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1.
Toxicol Lett ; 331: 242-253, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32579994

RESUMO

Dysregulated bile acid (BA) homeostasis is an extremely significant pathological phenomenon of intrahepatic cholestasis, and the accumulated BA could further trigger hepatocyte injury. Here, we showed that the expression of sphingosine-1-phosphate receptor 1 (S1PR1) was down-regulated by α-naphthylisothiocyanate (ANIT) in vivo and in vitro. The up-regulated S1PR1 induced by SEW2871 (a specific agonist of S1PR1) could improve ANIT-induced deficiency of hepatocyte tight junctions (TJs), cholestatic liver injury and the disrupted BA homeostasis in mice. BA metabolic profiles showed that SEW2871 not only reversed the disruption of plasma BA homeostasis, but also alleviated BA accumulation in the liver of ANIT-treated mice. Further quantitative analysis of 19 BAs showed that ANIT increased almost all BAs in mice plasma and liver, all of which were restored by SEW2871. Our data demonstrated that the top performing BAs were taurine conjugated bile acids (T-), especially taurocholic acid (TCA). Molecular mechanism studies indicated that BA transporters, synthetase, and BAs nuclear receptors (NRs) might be the important factors that maintained BA homeostasis by SEW2871 in ANIT-induced cholestasis. In conclusion, these results demonstrated that S1PR1 selective agonists might be the novel and potential effective agents for the treatment of intrahepatic cholestasis by recovering dysregulated BA homeostasis.


Assuntos
1-Naftilisotiocianato/toxicidade , Ácidos e Sais Biliares/sangue , Colestase/prevenção & controle , Fígado/efeitos dos fármacos , Oxidiazóis/farmacologia , Receptores de Esfingosina-1-Fosfato/agonistas , Tiofenos/farmacologia , Animais , Ácidos e Sais Biliares/metabolismo , Colestase/induzido quimicamente , Colestase/metabolismo , Regulação para Baixo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Homeostase , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Receptores de Esfingosina-1-Fosfato/genética , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/patologia
2.
J Environ Manage ; 270: 110825, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32501236

RESUMO

Nowadays, the production of green transportation fuels is essential for a healthy life and environment. Effective and complete removal of organosulfur recalcitrant compounds from fuel oils is crucial to meet the stringent requirements of sulfur standards. However, the industry's solution (Hydrodesulfurization, HDS) is not effective in the removal of complex sulfur heterocyclic hydrocarbons. Thus, the development of more efficient and ecofriendly/sustainable desulfurization methods is critical, as either an alternative or a complement to HDS, foreseeing the production of ultra-low sulfur fuels (ULSF). Among the desulfurization techniques available, microbial desulfurization of organosulfur hydrocarbons (biodesulfurization, BDS) is attracting great attention. BDS is carried out at mild operation conditions, making it energetically cheaper and more ecofriendly, since it does not require hydrogen and produces far less greenhouse gases emission than HDS. In this context, the behavior of Gordonia alkanivorans strain 1B, a desulfurizing bacterium and hyper-pigment producer, was evaluated in the presence of four sulfur sources common in fuel oils: dibenzothiophene (DBT); 4-mDBT; 4,6-dmDBT and 4,6-deDBT (single/mixed), in terms of both desulfurization rate and overall carotenoid production. Simultaneously, the influence of the carbon source used (fructose vs glucose) on the overall effectiveness of the coupled bioprocesses was also assessed. The results obtained highlight the potential of strain 1B to desulfurize all the tested recalcitrant compounds and simultaneously produce carotenoids. However, the highest BDS values were observed for 4,6-deDBT (5.75 µmol/g (DCW)/h) and for the mix of DBTs (5.20 µmol/g (DCW)/h), when fructose was used as carbon source. Indeed, when the mixture of DBTs ("model oil surrogate") was desulfurized by cells growing in fructose both desulfurization rate and total pigments amount were higher than those observed for glucose growing cells. Moreover, under these conditions, the strain 1B was able to produce high added-value carotenoids, namely astaxanthin, lutein and canthaxanthin. Hence, these results are promising when aiming to achieve a scale-up scenario. In fact, the inclusion of the production of high added-value products within a BDS process targeting ULSF may be a sustainable way to turn its scale-up economically viable.


Assuntos
Gordonia (Bactéria) , Tiofenos , Actinobacteria , Biodegradação Ambiental , Carotenoides
3.
Am J Physiol Heart Circ Physiol ; 318(6): H1487-H1508, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32357113

RESUMO

Cell-autonomous circadian clocks have emerged as temporal orchestrators of numerous biological processes. For example, the cardiomyocyte circadian clock modulates transcription, translation, posttranslational modifications, ion homeostasis, signaling cascades, metabolism, and contractility of the heart over the course of the day. Circadian clocks are composed of more than 10 interconnected transcriptional modulators, all of which have the potential to influence the cardiac transcriptome (and ultimately cardiac processes). These transcriptional modulators include BMAL1 and REV-ERBα/ß; BMAL1 induces REV-ERBα/ß, which in turn feeds back to inhibit BMAL1. Previous studies indicate that cardiomyocyte-specific BMAL1-knockout (CBK) mice exhibit a dysfunctional circadian clock (including decreased REV-ERBα/ß expression) in the heart associated with abnormalities in cardiac mitochondrial function, metabolism, signaling, and contractile function. Here, we hypothesized that decreased REV-ERBα/ß activity is responsible for distinct phenotypical alterations observed in CBK hearts. To test this hypothesis, CBK (and littermate control) mice were administered with the selective REV-ERBα/ß agonist SR-9009 (100 mg·kg-1·day-1 for 8 days). SR-9009 administration was sufficient to normalize cardiac glycogen synthesis rates, cardiomyocyte size, interstitial fibrosis, and contractility in CBK hearts (without influencing mitochondrial complex activities, nor normalizing substrate oxidation and Akt/mTOR/GSK3ß signaling). Collectively, these observations highlight a role for REV-ERBα/ß as a mediator of a subset of circadian clock-controlled processes in the heart.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Miocárdio/metabolismo , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/agonistas , Fatores de Transcrição ARNTL/metabolismo , Animais , Ritmo Circadiano/efeitos dos fármacos , Expressão Gênica , Regulação da Expressão Gênica , Coração/efeitos dos fármacos , Camundongos , Camundongos Knockout , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Pirrolidinas/farmacologia , Tiofenos/farmacologia
4.
Environ Sci Pollut Res Int ; 27(24): 30600-30614, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32472506

RESUMO

A uniformly distribution of 3 wt.% Mo (with tetrahedral coordination) on a commercial HY zeolite having both micro- and meso-pores, provided a new active catalyst which resulted 100% removal of DBT in this work. Respectively, H2O2 and acetonitrile were used as the oxidant and extraction solvent for oxidative desulfurization (ODS) at a mild condition. The structure of three-dimensional meso-pores, despite major micro-pores, was proved to be intriguing for the use of acidic HY zeolite as a support material in this process. The catalyst samples were characterized by different analyses of XRPD, XRF, FTIR, SEM, EDX, TEM, N2 adsorption desorption, BET, BJH, UV-vis, and NH3-TPD. High amounts of Mo were not in favor of the catalytic performance because of increasing non-framework polymolybdate formation, which led to decreasing meso-pore volume. Acid sites strength also decreased by increasing Mo content. The Mo active sites at a low loading of 3 wt.% reached the best performance for the complete removal of DBT (t = 90 min, T = 60 °C, catalyst/fuel = 8 g/L, O/S = 2, VSolvent/VOil = 1/2, DBT = 1000 ppm), mainly due to the presence of isolated Mo species in the framework of HY. The efficiency still reached to 90% after recycling the catalyst three times. The reusability of catalyst revealed the adsorption of the aqueous phase by this hydrophilic catalyst during the process being as a major deactivation factor. This was significantly diminished via a subsequent washing by acetonitrile.


Assuntos
Tiofenos , Zeolitas , Peróxido de Hidrogênio , Oxirredução
5.
Drugs Today (Barc) ; 56(4): 269-286, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32309822

RESUMO

Oliceridine is a next-generation investigational intravenous opioid that is a G protein-selective agonist at the µ-opioid receptor. The G protein selectivity of this compound results in potent analgesia with substantially reduced recruitment of ß-arrestin, a signaling pathway associated with opioid-related adverse events. In randomized, placebo- and active-controlled clinical studies, use of oliceridine for the management of moderate to severe acute pain provided potent analgesic effect superior to that observed with placebo, with lower incidence of adverse events, including respiratory events and gastrointestinal events of nausea and vomiting, compared with morphine. Here, we provide a review of the preclinical and clinical data of intravenous oliceridine, a selective agonist, which has the potential to offer a wider therapeutic window than conventional opioids.


Assuntos
Dor Aguda/tratamento farmacológico , Analgésicos Opioides/uso terapêutico , Compostos de Espiro/uso terapêutico , Tiofenos/uso terapêutico , Proteínas de Ligação ao GTP/agonistas , Humanos , Morfina , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores Opioides mu
6.
Am J Physiol Renal Physiol ; 318(5): F1258-F1270, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32249615

RESUMO

B lymphocyte hyperactivity plays a pathogenic role in systemic lupus erythematosus (SLE), and spliced X box-binding protein 1 (XBP1s) has been implicated in B cell maturation and differentiation. We hypothesized that blockade of the XBP1s pathway inhibits the B cell hyperactivity underlying SLE and lupus nephritis (LN) development. In the present study, we systematically evaluated the changes in B cell activation induced by the Xbp1 splicing inhibitor STF083010 in a pristane-induced lupus mouse model. The lupus mouse model was successfully established, as indicated by the presence of LN with markedly increased urine protein levels, renal deposition of Ig, and mesangial cell proliferation. In lupus mice, B cell hyperactivity was confirmed by increased CD40 and B cell-activating factor levels. B cell activation and plasma cell overproduction were determined by increases in CD40-positive and CD138-positive cells in the spleens of lupus mice by flow cytometry and further confirmed by CD45R and Ig light chain staining in the splenic tissues of lupus mice. mRNA and protein expression of XBP1s in B cells was assessed by real-time PCR, Western blot analysis, and immunofluorescence analysis and was increased in lupus mice. In addition, almost all changes were reversed by STF083010 treatment. However, the expression of XBP1s in the kidneys did not change when mice were exposed to pristane and STF083010. Taken together, these findings suggest that expression of XBP1s in B cells plays key roles in SLE and LN development. Blockade of the XBP1s pathway may be a potential strategy for SLE and LN treatment.


Assuntos
Linfócitos B/metabolismo , Rim/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Nefrite Lúpica/metabolismo , Ativação Linfocitária , Baço/metabolismo , Terpenos , Proteína 1 de Ligação a X-Box/metabolismo , Animais , Autoanticorpos/sangue , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Imunoglobulina G/sangue , Rim/efeitos dos fármacos , Rim/patologia , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/induzido quimicamente , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Transdução de Sinais , Baço/efeitos dos fármacos , Baço/patologia , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Proteína 1 de Ligação a X-Box/antagonistas & inibidores , Proteína 1 de Ligação a X-Box/genética
7.
Intern Med ; 59(5): 601-609, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115517

RESUMO

Objective To examine the add-on effects, compared to the existing antidiabetes treatment, of the sodium-glucose cotransporter 2 inhibitor ipragliflozin on glycemic control and the risk factors of cardiovascular disease (CVD) and chronic kidney disease (CKD) in patients with inadequately controlled type 2 diabetes. Methods This 12-week, randomized, open-label, active-controlled trial included 30 patients with type 2 diabetes who were randomized 1:1 to ipragliflozin and control groups (n=15 each). The ipragliflozin group received 50 mg of ipragliflozin once daily in addition to conventional therapy. The primary outcome was the change in hemoglobin A1c (HbA1c) from the baseline. Secondary outcomes were changes from the baseline in indices of glycemic control, uric acid (UA), renal function, and arterial stiffness. Results The patients' diminished estimated glomerular filtration rate (eGFR) was alleviated in the ipragliflozin group compared to the control group [difference between groups (Δ) =4.6 (95% confidence interval (CI): 1.5-7.7) mL/min/1.73 m2, p=0.006] prior to significant improvements in HbA1c and other parameters, including anthropometric indices and arterial stiffness. Furthermore, ipragliflozin add-on therapy resulted in a greater reduction in serum UA levels than control therapy [Δ=-52.3 (95% CI: -85.5-19.1) µmol/L, p=0.003]. The changes in the eGFR with ipragliflozin treatment were associated with ipragliflozin-mediated changes in the UA, even after adjusting for the age, sex, baseline HbA1c, baseline UA, and baseline eGFR (standardized regression coefficient=-0.535, p=0.010). Conclusion Ipragliflozin add-on therapy was associated with beneficial renal effects in parallel with reducing serum UA levels.


Assuntos
Diabetes Mellitus Tipo 2/prevenção & controle , Glucosídeos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Insuficiência Renal Crônica/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Tiofenos/administração & dosagem , Adulto , Idoso , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/fisiopatologia , Angiopatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/prevenção & controle , Esquema de Medicação , Quimioterapia Combinada , Feminino , Hemoglobina A Glicada/efeitos dos fármacos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Resultado do Tratamento , Ácido Úrico/metabolismo , Adulto Jovem
8.
Proc Natl Acad Sci U S A ; 117(13): 7150-7158, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32170014

RESUMO

Cholesterol biosynthesis is a high-cost process and, therefore, tightly regulated by both transcriptional and posttranslational negative feedback mechanisms in response to the level of cellular cholesterol. Squalene monooxygenase (SM, also known as squalene epoxidase or SQLE) is a rate-limiting enzyme in the cholesterol biosynthetic pathway and catalyzes epoxidation of squalene. The stability of SM is negatively regulated by cholesterol via its N-terminal regulatory domain (SM-N100). In this study, using a SM-luciferase fusion reporter cell line, we performed a chemical genetics screen that identified inhibitors of SM itself as up-regulators of SM. This effect was mediated through the SM-N100 region, competed with cholesterol-accelerated degradation, and required the E3 ubiquitin ligase MARCH6. However, up-regulation was not observed with statins, well-established cholesterol biosynthesis inhibitors, and this pointed to the presence of another mechanism other than reduced cholesterol synthesis. Further analyses revealed that squalene accumulation upon treatment with the SM inhibitor was responsible for the up-regulatory effect. Using photoaffinity labeling, we demonstrated that squalene directly bound to the N100 region, thereby reducing interaction with and ubiquitination by MARCH6. Our findings suggest that SM senses squalene via its N100 domain to increase its metabolic capacity, highlighting squalene as a feedforward factor for the cholesterol biosynthetic pathway.


Assuntos
Esqualeno Mono-Oxigenase/metabolismo , Esqualeno/metabolismo , Regulação Alostérica , Benzilaminas , Colesterol/biossíntese , Retículo Endoplasmático/enzimologia , Células HEK293 , Humanos , Proteínas de Membrana/metabolismo , Proteostase , Esqualeno Mono-Oxigenase/antagonistas & inibidores , Tiofenos , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
9.
Chem Biol Interact ; 320: 109028, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32119865

RESUMO

Reactive oxygen species (ROS) cause cell damage and death. To reverse these effects, cells produce substances such as reduced glutathione (GSH) that serve as substrates for antioxidant enzymes. One way to combat microbial resistance includes nullifying the effect of glutathione in microbial cells, causing them to die from oxidative stress. The compound 2-((5-nitrothiophen-2-yl)methylene)-N-(pyridin-3-yl) hydrazine carbothioamide (L10) is a new thiophene-thiosemicarbazone derivative with promising antifungal activity. The aim of this study was to evaluate its mechanism of action against Candida albicans using assays that evaluate its effects on redox balance. Treatment with L10 promoted significant changes in the minimum inhibitory concentration (MIC) values in ascorbic acid and GSH protection tests, the latter increasing up to 64-fold of the MIC. Using nuclear magnetic resonance, we demonstrated interaction of L10 and GSH. At concentrations of 4.0 and 8.0 µg/mL, significant changes were observed in ROS production and mitochondrial membrane potential. The cell death profile showed characteristics of initial apoptosis at inhibitory concentrations (4.0 µg/mL). Transmission electron microscopy data corroborated these results and indicated signs of apoptosis, damage to plasma and nuclear membranes, and to mitochondria. Taken together, these results suggest a possible mechanism of action for L10 antifungal activity, involving changes in cellular redox balance, ROS production, and apoptosis-compatible cellular changes.


Assuntos
Antifúngicos/farmacologia , Apoptose/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Tiofenos/farmacologia , Tiossemicarbazonas/farmacologia , Antifúngicos/química , Humanos , Estrutura Molecular , Tiofenos/química , Tiossemicarbazonas/química
10.
Cancer Sci ; 111(5): 1663-1675, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32176823

RESUMO

Loss of heterozygosity or mutation of the family with sequence similarity 46, member C (FAM46C) gene on chromosome band 1p12 is associated with shorter overall survival of patients with multiple myeloma (MM). In this study, using human MM cell lines (KMS-11, OCI-My5, and ANBL-6), we generated FAM46C-/- cell clones and examined the effect of disruption of FAM46C on cell survival and cellular signaling. Cell proliferation assays showed increased clonogenicity of FAM46C-/- KMS-11 cells compared to WT cells. Xenograft experiments showed significantly shorter overall survival of mice harboring the FAM46C-/- cell-derived tumors than mice with the FAM46CWT cell-derived tumors. Notably, levels of phosphorylated Akt and its substrates increased both in vitro and in vivo in the FAM46C-/- cells compared to WT cells. In addition, caspase activities decreased in the FAM46C-/- cells. Results of gene set enrichment analysis showed that loss of FAM46C significantly activated serum-responsive genes while inactivating phosphatase and tensin homolog (PTEN)-related genes. Mechanistically, loss of FAM46C decreased the PTEN activity, number of apoptotic cells, and caspase activities. PF-04691502, a selective PI3K inhibitor, suppressed the augmented phosphorylation of Akt and its substrate FoxO3a. Treatment with afuresertib (a specific Akt inhibitor) in combination with bortezomib additively decreased FAM46C-/- MM cell survival. Collectively, this study is the first to report that loss of FAM46C triggers the concomitant activation of the PI3K-Akt signaling pathway, which might be a therapeutic target for MM with abnormalities in the FAM46C gene.


Assuntos
Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Nucleotidiltransferases/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Animais , Antineoplásicos/farmacologia , Bortezomib/farmacologia , Carcinogênese/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Camundongos , Camundongos SCID , Mieloma Múltiplo/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirazóis/farmacologia , Tiofenos/farmacologia
11.
Plant Dis ; 104(5): 1421-1432, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32191161

RESUMO

Phytophthora, Phytopythium, and Pythium species that cause early-season seed decay and pre-emergence and post-emergence damping off of soybean are most commonly managed with seed treatments. The phenylamide fungicides metalaxyl and mefenoxam, and ethaboxam are effective toward some but not all species. The primary objective of this study was to evaluate the efficacy of ethaboxam in fungicide mixtures and compare those with other fungicides as seed treatments to protect soybean against Pythium, Phytopythium, and Phytophthora species in both high-disease field environments and laboratory seed plate assays. The second objective was to evaluate these seed treatment mixtures on cultivars that have varying levels and combinations of resistance to these soilborne pathogens. Five of eight environments received adequate precipitation in the 14 days after planting for high levels of seedling disease development and treatment evaluations. Three environments had significantly greater stands, and three had significantly greater yield when ethaboxam was used in the seed treatment mixture compared with treatments containing metalaxyl or mefenoxam alone. Three fungicide formulations significantly reduced disease severity compared with nontreated in the seed plate assay for 17 species. However, the combination of ethaboxam plus metalaxyl in a mixture was more effective than either fungicide alone against some Pythium and Phytopythium species. Overall, our results indicate that the addition of ethaboxam to a fungicide seed treatment is effective in reducing seed rot caused by these pathogens commonly isolated from soybean in Ohio but that these effects can be masked when cultivars with resistance are planted.


Assuntos
Phytophthora , Pythium , Ohio , Doenças das Plantas , Sementes , Soja , Tiazóis , Tiofenos
12.
PLoS One ; 15(2): e0229682, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32106236

RESUMO

BACKGROUND: Fixed-combination (FC) therapy is used in primary open-angle glaucoma (POAG) and ocular hypertension (OHT) patients who require more than one medication to reach their target intraocular pressure (IOP). Currently, there are several FC therapies available for the treatment of glaucoma. The FC of latanoprost/timolol (LTFC) is a commonly used FC. Here, we conducted systematic review to compare the IOP-lowering effects of LTFC with other FCs for patients with POAG and OHT. MATERIALS AND METHODS: We searched PubMed, EMBASE, the Cochrane Library, and Web of Science for randomized-controlled clinical trials and cross-over studies. The outcomes were mean IOP and IOP fluctuation after one month of treatment. Meta-analysis was carried out using RevMan (version 5.1) software. After conducting meta-analyses, we rated the quality of each meta-analysis as high, moderate, low, or very low using the "GRADE" system. RESULTS: We included 16 trials in this meta-analysis. Moderate-quality meta-analysis showed that LTFC had a comparable mean IOP to that of a fixed combination of travoprost and timolol (TTFC) [mean difference (MD): 0.07 mmHg] and a fixed combination of dorzolamide and timolol (DTFC) [MD: -0.31 mmHg], and it also had a comparable IOP-fluctuation effect compared to that of TTFC [MD: 0.13 mm Hg] and DTFC [MD: 0.25 mmHg]. Compared to the fixed combination of bimatoprost and timolol (BiTFC), moderate-quality evidence showed a higher mean IOP in the LTFC group [MD 0.76 mmHg], whereas low-quality meta-analysis showed higher IOP fluctuation [MD 1.09 mmHg] in the LTFC group. CONCLUSIONS: LTFC is as effective as TTFC and DTFC, but worse than BiTFC in controlling mean IOP and IOP fluctuation for POAG or OHT patients. The quality of our meta-analyses was assessed as moderate, with the exception of one low-quality analysis that compared the IOP fluctuation of LTFC and BiTFC.


Assuntos
Glaucoma de Ângulo Aberto/tratamento farmacológico , Latanoprosta/administração & dosagem , Hipertensão Ocular/tratamento farmacológico , Timolol/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Bimatoprost/administração & dosagem , Combinação de Medicamentos , Feminino , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Pressão Intraocular/efeitos dos fármacos , Masculino , Hipertensão Ocular/fisiopatologia , Sulfonamidas/administração & dosagem , Tiofenos/administração & dosagem , Travoprost/administração & dosagem , Resultado do Tratamento
13.
Environ Sci Pollut Res Int ; 27(13): 14963-14976, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32062775

RESUMO

In this work, three novel catalysts were prepared by 2.5, 5.0, and 10.0 wt.% facile impregnation with an iron and molybdenum mixed oxide (Fe/Mo) on an aluminum pillared clay (Al-PILC) support. These materials were characterized by scanning electron microscopy/energy dispersive spectroscopy (SEM/EDS), X-ray diffraction (XRD), temperature programed reduction (TPR), and nitrogen (N2) physisorption at 77 K. Characterizations indicated that the metal particles were dispersed on the surface of the three catalysts, and the interlayer d001 spacing of the pillared material remained unchanged after the impregnation process. The catalytic tests showed good results for DBT oxidation using the synthesized catalysts, with high turnover frequency (TOF) values, particularly for the material with 5.0 wt.% Fe/Mo. Theoretical calculations were carried out at the density functional theory (DFT) level, to investigate how the DBT molecules were adsorbed onto the surface of the mixed oxide. The lowest energy proposal was obtained when both Fe and Mo were present at the active sites, indicating a possible synergistic effect of the metals on catalyst activity. Reuse tests indicated that the catalysts could be employed effectively for up to 3 cycles in a row, then a decrease in activity occurred and the active sites needed to be regenerated.


Assuntos
Argila , Molibdênio , Alumínio , Catálise , Gasolina , Ferro , Estresse Oxidativo , Óxidos , Tiofenos
14.
Biochem J ; 477(2): 461-475, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32003437

RESUMO

Mitochondrial turnover is required for proper cellular function. Both mitochondrial biogenesis and mitophagy are impaired in several degenerative and age-related diseases. The search for mitophagy activators recently emerged as a new therapeutical approach; however, there is a lack in suitable tools to follow mitochondrial turnover in a high-throughput manner. We demonstrate that the fluorescent protein, MitoTimer, is a reliable and robust probe to follow mitochondrial turnover. The screening of 15 000 small molecules led us to two chemically-related benzothiophenes that stimulate basal mitophagy in the beta-cell line, INS1. Enhancing basal mitophagy was associated with improved mitochondrial function, higher Complex I activity and Complex II and III expressions in INS1 cells, as well as better insulin secretion performance in mouse islets. The possibility of further enhancing mitophagy in the absence of mitochondrial stressors points to the existence of a 'basal mitophagy spare capacity'. To this end, we found two small molecules that can be used as models to better understand the physiological regulation of mitophagy.


Assuntos
Envelhecimento/genética , Secreção de Insulina/genética , Mitocôndrias/genética , Mitofagia/genética , Envelhecimento/patologia , Animais , Autofagia/genética , Linhagem Celular , Citometria de Fluxo , Humanos , Camundongos , Mitocôndrias/efeitos dos fármacos , Renovação Mitocondrial , Mitofagia/efeitos dos fármacos , Complexos Multienzimáticos/química , Complexos Multienzimáticos/genética , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Tiofenos/química , Tiofenos/farmacologia
15.
Int J Nanomedicine ; 15: 1215-1228, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110018

RESUMO

Background: Helper T cell activity is dysregulated in a number of diseases including those associated with rheumatic autoimmunity. Treatment options are limited and usually consist of systemic immune suppression, resulting in undesirable consequences from compromised immunity. Hedgehog (Hh) signaling has been implicated in the activation of T cells and the formation of the immune synapse, but remains understudied in the context of autoimmunity. Modulation of Hh signaling has the potential to enable controlled immunosuppression but a potential therapy has not yet been developed to leverage this opportunity. Methods: In this work, we developed biodegradable nanoparticles to enable targeted delivery of eggmanone (Egm), a specific Hh inhibitor, to CD4+ T cell subsets. We utilized two FDA-approved polymers, poly(lactic-co-glycolic acid) and polyethylene glycol, to generate hydrolytically degradable nanoparticles. Furthermore, we employed maleimide-thiol mediated conjugation chemistry to decorate nanoparticles with anti-CD4 F(ab') antibody fragments to enable targeted delivery of Egm. Results: Our novel delivery system achieved a highly specific association with the majority of CD4+ T cells present among a complex cell population. Additionally, we have demonstrated antigen-specific inhibition of CD4+ T cell responses mediated by nanoparticle-formulated Egm. Conclusion: This work is the first characterization of Egm's immunomodulatory potential. Importantly, this study also suggests the potential benefit of a biodegradable delivery vehicle that is rationally designed for preferential interaction with a specific immune cell subtype for targeted modulation of Hh signaling.


Assuntos
Autoimunidade/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Fatores Imunológicos/administração & dosagem , Nanopartículas/administração & dosagem , Pirimidinonas/administração & dosagem , Linfócitos T/efeitos dos fármacos , Tiofenos/administração & dosagem , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Citocinas/metabolismo , Feminino , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Fragmentos de Imunoglobulinas/química , Camundongos Endogâmicos C57BL , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Doenças Reumáticas/imunologia , Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia
16.
Nat Chem Biol ; 16(3): 327-336, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32080624

RESUMO

The retrograde transport inhibitor Retro-2 has a protective effect on cells and in mice against Shiga-like toxins and ricin. Retro-2 causes toxin accumulation in early endosomes and relocalization of the Golgi SNARE protein syntaxin-5 to the endoplasmic reticulum. The molecular mechanisms by which this is achieved remain unknown. Here, we show that Retro-2 targets the endoplasmic reticulum exit site component Sec16A, affecting anterograde transport of syntaxin-5 from the endoplasmic reticulum to the Golgi. The formation of canonical SNARE complexes involving syntaxin-5 is not affected in Retro-2-treated cells. By contrast, the interaction of syntaxin-5 with a newly discovered binding partner, the retrograde trafficking chaperone GPP130, is abolished, and we show that GPP130 must indeed bind to syntaxin-5 to drive Shiga toxin transport from the endosomes to the Golgi. We therefore identify Sec16A as a druggable target and provide evidence for a non-SNARE function for syntaxin-5 in interaction with GPP130.


Assuntos
Benzamidas/metabolismo , Proteínas Qa-SNARE/metabolismo , Tiofenos/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Benzamidas/farmacologia , Transporte Biológico , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Endossomos/metabolismo , Complexo de Golgi/metabolismo , Células HeLa , Humanos , Transporte Proteico , Ricina/metabolismo , Toxina Shiga/metabolismo , Toxinas Shiga/metabolismo , Tiofenos/farmacologia , Proteínas de Transporte Vesicular/fisiologia
17.
AAPS PharmSciTech ; 21(3): 87, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32016607

RESUMO

This study aims to evaluate the effect of different formulation variables (surfactant type and HLB value) adopting full factorial design (51. 21) using coacervation phase technique on in vitro characterization of dorzolamide hydrochloride (DZ)-loaded proniosomal gels, namely, entrapment efficiency percentage (EE%), vesicle size distribution, polydispersion index (PDI), and in vitro DZ release. The optimum formula F2 with a desirability value of 0.937 composed of 40 mg DZ, 500 mg span 60, 500 mg of L-α-Lethicin, and 55.5 mg cholesterol showing EE% of 84.5 ± 1.5%, PS of 189.5 ± 35.76 nm with PDI 0.8 ± 0.28 and 58.51% ± 1.00 of DZ released after 8 h was further evaluated using differential scanning calorimetry (DSC) and transmission electron microscopy (TEM). The effect of gamma sterilization on transcorneal permeation and stability of DZ from the selected formulation (F2) revealed that F2 was significantly tolerable, stable, and competent to corneal permeation confirmed by histological examination, confocal laser microscopy, and intraocular pressure (IOP) measurement. Significant corneal bioavailability was attained from formula F2 (370.6 mg. h/m) compared to the market product Trusopt® eye drops (92.59 mg. h/ml) following IOP measurement, thereby proniosomal gels could be considered as tolerable and competent ocular platforms for improving the transcorneal permeation of DZ.


Assuntos
Córnea/metabolismo , Glaucoma/tratamento farmacológico , Sulfonamidas/administração & dosagem , Tiofenos/administração & dosagem , Animais , Composição de Medicamentos , Estabilidade de Medicamentos , Raios gama , Géis/química , Lipossomos/química , Masculino , Permeabilidade , Coelhos , Esterilização , Sulfonamidas/farmacocinética , Tiofenos/farmacocinética
18.
Nat Commun ; 11(1): 1032, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32098961

RESUMO

The AMP-activated protein kinase (AMPK) is a master sensor of the cellular energy status that is crucial for the adaptive response to limited energy availability. AMPK is implicated in the regulation of many cellular processes, including autophagy. However, the precise mechanisms by which AMPK controls these processes and the identities of relevant substrates are not fully understood. Using protein microarrays, we identify Cyclin Y as an AMPK substrate that is phosphorylated at Serine 326 (S326) both in vitro and in cells. Phosphorylation of Cyclin Y at S326 promotes its interaction with the Cyclin-dependent kinase 16 (CDK16), thereby stimulating its catalytic activity. When expressed in cells, Cyclin Y/CDK16 is sufficient to promote autophagy. Moreover, Cyclin Y/CDK16 is necessary for efficient AMPK-dependent activation of autophagy. This functional interaction is mediated by AMPK phosphorylating S326 of Cyclin Y. Collectively, we define Cyclin Y/CDK16 as downstream effector of AMPK for inducing autophagy.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/fisiologia , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/metabolismo , Animais , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/metabolismo , Quinases Ciclina-Dependentes/genética , Ciclinas/genética , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Células NIH 3T3 , Fosforilação/efeitos dos fármacos , Análise Serial de Proteínas , Pironas/farmacologia , Serina/metabolismo , Tiofenos/farmacologia
19.
BMC Infect Dis ; 20(1): 171, 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32087692

RESUMO

BACKGROUND: Trichophyton benhamiae is a zoophilic dermatophyte that can cause tinea in humans and animals. Lesions caused by T. benhamiae tend to be highly inflammatory, and patients are often infected by animals or other patients infected with T. benhamiae. In this paper, we report the first case of tinea faciei caused by T. benhamiae in a Chinese girl who might be transmitted from a fox. CASE PRESENTATION: A 4-year-old girl from HaiNing city developed an itchy, erythematous, and annular plaque on her right face for the past 2 months. Before the lesion appeared, she was in close contact with the fur of a fox for almost 1 week. Septate hyaline hyphae were detected by direct mycological examination of the scales. Cultures grew on Sabouraud's dextrose agar (SDA) at 26 °C for 2 weeks revealed the presence of T. mentagrophytes. A molecular sequencing test confirmed that the isolate was consistent with reference strains to T. benhamiae. Then, the diagnosis of tinea faciei due to T. benhamiae was made. Treatment with terbinafine (oral 125 mg/d) and sertaconazole nitrate cream (topical, twice daily) for 4 weeks was initiated and achieved significant improvement of the skin lesions. CONCLUSIONS: This rare dermatophytosis case highlights the importance of ITS sequencing in helping to recognize rare pathogenic fungi that can be easily misdiagnosed with a conventional morphological diagnosis.


Assuntos
Arthrodermataceae/genética , Dermatomicoses/diagnóstico , Tinha/diagnóstico , Trichophyton/genética , Administração Oral , Administração Tópica , Animais , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Arthrodermataceae/isolamento & purificação , Pré-Escolar , China , Dermatomicoses/tratamento farmacológico , Dermatomicoses/microbiologia , Face/patologia , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Pele/patologia , Terbinafina/administração & dosagem , Terbinafina/uso terapêutico , Tiofenos/administração & dosagem , Tiofenos/uso terapêutico , Tinha/tratamento farmacológico , Tinha/microbiologia , Resultado do Tratamento , Trichophyton/isolamento & purificação
20.
J Med Chem ; 63(2): 529-541, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31910011

RESUMO

Structure-activity relationships for a series of small-molecule thiophenes resulted in potent and selective antagonism of human Complement C3a receptor. The compounds are about 100-fold more potent than the most reported antagonist SB290157. A new compound JR14a was among the most potent of the new antagonists in vitro, assessed by (a) inhibition of intracellular calcium release (IC50 10 nM) induced in human monocyte-derived macrophages by 100 nM C3a, (b) inhibition of ß-hexosaminidase secretion (IC50 8 nM) from human LAD2 mast cells degranulated by 100 nM C3a, and (c) selectivity for human C3aR over C5aR. JR14a was metabolically stable in rat plasma and in rat liver microsomes and efficacious in rats when given orally to suppress rat paw inflammation, macrophage and mast cell activation, and histopathology induced by intraplantar paw administration of a C3aR agonist. Potent C3aR antagonists are now available for interrogating C3a receptor activation and suppressing C3aR-mediated inflammation in mammalian physiology and disease.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Arginina/análogos & derivados , Compostos Benzidrílicos/farmacologia , Complemento C3a , Receptores de Complemento/antagonistas & inibidores , Tiofenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Arginina/farmacocinética , Arginina/farmacologia , Compostos Benzidrílicos/farmacocinética , Cálcio/metabolismo , Hexosaminidases/metabolismo , Humanos , Macrófagos/efeitos dos fármacos , Mastócitos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Ratos Wistar , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/farmacocinética
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