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1.
Biomolecules ; 11(12)2021 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-34944543

RESUMO

Hydrogen sulfide (H2S) is a ubiquitous gaseous signaling molecule that has an important role in many physiological and pathological processes in mammalian tissues, with the same importance as two others endogenous gasotransmitters such as NO (nitric oxide) and CO (carbon monoxide). Endogenous H2S is involved in a broad gamut of processes in mammalian tissues including inflammation, vascular tone, hypertension, gastric mucosal integrity, neuromodulation, and defense mechanisms against viral infections as well as SARS-CoV-2 infection. These results suggest that the modulation of H2S levels has a potential therapeutic value. Consequently, synthetic H2S-releasing agents represent not only important research tools, but also potent therapeutic agents. This review has been designed in order to summarize the currently available H2S donors; furthermore, herein we discuss their preparation, the H2S-releasing mechanisms, and their -biological applications.


Assuntos
Descoberta de Drogas , Gasotransmissores/farmacologia , Sulfeto de Hidrogênio/farmacologia , Animais , Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/metabolismo , Benzenossulfonatos/farmacologia , Benzenossulfonatos/uso terapêutico , Química Farmacêutica , Gasotransmissores/administração & dosagem , Gasotransmissores/metabolismo , Gasotransmissores/uso terapêutico , Humanos , Sulfeto de Hidrogênio/administração & dosagem , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/uso terapêutico , Morfolinas/administração & dosagem , Morfolinas/metabolismo , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Naproxeno/administração & dosagem , Naproxeno/análogos & derivados , Naproxeno/metabolismo , Naproxeno/farmacologia , Naproxeno/uso terapêutico , Compostos Organotiofosforados/administração & dosagem , Compostos Organotiofosforados/metabolismo , Compostos Organotiofosforados/farmacologia , Compostos Organotiofosforados/uso terapêutico
2.
Arch Biochem Biophys ; 712: 109044, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34597656

RESUMO

The pathogenesis of chronic kidney disease (CKD) is closely related to the changes in the intestinal microbiota and integrity. Our previous studies have shown the accumulation of hydrogen sulfide (H2S)-producing bacterial family, Desulfovibrionacea, in the colon of a murine model of CKD, suggesting that the increased H2S contributes to the impaired intestinal integrity in CKD. Here, we investigated the anti-proliferative effect of H2S in the intestinal epithelial cells. A slow- H2S releasing molecule GYY4137 ((p-methoxyphenyl)morpholino-phosphinodithioic acid) reduced the proliferation of Caco-2 and IEC-6 cells. Flow cytometric analysis demonstrated that GYY4137 accumulated Caco-2 cells in the S phase fraction, suggesting that H2S arrested the cell cycle at G2 and/or M phases. The RNA sequencing analysis demonstrated that GYY4137 modulated the mRNA expression of the genes involved in the G2/M and the spindle assembly checkpoints; increased mRNA levels of Cdkn1a, Gadd45a, and Sfn and decreased mRNA levels of Cdc20, Pttg1, and Ccnb1 were observed. These alterations were confirmed by quantitative reverse transcription-polymerase chain reaction and Western blot analyses. Besides, studies exploring the MEK inhibitor indicated that MEK activation is involved in the GYY4137-mediated increase in the Sfn expression. Altogether, our data showed that H2S reduced the proliferation of intestinal epithelial cells through transcriptional regulation in G2/M and the spindle assembly checkpoints. This may be one of the underlying mechanisms for the observed impaired intestinal integrity in CKD.


Assuntos
Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Animais , Linhagem Celular Tumoral , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Intestinos/citologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Ratos
3.
Arch Insect Biochem Physiol ; 108(3): e21842, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34499777

RESUMO

Glyphodes pyloalis Walker has become one of the most significant mulberry pests, and it has caused serious economic losses in major mulberry growing regions in China. Peptidoglycan recognition proteins (PGRPs) are responsible for initiating and regulating immune signalling pathways in insects. However, their roles responding to chemical pesticides is still less known. This study aimed to investigate the possible detoxication function of GpPGRP-S2 and GpPGRP-S3 in G. pyloalis in response to chlorfenapyr and phoxim. The chlorfenapyr and phoxim treatment significantly induced the expression level of GpPGRP-S3 at 48 h. In addition, the expression levels of GpPGRP-S2 and GpPGRP-S3 in the chlorfenapyr/phoxim treatment group were significantly higher in midgut than those in the control group at 48 h. The results of the survival experiment showed that silencing either GpPGRP-S2 or GpPGRP-S3 would not influence the survival rate of G. pyloalis which treated with phoxim, however, silencing GpPGRP-S2 or GpPGRP-S3 would cause G. pyloalis to be more easily killed by chlorfenapyr. The expression of carboxylesterase GpCXE1 was significantly induced by chlorfenapyr/phoxim treatment, while it was suppressed once silenced GpPGRP-S2 followed with chlorfenapyr treatment or silenced GpPGRP-S3 followed with phoxim treatment. These results might suggest that under the chlorfenapyr/phoxim treatment condition, the connection between GpPGRPs and detoxification genes in insect was induced to maintain physiological homeostasis; and these results may further enrich the mechanisms of insects challenged by insecticides.


Assuntos
Proteínas de Transporte , Inseticidas , Mariposas , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Inseticidas/metabolismo , Inseticidas/farmacologia , Mariposas/efeitos dos fármacos , Mariposas/genética , Mariposas/metabolismo , Compostos Organotiofosforados/metabolismo , Compostos Organotiofosforados/farmacologia , Controle de Pragas/métodos , Piretrinas/metabolismo , Piretrinas/farmacologia
4.
Life Sci ; 284: 119869, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34358552

RESUMO

AIMS: Investigate the involvement of Hydrogen sulfide (H2S) in inflammatory parameters and intestinal morphology caused by cholera toxin (CT) in mice. MAIN METHODS: Mice were subjected to the procedure of inducing diarrhea by CT in the isolated intestinal loop model. The intestinal loops were inoculated with H2S donor molecules (NaHS and GYY 4137) or saline and CT. To study the role of EP2 and EP4 prostaglandin E2 (PGE2) receptors in the H2S antisecretory effect, PAG (DL-propargylglycine - inhibitor of cystathionine-γ-lyase (CSE)), PF-04418948 (EP2 antagonist) and ONO-AE3-208 (EP4 antagonist) were used. The intestinal loops were evaluated for intestinal secretion, relation of the depth of villi and intestinal crypts, and real-time PCR for the mRNA of the CXCL2, IL-6, NOS-2, IL-17, NF-κB1, NF-κBIA, SLC6A4 and IFN-γ genes. KEY FINDINGS: H2S restored the villus/crypt depth ratio caused by CT. NaHS and GYY 4137 increased the expression of NF-κB1 and for the NF-κBIA gene, only GYY 4137 increased the expression of this gene. The increased expression of NF-κB inhibitors, NF-κB1 and NF-κBIA by H2S indicates a possible decrease in NF-κB activity. The pretreatment with PAG reversed the protective effect of PF-04418948 and ONO-AE3-208, indicating that H2S probably decreases PGE2 because in the presence of antagonists of this pathway, PAG promotes intestinal secretion. SIGNIFICANCE: Our results point to a protective activity of H2S against CT for promoting a protection of villus and crypt intestine morphology and also that its mechanism occurs at least in part due to decreasing the activity of NF-κB and PGE2.


Assuntos
Diarreia/induzido quimicamente , Diarreia/metabolismo , Dinoprostona/metabolismo , Sulfeto de Hidrogênio/farmacologia , Mucosa Intestinal/patologia , NF-kappa B/metabolismo , Animais , Toxina da Cólera , Feminino , Perfilação da Expressão Gênica , Masculino , Camundongos , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo
5.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445355

RESUMO

Recently, lithium nitride (Li3N) has been proposed as a chemical warfare agent (CWA) neutralization reagent for its ability to produce nucleophilic ammonia molecules and hydroxide ions in aqueous solution. Quantum chemical calculations can provide insight into the Li3N neutralization process that has been studied experimentally. Here, we calculate reaction-free energies associated with the Li3N-based neutralization of the CWA VX using quantum chemical density functional theory and ab initio methods. We find that alkaline hydrolysis is more favorable to either ammonolysis or neutral hydrolysis for initial P-S and P-O bond cleavages. Reaction-free energies of subsequent reactions are calculated to determine the full reaction pathway. Notably, products predicted from favorable reactions have been identified in previous experiments.


Assuntos
Descontaminação , Compostos de Lítio/química , Compostos Organotiofosforados/química , Água/química , Amônia/química , Substâncias para a Guerra Química/química , Substâncias para a Guerra Química/farmacologia , Descontaminação/métodos , Hidrólise/efeitos dos fármacos , Cinética , Lítio/química , Modelos Moleculares , Compostos Organotiofosforados/farmacologia , Teoria Quântica
6.
Biomed Pharmacother ; 138: 111486, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311523

RESUMO

Erectile dysfunction (ED) is a common diabetic complication. Recent evidence has illuminated the role of hydrogen sulfide (H2S) as a dynamic mediator of the erection process. H2S is a potent endogenous relaxant gas. It has been shown to relax human and animal penile tissue in vitro and induce erection in animals in vivo. The reported penile expression of H2S-synthesizing enzymes also supports the potential role of the endogenous L-cysteine/H2S pathway in penile homeostasis. Several pathological changes take place in the diabetic penile tissue, including inflammation, oxidative stress, neuropathy and fibrosis of the corpus cavernosum (CC), the major erectile structure of the penis. The present study is experimental and has been performed in the diabetic rat model. The study will investigate the role of H2S as a potential protective mediator against diabetes-induced structural and functional alterations in the CC by examining if it: (1) reduces corporal contraction and/or enhances corporal relaxation following pharmacological stimulation, (2) attenuates fibromuscular changes in diabetic CC, and (3) whether there is a link with H2S plasma/urine level and CC tissue generation, as well as studying the expression of some proteins in the transforming growth factor (TGF)-ß1-associated pathway. The major findings of the study reveal that- compared to the nondiabetic controls - the diabetic animals CC showed: (1) augmented contraction and attenuated relaxation in response to phenylephrine and carbachol, respectively, (2) marked fibromuscular degeneration with a significantly lower smooth muscle/collagen ratio and upregulation of TGF-ß-1/Smad/CTGF fibrosis signaling pathway, (3) reduced H2S plasma and urinary levels and cavernosal tissue generation. Chronic GYY4137 treatment prevented most of these pathological changes in diabetic CC, thus may be considered a potential new strategy for the prevention and/or treatment of diabetes-induced ED.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Disfunção Erétil/prevenção & controle , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Ereção Peniana/efeitos dos fármacos , Pênis/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Disfunção Erétil/etiologia , Disfunção Erétil/metabolismo , Disfunção Erétil/fisiopatologia , Fibrose , Sulfeto de Hidrogênio/metabolismo , Masculino , Pênis/metabolismo , Pênis/patologia , Pênis/fisiopatologia , Ratos Sprague-Dawley , Transdução de Sinais , Estreptozocina
7.
FASEB J ; 35(7): e21710, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34143548

RESUMO

Injury to the blood-brain barrier (BBB) plays a vital role in sepsis-associated encephalopathy (SAE), which is one of the most common complications of sepsis. GYY4137, a new synthetic compound of hydrogen sulfide (H2 S), has extensive biological benefits. In this study, we focused on the protective effects of GYY4137 on the BBB in septic mice and the underlying mechanisms. The results suggested that whether administrated at the same time or 3 hours after LPS injection, GYY4137 both significantly alleviated the clinical symptoms and the long-term prognosis. Besides, GYY4137 improved the pathological abnormalities of septic mice. Moreover, the degradation of tight junctions in the BBB was considerably inhibited by GYY4137. In addition, GYY4137 significantly attenuated inflammation and apoptosis in the brain. Furthermore, GYY4137 activated the Nrf2/ARE pathway through the sulfhydrylation of Keap1 and inhibited oxidative stress. ML385, the specific inhibitor of Nrf2, significantly reversed the protective effects of GYY4137 in sepsis mice. In conclusion, this study indicated that through the sulfhydrylation of Keap1, GYY4137 activated the Nrf2/ARE pathway and exerted anti-inflammatory, anti-apoptotic and antioxidant effects in septic mice that consequently protected the integrity of the BBB and improved the clinical outcome of sepsis. Our findings suggest that GYY4137 might be a promising agent for the treatment of SAE.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Morfolinas/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Compostos Organotiofosforados/farmacologia , Sepse/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Sulfeto de Hidrogênio/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Sepse/metabolismo
8.
Sci Rep ; 11(1): 9655, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33958646

RESUMO

Fungicides among agrochemicals are consistently used in high throughput agricultural practices to protect plants from damaging impact of phytopathogens and hence to optimize crop production. However, the negative impact of fungicides on composition and functions of soil microbiota, plants and via food chain, on human health is a matter of grave concern. Considering such agrochemical threats, the present study was undertaken to know that how fungicide-tolerant symbiotic bacterium, Mesorhizobium ciceri affects the Cicer arietinum crop while growing in kitazin (KITZ) stressed soils under greenhouse conditions. Both in vitro and soil systems, KITZ imparted deleterious impacts on C. arietinum as a function of dose. The three-time more of normal rate of KITZ dose detrimentally but maximally reduced the germination efficiency, vigor index, dry matter production, symbiotic features, leaf pigments and seed attributes of C. arietinum. KITZ-induced morphological alterations in root tips, oxidative damage and cell death in root cells of C. arietinum were visible under scanning electron microscope (SEM). M. ciceri tolerated up to 2400 µg mL-1 of KITZ, synthesized considerable amounts of bioactive molecules including indole-3-acetic-acid (IAA), 1-aminocyclopropane 1-carboxylate (ACC) deaminase, siderophores, exopolysaccharides (EPS), hydrogen cyanide, ammonia, and solubilised inorganic phosphate even in fungicide-stressed media. Following application to soil, M. ciceri improved performance of C. arietinum and enhanced dry biomass production, yield, symbiosis and leaf pigments even in a fungicide-polluted environment. At 96 µg KITZ kg-1 soil, M. ciceri maximally and significantly (p ≤ 0.05) augmented the length of plants by 41%, total dry matter by 18%, carotenoid content by 9%, LHb content by 21%, root N by 9%, shoot P by 11% and pod yield by 15% over control plants. Additionally, the nodule bacterium M. ciceri efficiently colonized the plant rhizosphere/rhizoplane and considerably decreased the levels of stressor molecules (proline and malondialdehyde) and antioxidant defence enzymes viz. ascorbate peroxidise (APX), guaiacol peroxidise (GPX), catalase (CAT) and peroxidises (POD) of C. arietinum plants when inoculated in soil. The symbiotic strain effectively colonized the plant rhizosphere/rhizoplane. Conclusively, the ability to endure higher fungicide concentrations, capacity to secrete plant growth modulators even under fungicide pressure, and inherent features to lower the level of proline and plant defence enzymes makes this M. ciceri as a superb choice for augmenting the safe production of C. arietinum even under fungicide-contaminated soils.


Assuntos
Antifúngicos/farmacologia , Cicer/efeitos dos fármacos , Mesorhizobium/efeitos dos fármacos , Compostos Organotiofosforados/farmacologia , Cicer/crescimento & desenvolvimento , Cicer/microbiologia , Relação Dose-Resposta a Droga , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Nodulação/efeitos dos fármacos , Raízes de Plantas/efeitos dos fármacos , Rizosfera
9.
Sci Rep ; 11(1): 8194, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33854181

RESUMO

Hydrogen sulfide (H2S) is gaining interest as a mammalian signalling molecule with wide ranging effects. S-sulfhydration is one mechanism that is emerging as a key post translational modification through which H2S acts. Ion channels and neuronal receptors are key target proteins for S-sulfhydration and this can influence a range of neuronal functions. Voltage-gated K+ channels, including Kv2.1, are fundamental components of neuronal excitability. Here, we show that both recombinant and native rat Kv2.1 channels are inhibited by the H2S donors, NaHS and GYY4137. Biochemical investigations revealed that NaHS treatment leads to S-sulfhydration of the full length wild type Kv2.1 protein which was absent (as was functional regulation by H2S) in the C73A mutant form of the channel. Functional experiments utilising primary rat hippocampal neurons indicated that NaHS augments action potential firing and thereby increases neuronal excitability. These studies highlight an important role for H2S in shaping cellular excitability through S-sulfhydration of Kv2.1 at C73 within the central nervous system.


Assuntos
Hipocampo/citologia , Sulfeto de Hidrogênio/farmacologia , Canais de Potássio Shab/genética , Canais de Potássio Shab/metabolismo , Potenciais de Ação , Animais , Células Cultivadas , Regulação para Baixo , Células HEK293 , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Morfolinas/farmacologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Compostos Organotiofosforados/farmacologia , Fosforilação , Cultura Primária de Células , Ratos
10.
Life Sci ; 274: 119363, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33737083

RESUMO

AIMS: Post-fracture calcium and phosphorus excretion is greater than influx, which might be caused by stress. Glucocorticoid is known to enhance calcium and phosphorous excretion, and hydrogen sulfide (H2S) has been shown to exert inhibitory effects on glucocorticoid. Therefore, this study explored whether H2S could inhibit calcium and phosphorus loss after fracture by regulating glucocorticoid and/or its receptor. MAIN METHODS: The following properties were analyzed in rats with femur fractures: serum and urinary calcium and phosphorus (by colorimetry); bone turnover markers alkaline phosphatase, serum type 1 collagen amino terminal peptide, type 1 procollagen carboxy terminal peptide, and anti-tartaric acid phosphatase (by ELISA); factors related to calcium-phosphorus metabolism including glucocorticoid, parathyroid hormone, calcitonin, fibroblast growth factor 23, and 1,25(OH)2D3 (by ELISA); and sulfhydration of glucocorticoid receptor α in the kidney (by immunoprecipitation linked biotin-switch assay), after supplementing with mifepristone, the H2S donor GYY4137 or H2S generating enzyme inhibitors aminooxyacetic acid and propargylglycine. KEY FINDINGS: Serum H2S decreased and glucocorticoid secretion increased in rats post-fracture. The glucocorticoid receptor inhibitor mifepristone partly blunted calcium and phosphorus loss. Furthermore, supplementation with GYY4137 reduced glucocorticoid secretion; inhibited glucocorticoid receptor α activity by sulfhydration; downregulated vitamin D 1α-hydroxylase expression; and upregulated 24-hydroxylase, calbindin-D28k, and sodium phosphate cotransporter 2a expression in the kidney; thereby inhibiting calcium and phosphorus loss induced by fracture. Moreover, inhibiting endogenous H2S generation showed opposite effects. SIGNIFICANCE: Our findings suggest that H2S antagonized calcium and phosphorus loss after fracture by reducing glucocorticoid secretion and inhibiting glucocorticoid receptor α activity by sulfhydration.


Assuntos
Cálcio/metabolismo , Fraturas do Fêmur/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Fósforo/metabolismo , Receptores de Glucocorticoides/antagonistas & inibidores , Animais , Fraturas do Fêmur/metabolismo , Fraturas do Fêmur/patologia , Gasotransmissores/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley
11.
Proc Natl Acad Sci U S A ; 118(9)2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33627403

RESUMO

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive muscle degeneration and weakness due to mutations in the dystrophin gene. The symptoms of DMD share similarities with those of accelerated aging. Recently, hydrogen sulfide (H2S) supplementation has been suggested to modulate the effects of age-related decline in muscle function, and metabolic H2S deficiencies have been implicated in affecting muscle mass in conditions such as phenylketonuria. We therefore evaluated the use of sodium GYY4137 (NaGYY), a H2S-releasing molecule, as a possible approach for DMD treatment. Using the dys-1(eg33) Caenorhabditis elegans DMD model, we found that NaGYY treatment (100 µM) improved movement, strength, gait, and muscle mitochondrial structure, similar to the gold-standard therapeutic treatment, prednisone (370 µM). The health improvements of either treatment required the action of the kinase JNK-1, the transcription factor SKN-1, and the NAD-dependent deacetylase SIR-2.1. The transcription factor DAF-16 was required for the health benefits of NaGYY treatment, but not prednisone treatment. AP39 (100 pM), a mitochondria-targeted H2S compound, also improved movement and strength in the dys-1(eg33) model, further implying that these improvements are mitochondria-based. Additionally, we found a decline in total sulfide and H2S-producing enzymes in dystrophin/utrophin knockout mice. Overall, our results suggest that H2S deficit may contribute to DMD pathology, and rectifying/overcoming the deficit with H2S delivery compounds has potential as a therapeutic approach to DMD treatment.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Distrofina/genética , Sulfeto de Hidrogênio/farmacologia , Mitocôndrias Musculares/efeitos dos fármacos , Morfolinas/farmacologia , Músculo Esquelético/efeitos dos fármacos , Distrofia Muscular Animal/tratamento farmacológico , Compostos Organofosforados/farmacologia , Compostos Organotiofosforados/farmacologia , Tionas/farmacologia , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Distrofina/deficiência , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Humanos , Sulfeto de Hidrogênio/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/genética , Masculino , Camundongos , Camundongos Endogâmicos mdx , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/patologia , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Morfolinas/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/metabolismo , Distrofia Muscular Animal/patologia , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patologia , Compostos Organofosforados/metabolismo , Compostos Organotiofosforados/metabolismo , Prednisona/farmacologia , Sirtuínas/genética , Sirtuínas/metabolismo , Tionas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Utrofina/deficiência , Utrofina/genética
12.
Life Sci ; 271: 119192, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33577850

RESUMO

AIMS: GYY4137 [GYY, morpholin-4-ium-4-methoxyphenyl (morpholino) phosphinodithioate] is a novel and perfect hydrogen sulfide (H2S) donor that is stable in vivo and in vitro. H2S, along with CO and NO, has been recognized as the third physiological gas signaling molecule that plays an active role in fighting various lung infections. However, the mechanism by which GYY4137 affects cecal ligation and puncture (CLP)-induced acute lung injury (ALI) is not understood. This study aimed to investigate whether GYY4137 inhibits the activation of the pyrin domain-containing protein 3 (NLRP3) inflammasome by inhibiting the PDGFRß/Akt/NF-κB pathway. MAIN METHODS: The model of CLP-induced ALI was established in vivo. The mice were subsequently treated with GYY4137 (25 µg/g and 50 µg/g) to simulate the realistic conditions of pathogenesis. Western blotting and immunohistochemical staining were used to examine protein expression, hematoxylin and eosin staining was used for the histopathological analysis, and the levels of inflammatory factors were determined using enzyme-linked immunosorbent assays (ELISAs). KEY FINDINGS: GYY4137 significantly increased the 7-day survival of mice with septic peritonitis and protected against CLP-induced ALI, including decreasing neutrophil infiltration, improving sepsis-induced lung histopathological changes, diminishing lung tissue damage, and attenuating the severity of lung injury in mice. The protective effect of GYY4137 was undoubtedly dose-dependent. We discovered that GYY4137 reduced the levels of the p-PDGFRß, p-NF-κB, ASC, NLRP3, caspase-1, and p-Akt proteins in septic mouse lung tissue. Akt regulates the generation of proinflammatory cytokines in endotoxemia-associated ALI by enhancing the nuclear translocation of NF-κB. SIGNIFICANCE: These results indicate a new molecular mechanism explaining the effect of GYY4137 on the treatment of CLP-induced ALI in mice.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Morfolinas/uso terapêutico , NF-kappa B/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Compostos Organotiofosforados/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Sepse/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Compostos Organotiofosforados/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células RAW 264.7 , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Sepse/complicações , Sepse/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
13.
Int J Mol Med ; 47(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33537813

RESUMO

The activation of oxidative stress is a primary cause of chondrocyte apoptosis in osteoarthritis (OA). The 78­kDa glucose­regulated protein (GRP78)/mammalian target of rapamycin (mTOR) signaling pathway has been demonstrated to be linked with the endoplasmic reticulum (ER) and autophagy. Hydrogen sulfide (H2S) has been reported to exert antioxidant effects. The present study investigated oxidative stress levels via 2',7'­dichlorofluorescin diacetate and MitoSOX staining, apoptosis rates via flow cytometry and the expression levels of ER stress­related proteins in GYY4137 (donor of H2S)­treated chondrocytes (CHs). CHs were isolated from the bilateral hip joints of male rats to examine mitochondrial permeability transition pore opening­ and mTOR signaling pathway­related proteins. The results demonstrated that tert­Butyl hydroperoxide (TBHP) increased CH apoptosis, and treatment with GYY4137 ameliorated TBHP­mediated the generation of ROS and CH apoptosis. Moreover, TBHP­treated CHs displayed elevated ER stress sensor expression levels and apoptotic rates; however, the TBHP­induced protein expression levels were decreased following GYY4137 treatment. In the present study, treatment with either GYY4137 or transfection with GRP78 siRNA both suppressed the activation of p­P70S6k and p­mTOR. H2S played an important role in regulating ER stress in TBHP­stimulated CHs. GYY4137 promoted autophagy, which was accompanied by the inhibition of ER stress. On the whole, the present study demonstrates that TBHP­induced oxidative stress stimulates ER interactions and CH apoptosis, which are suppressed by exogenous H2S via modulating the GRP78/mTOR signaling pathway.


Assuntos
Condrócitos/metabolismo , Condrócitos/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Proteínas de Choque Térmico/metabolismo , Sulfeto de Hidrogênio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cloroquina/farmacologia , Condrócitos/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Masculino , Morfolinas/química , Morfolinas/farmacologia , Compostos Organotiofosforados/química , Compostos Organotiofosforados/farmacologia , Peróxidos/farmacologia , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Acta Trop ; 216: 105820, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33400915

RESUMO

Malaria vector control in Mali relies heavily on the use of long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) in selected districts. As part of strengthening vector control strategies in Koulikoro district, the National Malaria Control Programme (NMCP) through the support from the US President's Malaria Initiative (PMI) has strategically driven the implementation of IRS, with the LLINs coverage also rising from 93.3% and 98.2%. Due to the increased reports of vector resistance to both pyrethroid and carbamates, there was a campaign for the use of pirimiphos-methyl, an organophosphate at Koulikoro between 2015 and 2016. In this study, the effect of IRS on malaria transmission was assessed, by comparing some key entomological indices between Koulikoro, where IRS was implemented and its neighboring district, Banamba that has never received IRS as vector control intervention. The study was conducted in two villages of each district (Koulikoro and Banamba). Pyrethrum spray catches and entry window trapping were used to collect mosquitoes on a monthly basis. WHO tube tests were carried out to assess mosquito susceptibility to insecticides. Mosquitoes were identified to species level by PCR and their infection to P. falciparum was detected by Enzyme Linked-Immuno-Sorbent Assay (ELISA). Of the 527 specimens identified, An. coluzzii was the most frequent species (95%) followed by An. gambiae (4%) and An. arabiensis (1%). Its density was rainfall dependent in the no-IRS area, and almost independent in the IRS area. The infection rate (IR) in the no-IRS area was 0.96%, while it was null in the IRS area. In the no-IRS area, the entomological inoculation rate (EIR) was 0.21 infective bites /person month with a peak in September. High resistance to pyrethroids and carbamates and susceptibility to organophosphates was observed at all sites. The introduction of pirimiphos-methyl based IRS for vector control resulted in a significant decrease in malaria transmission. An. gambiae s.l., the main malaria vector in the area, was resistant to pyrethroids and carbamates but remained susceptible to the organophosphate pirimiphos-methyl.


Assuntos
Anopheles/efeitos dos fármacos , Anopheles/parasitologia , Carbamatos/farmacologia , Malária/prevenção & controle , Malária/transmissão , Compostos Organotiofosforados/farmacologia , Piretrinas/farmacologia , Animais , Anopheles/genética , Vetores de Doenças , Feminino , Humanos , Mordeduras e Picadas de Insetos/parasitologia , Resistência a Inseticidas , Inseticidas/farmacologia , Mali , Tipagem Molecular , Controle de Mosquitos/métodos , Mosquitos Vetores/efeitos dos fármacos , Mosquitos Vetores/genética , Reação em Cadeia da Polimerase
15.
Proc Natl Acad Sci U S A ; 118(4)2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33431651

RESUMO

Alzheimer's disease (AD), the most common cause of dementia and neurodegeneration in the elderly, is characterized by deterioration of memory and executive and motor functions. Neuropathologic hallmarks of AD include neurofibrillary tangles (NFTs), paired helical filaments, and amyloid plaques. Mutations in the microtubule-associated protein Tau, a major component of the NFTs, cause its hyperphosphorylation in AD. We have shown that signaling by the gaseous molecule hydrogen sulfide (H2S) is dysregulated during aging. H2S signals via a posttranslational modification termed sulfhydration/persulfidation, which participates in diverse cellular processes. Here we show that cystathionine γ-lyase (CSE), the biosynthetic enzyme for H2S, binds wild type Tau, which enhances its catalytic activity. By contrast, CSE fails to bind Tau P301L, a mutant that is present in the 3xTg-AD mouse model of AD. We further show that CSE is depleted in 3xTg-AD mice as well as in human AD brains, and that H2S prevents hyperphosphorylation of Tau by sulfhydrating its kinase, glycogen synthase kinase 3ß (GSK3ß). Finally, we demonstrate that sulfhydration is diminished in AD, while administering the H2S donor sodium GYY4137 (NaGYY) to 3xTg-AD mice ameliorates motor and cognitive deficits in AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Cistationina gama-Liase/genética , Glicogênio Sintase Quinase 3 beta/genética , Sulfeto de Hidrogênio/farmacologia , Morfolinas/farmacologia , Fármacos Neuroprotetores/farmacologia , Compostos Organotiofosforados/farmacologia , Proteínas tau/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Cistationina gama-Liase/metabolismo , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HEK293 , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Camundongos , Camundongos Transgênicos , Mutação , Emaranhados Neurofibrilares/efeitos dos fármacos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fosforilação , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Placa Amiloide/prevenção & controle , Ligação Proteica , Processamento de Proteína Pós-Traducional , Sulfatos/metabolismo , Proteínas tau/metabolismo
16.
Parasit Vectors ; 14(1): 58, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33461621

RESUMO

BACKGROUND: The rapid spread of insecticide resistance in malaria vectors and the rebound in malaria cases observed recently in some endemic areas underscore the urgent need to evaluate and deploy new effective control interventions. A randomized control trial (RCT) was conducted with the aim to investigate the benefit of deploying complementary strategies, including indoor residual spraying (IRS) with pirimiphos-methyl in addition to long-lasting insecticidal nets (LLINs) in Diébougou, southwest Burkina Faso. METHODS: We measured the susceptibility of the Anopheles gambiae (s.l.) population from Diébougou to conventional insecticides. We further monitored the efficacy and residual activity of pirimiphos-methyl on both cement and mud walls using a laboratory susceptible strain (Kisumu) and the local An. gambiae (s.l.) population. RESULTS: An. gambiae (s.l.) from Diébougou was resistant to DDT, pyrethroids (deltamethrin, permethrin and alphacypermethrin) and bendiocarb but showed susceptibility to organophosphates (pirimiphos-methyl and chlorpyrimiphos-methyl). A mixed-effect generalized linear model predicted that pirimiphos-methyl applied on cement or mud walls was effective for 210 days against the laboratory susceptible strain and 247 days against the local population. The residual efficacy of pirimiphos-methyl against the local population on walls made of mud was similar to that of cement (OR = 0.792, [0.55-1.12], Tukey's test p-value = 0.19). CONCLUSIONS: If data on malaria transmission and malaria cases (as measured trough the RCT) are consistent with data on residual activity of pirimiphos-methyl regardless of the type of wall, one round of IRS with pirimiphos-methyl would have the potential to control malaria in a context of multi-resistant An. gambiae (s.l.) for at least 7 months.


Assuntos
Anopheles/efeitos dos fármacos , Habitação , Resistência a Inseticidas , Inseticidas/farmacologia , Malária/prevenção & controle , Mosquitos Vetores/efeitos dos fármacos , Compostos Organotiofosforados/farmacologia , Animais , Burkina Faso , Feminino , Humanos , Mosquiteiros Tratados com Inseticida , Malária/transmissão , Controle de Mosquitos/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
PLoS Genet ; 17(1): e1009253, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33476334

RESUMO

Vector population control using insecticides is a key element of current strategies to prevent malaria transmission in Africa. The introduction of effective insecticides, such as the organophosphate pirimiphos-methyl, is essential to overcome the recurrent emergence of resistance driven by the highly diverse Anopheles genomes. Here, we use a population genomic approach to investigate the basis of pirimiphos-methyl resistance in the major malaria vectors Anopheles gambiae and A. coluzzii. A combination of copy number variation and a single non-synonymous substitution in the acetylcholinesterase gene, Ace1, provides the key resistance diagnostic in an A. coluzzii population from Côte d'Ivoire that we used for sequence-based association mapping, with replication in other West African populations. The Ace1 substitution and duplications occur on a unique resistance haplotype that evolved in A. gambiae and introgressed into A. coluzzii, and is now common in West Africa primarily due to selection imposed by other organophosphate or carbamate insecticides. Our findings highlight the predictive value of this complex resistance haplotype for phenotypic resistance and clarify its evolutionary history, providing tools to for molecular surveillance of the current and future effectiveness of pirimiphos-methyl based interventions.


Assuntos
Acetilcolinesterase/genética , Resistência a Inseticidas/genética , Malária/genética , Malária/transmissão , África Ocidental , Animais , Anopheles/efeitos dos fármacos , Anopheles/genética , Anopheles/parasitologia , Variações do Número de Cópias de DNA/genética , Genes Duplicados/genética , Introgressão Genética/genética , Humanos , Inseticidas/efeitos adversos , Malária/parasitologia , Malária/prevenção & controle , Mosquitos Vetores/genética , Compostos Organotiofosforados/efeitos adversos , Compostos Organotiofosforados/farmacologia
18.
Chem Biol Interact ; 336: 109393, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33508307

RESUMO

Skin decontamination following exposure to chemical agents is a most important component of the individual defense doctrine, removing the agent, ceasing its penetration and preventing secondary contamination of the first responders. The goal of the current study was to compare the efficacy of Reactive Skin Decontaminant Lotion (RSDL) and Fuller's Earth (FE) following exposure to sulfur mustard (SM) and VX, aiming to find the optimal procedure for mass casualty decontamination protocol. Decontamination efficacy was evaluated in pigs by measurement of lesion area and erythema (SM) and cholinesterase inhibition and clinical symptoms (VX). FE and RSDL were highly effective against both agents. Following SM exposure, the two decontaminants demonstrated a significant decrease in lesions' size together with the decrease in exposure duration. Likewise, skin decontamination following exposure to VX with either FE or RSDL resulted in reduction in clinical symptoms and prevention of death. Decontamination was worthwhile even if postponed, up to 30 min (SM) and 2 h (VX). In conclusion, both decontamination products were efficient in ameliorating the toxic effects even though in a different mechanism. Finally, for mass casualty scenario, FE is preferred as a universal decontaminant, considering its safety, ease of use and longer shelf life.


Assuntos
Compostos de Alumínio/farmacologia , Descontaminação , Compostos de Magnésio/farmacologia , Modelos Animais , Gás de Mostarda/farmacologia , Compostos Organotiofosforados/farmacologia , Silicatos/farmacologia , Creme para a Pele/farmacologia , Pele/efeitos dos fármacos , Suínos , Animais , Feminino , Pele/patologia
19.
Malar J ; 20(1): 54, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33478533

RESUMO

BACKGROUND: The need to develop new products and novel approaches for malaria vector control is recognized as a global health priority. One approach to meeting this need has been the development of new products for indoor residual spraying (IRS) with novel active ingredients for public health. While initial results showing the impact of several of these next-generation IRS products have been encouraging, questions remain about how to best deploy them for maximum impact. To help address these questions, a 2-year cluster-randomized controlled trial to measure the impact of IRS with a microencapsulated formulation of pirimiphos-methyl (PM) in an area with high ownership of long-lasting insecticidal nets (LLINs) was conducted in a high-transmission district of central Mozambique with pyrethroid resistant vectors. Presented here are the results of the vector surveillance component of the trial. METHODS: The 2 year, two-armed trial was conducted in Mopeia District, Zambezia Province, Mozambique. In ten sentinel villages, five that received IRS with PM in October-November 2016 and again in October-November 2017 and five that received no IRS, indoor light trap collections and paired indoor-outdoor human landing collections catches (HLCs) were conducted monthly from September 2016 through October 2018. A universal coverage campaign in June 2017, just prior to the second spray round, distributed 131,540 standard alpha-cypermethrin LLINs across all study villages and increased overall net usage rates in children under 5 years old to over 90%. RESULTS: The primary malaria vector during the trial was Anopheles funestus sensu lato (s.l.), and standard World Health Organization (WHO) tube tests with this population indicated variable but increasing resistance to pyrethroids (including alpha-cypermethrin, from > 85% mortality in 2017 to 7% mortality in 2018) and uniform susceptibility to PM (100% mortality in both years). Over the entire duration of the study, IRS reduced An. funestus s.l. densities by 48% (CI95 33-59%; p < 0.001) in indoor light traps and by 74% (CI95 38-90%; p = 0.010) during indoor and outdoor HLC, though in each study year reductions in vector density were consistently greatest in those months immediately following the IRS campaigns and waned over time. Overall there was no strong preference for An. funestus to feed indoors or outdoors, and these biting behaviours did not differ significantly across study arms: observed indoor-outdoor biting ratios were 1.10 (CI95 1.00-1.21) in no-IRS villages and 0.88 (CI95 0.67-1.15) in IRS villages. The impact of IRS was consistent in reducing HLC exposures both indoors (75% reduction: CI95 47-88%; p = 0. < 0.001) and outdoors (68% reduction: CI95 22-87%; p = 0.012). While substantially fewer Anopheles gambiae s.l. were collected during the study, trends show a similar impact of IRS on this key vector group as well, with a 33% (CI95 7-53%; p = 0.019) reduction in mosquitoes collected in light traps and a non-statistically significant 39% reduction (p = 0.249) in HLC landing rates. CONCLUSION: IRS with PM used in addition to pyrethroid-only LLINs substantially reduced human exposures to malaria vectors during both years of the cluster-randomized controlled trial in Mopeia-a high-burden district where the primary vector, An. funestus s.l., was equally likely to feed indoors or outdoors and demonstrated increasing resistance to pyrethroids. Findings suggest that IRS with PM can provide effective vector control, including in some settings where pyrethroid-only ITNs are widely used. Trial registration clinicaltrials.gov , NCT02910934. Registered 22 September 2016, https://www.clinicaltrials.gov/ct2/show/NCT02910934.


Assuntos
Inseticidas/farmacologia , Malária/prevenção & controle , Controle de Mosquitos/métodos , Mosquitos Vetores/efeitos dos fármacos , Compostos Organotiofosforados/farmacologia , Animais , Anopheles/efeitos dos fármacos , Entomologia/métodos , Monitoramento Ambiental/estatística & dados numéricos , Feminino , Humanos , Mosquiteiros Tratados com Inseticida , Moçambique , Propriedade/estatística & dados numéricos , Piretrinas/farmacologia
20.
Hepatology ; 73(1): 282-302, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32219872

RESUMO

BACKGROUND AND AIMS: Protein S-sulfhydration mediated by H2 S has been shown to play important roles in several diseases. However, its precise role in liver disease and the related mechanism remain unclear. APPROACH AND RESULTS: We showed that in streptozotocin (STZ)-treated and high-fat diet (HFD)-treated low-density lipoprotein receptor-negative (LDLr-/- ) mice, the H2 S donor GYY4137 ameliorated liver injury, decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, mitigated lipid deposition, and reduced hepatocyte death. Strikingly, S-sulfhydration of Kelch-like ECH-associated protein 1 (Keap1) was decreased in the livers of patients with fatty liver under diabetic conditions. In STZ+HFD-treated LDLr-/- mice and in high glucose-treated and oxidized low-density lipoprotein (ox-LDL)-treated primary mouse hepatocytes, the GYY4137-mediated increase in Keap1 S-sulfhydration induced nuclear erythroid 2-related factor 2 (Nrf2) dissociation from Keap1, which enhanced the nuclear translocation of Nrf2 itself and the consequent expression of antioxidant proteins. Keap1 Cys151 mutation significantly reduced Keap1 S-sulfhydration and abolished the hepatoprotective effects of H2 S both in vivo and in vitro. Nrf2 deficiency inhibited the H2 S-induced beneficial impacts in Nrf2-/- mice. Similarly, in CCl4 -stimulated mice, GYY4137 increased Keap1 S-sulfhydration, improved liver function, alleviated liver fibrosis, decreased hepatic oxidative stress, and activated the Nrf2 signaling pathway; and these effects were abrogated after Keap1 Cys151 mutation. Moreover, H2 S increased the binding of Nrf2 to the promoter region of LDLr-related protein 1 (Lrp1) and consequently up-regulated LRP1 expression, but these effects were disrupted by Keap1 Cys151 mutation. CONCLUSIONS: H2 S-mediated Keap1 S-sulfhydration alleviates liver damage through activation of Nrf2. Hence, administration of exogenous H2 S in the form of the H2 S donor GYY4137 may be of therapeutic benefit in the context of concurrent hyperlipidemia and hyperglycemia-induced or CCl4 -stimulated liver dysfunction.


Assuntos
Sulfeto de Hidrogênio/sangue , Sulfeto de Hidrogênio/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fígado/irrigação sanguínea , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Dieta Hiperlipídica , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Lipoproteínas LDL/farmacologia , Fígado/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Fator 2 Relacionado a NF-E2/deficiência , Fator 2 Relacionado a NF-E2/genética , Compostos Organotiofosforados/farmacologia , Compostos Organotiofosforados/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Estreptozocina
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