and the inferior inner ring of parapapillary CT may be more advanced.

13.
Cell Microbiol ; : e13092, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31376233

RESUMO

Previous studies identified that the budding yeast Saccharomyces cerevisiae have two sphingolipid synthesis-related proteins, Orm1p and Orm2p, that negatively regulate the activities of SPT, which is a key rate-limiting enzyme in sphingolipid synthesis. However, little is known about whether sphingolipids in the cell membrane, which are closely related to ergosterols, could affect the efficacy of azole drugs, which target to the ergosterol biosynthesis. In this study, through genome-wide homologue search analysis, we found that the Aspergillus fumigatus genome only contains one Orm homologue, referred to as OrmA for which the protein expression could be induced by azole antifungals in a dose-dependent manner. Deletion of ormA caused hypersensitivity to azoles, and adding the sphingolipid synthesis inhibitor myriocin rescued the azole susceptibility induced by lack of ormA. In contrast, overexpression of OrmA resulted in azole resistance, indicating that OrmA is a positive azole-response regulator. Further mechanism analysis verified that OrmA is related to drug susceptibility by affecting endoplasmic reticulum stress responses in an unfolded protein response pathway-HacA-dependent manner. Lack of ormA led to an abnormal profile of sphingolipid ceramide components accompanied by hypersensitivity to low temperatures. Furthermore, deletion of OrmA significantly reduced virulence in an immunosuppressed mouse model. The findings in this study collectively suggest that the sphingolipid metabolism pathway in A. fumigatus plays a critical role in azole susceptibility and fungal virulence.

14.
Endocr Connect ; 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31340196

RESUMO

OBJECTIVE: To investigate the validity of discharge ICD-10 codes in detecting the etiology of endogenous Cushing's syndrome (CS) in hospitalized patients. METHODS: We evaluated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CS etiology-related ICD-10 codes or code combinations by comparing hospital discharge administrative data (DAD) with established diagnoses from medical records. RESULTS: Coding for patients with adrenocortical adenoma (ACA) and those with bilateral macronodular adrenal hyperplasia (BMAH) demonstrated disappointingly low sensitivity at 78.8% (95% CI: 70.1% - 85.6%) and 83.9% (95% CI: 65.5% - 93.9%), respectively. BMAH had the lowest PPV of 74.3% (95% CI: 56.4% - 86.9%). In confirmed ACA patients, the sensitivity for ACA code combinations was higher in patients initially admitted to the Department of Endocrinology before surgery than that in patients directly admitted to the Department of Urology (90.0% vs 73.1%, P = 0.033). The same phenomenon was observed in the PPV for the BMAH code (100.0% vs 60.9%, P = 0.012). Misinterpreted or confusing situations caused by coders (68.1%) and by the omission or denormalized documentation of symptomatic diagnosis by clinicians (26.1%) accounted for the main source of coding errors. CONCLUSIONS: Hospital DAD is an effective data source for evaluating the etiology of CS but not ACA and BMAH. Improving surgeons' documentation, especially in the delineation of symptomatic and locative diagnoses in discharge abstracts; department- or disease-specific training for coders; and more multidisciplinary collaboration are ways to enhance the applicability of administrative data for CS etiologies.

15.
Oxid Med Cell Longev ; 2019: 3206542, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354905

RESUMO

Previous studies demonstrated that Bailcalin (BAI) prevented cardiac injuries under different disease models. Whether BAI protected against type 2 diabetes mellitus- (T2DM-) associated cardiomyopathy was investigated in this study. T2DM was established by the combination of streptozotocin injection and high-fat diet in mice. BAI was administered daily for 6 months. After evaluating cardiac functions, mice hearts were removed and processed for morphological, biochemical, and molecular mechanism analyses. Neonatal rat cardiomyocytes (NRCM) were isolated and treated with high glucose and palmitate (HG/Pal) for in vitro investigation. BAI significantly ameliorated T2DM-induced cardiomyocyte hypertrophy, interstitial fibrosis, and lipid accumulation accompanied by markedly improved cardiac functions in diabetic mice. Mechanically, BAI restored decreased phosphorylation of AMPK and enhanced expression and nuclei translocation of Nrf2. In in vitro experiments, BAI also prevented NRCM from HG/Pal-induced apoptosis and oxidative stress injuries by increasing p-AMPK and Nrf2 accumulation. The means by which BAI restored p-AMPK seemed to be related to the antioxidative effects of Nrf2 after silencing AMPK or Nrf2 in NRCM. Furthermore, BAI regulated Nrf2 by inhibiting Nrf2 ubiquitination and consequent degradation mediated by Keap1. This study showed that BAI alleviated diabetes-associated cardiac dysfunction and cardiomyocyte injuries in vivo and in vitro via Keap1/Nrf2/AMPK-mediated antioxidation and lipid-lowering effects. BAI might be a potential adjuvant drug for diabetes cardiomyopathy treatment.

16.
Toxicol Lett ; 313: 188-195, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31284022

RESUMO

Brucine is one of the main bioactive and toxic constituents of the herb drug Semen Strychni. Here we aimed to determine dosing time-dependent hepatotoxicity of brucine, and to investigate the role of metabolism in generation of brucine chronotoxicity. Brucine was administered to wild-type or Npas2-/- (a clock disrupted model) mice at different circadian time points for toxicity and pharmacokinetic characterization. The hepatotoxicity was evaluated by plasma alanine aminotransferase and aspartate aminotransferase measurements and histopathological analysis. The role of Cyp3a11 in brucine metabolism was determined by chemical inhibition assays and Cyp3a11-overexpressing HEK293 cells. Hepatic circadian Cyp3a11 mRNA and protein levels were determined by qPCR and Western blotting, respectively. The toxicity of brucine was more severe in the light phase [Zeitgeber time (ZT) 2 and ZT8] than in the dark phase (ZT14 and ZT20). Chemical inhibition and substrate metabolism assays suggested Cyp3a11 as a significant contributor to brucine metabolism. The Cyp3a11 mRNA, protein and activity in the livers of wild-type mice displayed significant circadian fluctuations. Npas2 ablation markedly down-regulated Cyp3a11 mRNA, protein and activity, and abrogated their circadian rhythms. The circadian time differences in brucine pharmacokinetics and liver distribution were lost in Npas2-/- mice, so were the time differences in brucine hepatotoxicity. In conclusion, chronotoxicity of brucine was determined by circadian variations in Cyp3a11 metabolism. The findings have implications in improving brucine (and possibly Semen Strychni) efficacy via dosing time optimization.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Ritmo Circadiano , Citocromo P-450 CYP3A/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Proteínas de Membrana/metabolismo , Fotoperíodo , Estricnina/análogos & derivados , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Ritmo Circadiano/genética , Cronoterapia Farmacológica , Células HEK293 , Humanos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Estricnina/administração & dosagem , Estricnina/metabolismo , Estricnina/farmacocinética , Estricnina/toxicidade
17.
Mol Genet Genomic Med ; 7(9): e880, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31317677

RESUMO

BACKGROUND: von Hippel-Lindau (VHL) disease has a hereditary, autosomal dominant pattern, and multiple tumors can develop in multiple organs of a single patient. However, the exact mechanisms of tumorigenesis are unclear, and further studies are needed to clarify whether the same signaling pathways are involved in different VHL-related tumors. METHODS: Whole-exome sequencing (WES) of tumor and paired peripheral blood samples were performed for a VHL disease pedigree. A bioinformatics analysis was conducted to identify candidate somatic single-nucleotide variants (SNVs) present in all tumor tissues. Sanger sequencing was then used to validate the SNVs identified using WES. Immunohistochemistry was performed to analyze components of the mTOR pathway, which was abnormally activated in tumor tissues. RESULTS: Two hemangioblastomas and two renal cell carcinomas were sequenced. The bioinformatics analysis revealed a VHL somatic variant in all tumors; no other SNV was detected. Immunohistochemistry showed the abnormal expression of the phospho-S6 ribosomal protein in the hemangioblastomas, but not in the renal clear cell carcinomas. CONCLUSION: Except for a SNV in the VHL gene, no other somatic SNVs were detected using WES. The phospho-S6 ribosomal protein in the mTOR pathway is a potential target in VHL-related cerebellum hemangioblastomas.

18.
Curr Eye Res ; : 1-7, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31294638

RESUMO

Purpose: To compare the prevalence of dry eye disease between children with and without diabetes, and analyze the factors associated with dry eye disease in children with diabetes. Materials and methods: 38 children with diabetes were selected as cases, and 40 children without diabetes constituted the control group. The prevalence of dry eye disease in both groups was statistically analyzed. Related factors of dry eye disease were analyzed in children with diabetes. Results: The prevalence of dry eye disease in the case group was significantly higher than that in the control group (P < .01), with the attributable proportion among the exposed (0.827) and the population attributable fraction (0.700). Univariate analysis showed that the diabetes duration, best-corrected visual acuity, corneal sensation, and levels of glycosylated hemoglobin were associated with dry eye disease in children with diabetes. Logistic regression analysis revealed that only diabetes duration and corneal sensation were independent factors associated with dry eye disease. The diabetes duration was significantly higher and the level of corneal sensation was significantly lower in subjects with dry eye disease than in those without dry eye disease. Conclusions: Early screening and close follow-up of dry eye disease in children with diabetes should be strictly implemented, especially in children with a long duration of diabetes and those with peripheral neuropathy.

19.
Trials ; 20(1): 399, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31272502

RESUMO

BACKGROUND: The morbidity of knee arthritis is increasing among aged people and total knee arthroplasty has been its mainstream treatment to date. Postoperative rehabilitation is an important part of the procedure. However, the intense pain during the functional exercise involved has always been a challenge for both patients and health care professionals. The aim of this study is to test the analgesic effect of a mixture of nitrous oxide/oxygeb (1:1) inhalation for patients who are doing functional exercise 1 month after total knee arthroplasty. METHODS/DESIGN: This double-blind, randomized, placebo-controlled study will be implemented in the Rehabilitation Department in the General Hospital of Ningxia Medical University. Patients aged between 50 and 75 years who underwent a primary unilateral total knee arthroplasty are eligible for inclusion. The key exclusion criteria include: epilepsy, pulmonary embolism, intestinal obstruction, aerothorax. The treatment group (A) will receive a pre-prepared nitrous oxide/oxygen mixture plus conventional treatment (no analgesics), and the control group (B) will receive oxygen plus conventional treatment (no analgesics). Patients, physicians, therapists, and data collectors are all blind to the experiment. Assessments will be taken immediately after functional exercise begins (T0), 5 min (T1) after functional exercise begins, and 5 min after functional exercise has finished (T2). Patients will be randomly allocated between a treatment group (A) and a control group (B) in a ratio of 1:1. Primary outcome, including pain severity in the procedure, will be taken for each group. Secondary outcomes include blood pressure, heart rate, oxygen saturation, side effects, knee joint range of motion, Knee Society Score (KSS), rescue analgesia need, and satisfaction from both therapists and patients. DISCUSSION: This study will focus on exploring a fast and efficient analgesic for patients who are doing functional exercise after total knee arthroplasty. Our previous studies suggested that the prefixed nitrous oxide/oxygen mixture was an efficacious analgesic for the management of burn-dressing pain and breakthrough cancer pain. The results of this study should provide a more in-depth insight into the effects of this analgesic method. If this treatment proves successful, it could be implemented widely for patients doing functional exercise in the rehabilitation department. TRIAL REGISTRATION: ChiCTR-INR-17012891 . Registered on 6 October 2017.

20.
Food Chem Toxicol ; 131: 110562, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31181236

RESUMO

Brown seaweed Sargassum confusum (C. Agardh) has been used in traditional Chinese medicine to treat a variety of diseases. The aim of the present study was to evaluate the anti-diabetic effect of oligosaccharides from brown seaweed S. confusum (SCO). The anti-diabetic effect of SCO was evaluated in vivo using high-fat/high-sucrose fed hamsters. Molecular mechanisms of modulating gene expression of specific members of insulin signaling pathways were determined. The components of the intestinal microflora in diabetic animals were also analyzed by high-throughput 16S rRNA gene sequencing. And it was found that SCO had a sequence of sulfated anhydrogalactose and methyl sulfated galactoside units. Fasting blood glucose levels were significantly decreased after SCO administration. Histology showed that SCO could protect the cellular architecture of the liver. SCO could also significantly increase the relative abundance of Lactobacillus and Clostridium XIVa and decrease that of Allobaculum, Bacteroides and Clostridium IV. The active role of SCO in anti-diabetic effect was revealed by its regulation of insulin receptor substrate 1/phosphatidylinositol 3-kinase and c-Jun N-terminal kinase pathways. These results suggested that SCO might be used as a functional material to regulate gut microbiota in obese and diabetic individuals.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Oligossacarídeos/uso terapêutico , Sargassum/química , Animais , Bactérias/genética , Sequência de Bases , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Dieta da Carga de Carboidratos , Dieta Hiperlipídica , Hipoglicemiantes/isolamento & purificação , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Mesocricetus , Oligossacarídeos/isolamento & purificação , Substâncias Protetoras/isolamento & purificação , Substâncias Protetoras/uso terapêutico , RNA Ribossômico 16S/genética , Alga Marinha/química
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