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1.
Biomed Res Int ; 2022: 7659765, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36132078

RESUMO

Background: The present study aimed to evaluate the effect of nanocurcumin and curcumin on liver transaminases, lipid profile, oxidant and antioxidant system, and pathophysiological changes in aluminium phosphide (ALP) induced hepatoxicity. Material and Methods. In this experimental study, thirty-six male Wistar rats were randomly divided into six groups curcumin (Cur), nanocurcumin (Nanocur), ALP, ALP+Cur, and ALP+Nanocur. All treatments were performed by oral gavage for seven days. After treatment, animals were sacrificed, and liver and blood samples were taken. Serum levels of aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (AP), total bilirubin, cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) were measured by photometric methods. Total antioxidant capacity (TAC) and malondialdehyde (MDA) as parameters of oxidative stress and mRNA expression of the nonenzyme protein including Sirtuin 1 (STR1), Forkhead box protein O1 (FOXO1) and protein O3 (FOXO3), catalase (CAT), and glutathione peroxidase (GPX) as the enzyme protein in homogenized tissues have been investigated. A histologist analyzed liver tissue sections after staining with hematoxylin-eosin. Results: In the aluminium phosphide group, there was a significant increase in MDA, ALT, AST, and AP and total bilirubin, cholesterol, triglyceride, LDL, and VLDL; AST, ALT, total bilirubin, LDL, VLDL, cholesterol, and MDA were significantly decreased; and HDL and TAC were significantly increased compared to ALP (P < 0.05). In the ALP+Nanocur group, ALT, AST, ALP, total bilirubin, cholesterol, LDL, VLDL, triglyceride, and MDA were significantly decreased and HDL and TAC were increased significantly (P < 0.05). The effect of nanocurcumin on controlling serum levels of LDL, VLDL, triglyceride, and MDA in ALP-poisoned rats was significantly more than curcumin (P < 0.05). The ALP group had significant changes in genes SIRT1, FOXO1a, FOXO3a, CAT, and GPX compared to healthy controls (P < 0.05). Nanocurcumin mice expressed more SIRT1, FOXO1a, CAT, and GPX genes than controls, and curcumin-treated mice expressed more SIRT1 and FOXO1a genes (P < 0.05). Histopathological findings also indicated a more significant protective effect of nanocurcumin relative to curcumin against ALP-induced hepatotoxicity. Conclusion: Nanocurcumin significantly protects the liver against aluminum phosphide toxicity. It is suggested that nanocurcumin-based drugs be developed to reduce the toxic effects of ALP in poisoned patients.


Assuntos
Antioxidantes , Curcumina , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Compostos de Alumínio , Animais , Antioxidantes/farmacologia , Aspartato Aminotransferases , Bilirrubina/metabolismo , Catalase/metabolismo , LDL-Colesterol/metabolismo , Curcumina/metabolismo , Curcumina/farmacologia , Amarelo de Eosina-(YS)/metabolismo , Proteína Forkhead Box O1/metabolismo , Glutationa Peroxidase/metabolismo , Hematoxilina/metabolismo , Lipoproteínas HDL , Lipoproteínas VLDL/metabolismo , Lipoproteínas VLDL/farmacologia , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Oxidantes/metabolismo , Estresse Oxidativo , Fosfinas , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Sirtuína 1/metabolismo , Triglicerídeos/metabolismo
2.
Int J Mol Sci ; 23(15)2022 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-35955910

RESUMO

Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM). Studies have also shown that canagliflozin directly acts on endothelial cells (ECs). Since heme oxygenase-1 (HO-1) is an established modulator of EC function, we investigated if canagliflozin regulates the endothelial expression of HO-1, and if this enzyme influences the biological actions of canagliflozin in these cells. Treatment of human ECs with canagliflozin stimulated a concentration- and time-dependent increase in HO-1 that was associated with a significant increase in HO activity. Canagliflozin also evoked a concentration-dependent blockade of EC proliferation, DNA synthesis, and migration that was unaffected by inhibition of HO-1 activity and/or expression. Exposure of ECs to a diabetic environment increased the adhesion of monocytes to ECs, and this was attenuated by canagliflozin. Knockdown of HO-1 reduced the anti-inflammatory effect of canagliflozin which was restored by bilirubin but not carbon monoxide. In conclusion, this study identified canagliflozin as a novel inducer of HO-1 in human ECs. It also found that HO-1-derived bilirubin contributed to the anti-inflammatory action of canagliflozin, but not the anti-proliferative and antimigratory effects of the drug. The ability of canagliflozin to regulate HO-1 expression and EC function may contribute to the clinical profile of the drug.


Assuntos
Diabetes Mellitus Tipo 2 , Heme Oxigenase-1 , Bilirrubina/metabolismo , Canagliflozina/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo
3.
Oxid Med Cell Longev ; 2022: 1735204, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35923861

RESUMO

We verified whether caffeinated coffee consumption influenced the concentrations of prolactin (PRL) and oxidative stress parameters: total antioxidant status (TAS), ferric reducing antioxidant power (FRAP), total oxidant status (TOS), oxidative stress index (OSI), advanced oxidation protein products (AOPP), uric acid (UA), total bilirubin (T-Bil), albumin (ALB), iron (Fe), calcium (Ca), magnesium (Mg), and inflammatory marker C-reactive protein (CRP)-in blood sera obtained at 15, 60, and 120 minutes after caffeinated coffee intake, in relation to the fasting point. The study participants were 33 young, healthy, nonsmoking volunteers (15 men, 18 women) aged 19-29 years. PRL concentrations significantly decreased (p < 0.05) after consumption, except at time point 15' in men (p > 0.05). In women, FRAP levels significantly increased over time, and significant changes were also observed for UA at 120' and ALB at 15'. In men, significant changes were found for levels of AOPP at 15', T-Bil and ALB at 15', iron at 60' and 120', and calcium at 120'. There were no significant differences in the levels of other examined parameters between the defined time points. In conclusion, the substances contained in caffeinated coffee decrease the level of prolactin and may also have an impact on selected parameters of oxidative stress, which could be the basis of future research focused on the identification of new therapeutic targets.


Assuntos
Antioxidantes , Café , Adulto , Produtos da Oxidação Avançada de Proteínas/metabolismo , Antioxidantes/metabolismo , Bilirrubina/metabolismo , Cálcio/metabolismo , Feminino , Humanos , Ferro , Masculino , Estresse Oxidativo , Prolactina/metabolismo , Ácido Úrico , Adulto Jovem
4.
Biomed Res Int ; 2022: 4949148, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36017390

RESUMO

Objective: The aims of this study were to investigate the impact of TAK-242 on the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear transcription factor-κB (NF-κB) signal transduction pathway in rats with hepatic fibrosis (HF) using the liver gut axis and to investigate the molecular mechanism of its intervention on HF. Methods: SPF grade SD male rats were randomly allocated to the control, model, and TAK-242 groups. For 8 weeks, the model and TAK-242 groups received 3 mL·kg-1 (the initial dose 5 mL·kg-1) intraperitoneal injections of 40% CCL4 olive oil solution. TAK-242 (5 mg·kg-1) was administered once a day for 5 days after modeling. The pathological alterations of liver and small intestine tissues in each group were observed using H&E and Masson staining. ELISA was used to measure serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin (DBIL), total bilirubin (TBIL), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). RT-qPCR was utilized to identify the mRNA expression level of IL-1ß, IL-6, TNF-α, TLR4, MyD88, and NF-κB in rat liver and small intestine tissues. The protein level of IL-1ß, IL-6, TNF-α, TLR4, MyD88, and NF-κB protein in rat liver and small intestine tissues was determined utilizing Western blot and IHC. Results: TAK-242 significantly reduced AST, ALT, TBIL, and DBIL expression in HF rats' serum (P < 0.01) and alleviated liver tissue injury. Hematoxylin-eosin (H&E) and Masson staining revealed inflammatory cell infiltration and fibrous proliferation in the liver and small intestine tissue in the model group and partial cell swelling in the TAK-242 group, which indicated a considerable improvement compared to the model group. RT-qPCR, Western blot, and IHC data indicated that TAK-242 reduced the IL-1ß, IL-6, TNF-α, TLR4, MyD88, and NF-κB expression in the liver and small intestine tissues of HF rats. Conclusion: TAK-242 might downregulate the TLR4/MyD88/NF-κB signal pathway through the liver-gut axis, suppress the inflammatory response, and eventually alleviate HF in rats.


Assuntos
Fator 88 de Diferenciação Mieloide , Receptor 4 Toll-Like , Animais , Bilirrubina/metabolismo , Interleucina-6/metabolismo , Cirrose Hepática/patologia , Masculino , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Ratos , Sulfonamidas , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
5.
J Oleo Sci ; 71(9): 1327-1335, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35965085

RESUMO

Hepatocellular Carcinoma (HCC) is the 5th most common type of cancer in all types of cancers, globally. It is well known that the frequency of inflammatory reaction and oxidative stress increases during the HCC. The goal of this study was to see if decalactone could prevent rats against HCC caused by diethylnitrosamine (DEN). Single intraperitoneal administration of DEN (200 mg/kg) used as inducer and weekly intraperitoneal injection of phenobarbital (8 mg/kg) was used as promotor for induction the HCC in rats. Serum alpha fetoprotein (AFP) was used for the confirmation of HCC. Different doses of decalactone (5, 10 and 15 mg/kg) were orally administered to the rats. The body weight was determined at regular time. The hepatic, non-hepatic, antioxidant markers and inflammatory mediators were scrutinized. All groups of animals were scarified and macroscopically examination of the liver tissue was performed and the weight of organ (hepatic tissue) were estimated. Decalactone increased body weight while also suppressing hepatic nodules and tissue weight. Decalactone treatment reduced AFP, total bilirubin, and direct bilirubin levels while increasing albumin and total protein levels in a dose-dependent manner. Decalactone reduced lipid peroxidation (LPO) and increased catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), and superoxide dismutase (SOD) levels significantly (p < 0.001) (SOD). Decalactone lowered the levels of significantly (p < 0.001) inflammatory cytokines and inflammatory markers in the liver. Based on the findings, we may conclude that decalactone inhibited HCC in DEN-induced HCC animals via reducing oxidative stress and inflammatory mediators.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Antioxidantes/uso terapêutico , Bilirrubina/metabolismo , Bilirrubina/farmacologia , Bilirrubina/uso terapêutico , Peso Corporal , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/prevenção & controle , Dietilnitrosamina/metabolismo , Dietilnitrosamina/toxicidade , Glutationa/metabolismo , Mediadores da Inflamação/metabolismo , Fígado/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Estresse Oxidativo , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , alfa-Fetoproteínas/metabolismo , alfa-Fetoproteínas/farmacologia , alfa-Fetoproteínas/uso terapêutico
6.
Molecules ; 27(14)2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35889371

RESUMO

The current study was conducted to exemplify the effect of debelalactone on tissue protection, chronic hepatic inflammation, hepatic protection and oxidative stress induced by diethyl nitrosamine in Wistar rats. Therefore, DEN (200 mg/kg) was used for the induction the hepatocellular carcinoma (HCC) and the level of serum alpha fetoprotein was used for the estimation and confirmation of HCC. The study illustrated that debelalactone (DL) significantly downregulated the hepatic, non-hepatic parameters such as aspartate aminotransferase, alanine aminotransferase, alpha fetoprotein, NO levels, total protein, albumin, blood urea nitrogen, total bilirubin, and direct bilirubin in dose dependent manner, as well as noticeably improving the body weight, of treated animals. The macroscopically observation of DEN-induced rat liver showed the formation of informalities in liver tissue, which was reduced with treatment of DL at dose dependent manner. However, antioxidant markers and inflammatory mediators such as lipid peroxidation, catalase, superoxide dismutase, glutathione peroxidase and transferase, TNF-α, IL-1ß, IL-6, and NF-kB restored up to the normal level by DL. The histopathology studies showed that the treated group of animals returned to a normal status. Collectively, it can be concluded that debelalactone mediated chemoprevention in the DEN-induced rats via an increase in the activities of endogenous enzymes and/or inhibition the precancerous cells.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Antioxidantes/metabolismo , Bilirrubina/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Furocumarinas , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Peroxidação de Lipídeos , Fígado , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar , alfa-Fetoproteínas
7.
Bone ; 162: 116483, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35787483

RESUMO

Bilirubin and bile acids have deleterious effects on osteoblasts, which may explain the low bone formation of liver diseases with cholestasis. Although there is some clinical evidence of increased bone resorption in this condition, the effects of these substances on osteoclasts are unknown. The objective was to analyze the effects of bilirubin and bile acids -lithocholic acid (LCA) and ursodeoxycholic acid (UDCA)- on osteoclast viability and apoptosis, and on the expression of osteoclast-related microRNAs (miRNAs). RAW 264.7 cells and human PBMCs were differentiated into osteoclasts. Success in differentiation was assessed by TRAP stain and osteoclast-specific gene expression; osteoclast activity was detected by the resorption pits in Corning® Osteo Assay Surface Plates. Cells were treated with camptothecin (CAM) or with bilirubin, LCA or UDCA, at several concentrations and combinations, including non-treated cells as control. Cell viability was measured using WST-1 assay and apoptosis assessing Caspase-3 by Western blot. Expression of miR-21a, miR-29b, miR-31, miR-148a, miR-155 and miR-223 were analyzed by Real Time. Viability increased gradually in osteoclasts differentiated from RAW 264.7 cells, as the concentration of bilirubin increased, being particularly high with bilirubin 100 µM (61 %) as compared to the untreated control (p < 0.007). Viability decreased significantly with CAM, LCA and UDCA (80 %, 62 % and 27 %, respectively), effects which were abolished by bilirubin. Moreover, bilirubin increased viability in osteoclasts derived from human PBMCs (p < 0.03). Caspase-3 decreased by 46 % with bilirubin 50 µM and increased 10-fold with LCA 100 µM and CAM (p < 0.01). Bilirubin increased miR-21 and miR-148a expression as compared to controls (115 % and 59 %, respectively; p < 0.007). In conclusion, bilirubin increases viability and decreases apoptosis of osteoclasts, and overexpresses the osteoclastogenic miR-21 and miR-148a. The effects of bilirubin counteract the actions of LCA and UDCA. Therefore, bilirubin may contribute to the increased bone resorption and to the development of osteoporosis in advanced liver diseases.


Assuntos
Reabsorção Óssea , Hepatopatias , MicroRNAs , Osteoporose , Apoptose , Ácidos e Sais Biliares/metabolismo , Ácidos e Sais Biliares/farmacologia , Bilirrubina/metabolismo , Bilirrubina/farmacologia , Reabsorção Óssea/metabolismo , Caspase 3/metabolismo , Diferenciação Celular , Humanos , Hepatopatias/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Osteoclastos/metabolismo , Osteoporose/genética , Ligante RANK/metabolismo
8.
Sci Rep ; 12(1): 11798, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35821401

RESUMO

Lumirubin is the most prevalently excreted hydrophilic bilirubin photoisomer in phototherapy for neonatal jaundice caused by excess hydrophobic unconjugated bilirubin (ZZ-bilirubin). We developed a simple method to estimate the amount of lumirubin by monitoring the reverse photoisomerization of lumirubin to ZZ-bilirubin. Although lumirubin formation was long considered irreversible, exposure to blue light in the presence of the fluorescent protein UnaG, which binds specifically and tightly to ZZ-bilirubin, enables the reverse photoisomerization of lumirubin. This reaction was first detected using a fluorescence assay of neonatal urine sampled during phototherapy and purified lumirubin. The phenomenon of reverse photoisomerization of lumirubin was validated using liquid chromatography-mass spectrometry, which confirmed that lumirubin is reconverted to ZZ-bilirubin in the presence of UnaG. Analyses of 20 urine samples from 17 neonates revealed a significant correlation (correlation coefficient [r] = 0.978; 95% confidence interval 0.867-0.979; P < .001) between lumirubin and ZZ-bilirubin concentration before and after reverse photoisomerization. In general, the rate of photo-reconversion of lumirubin to ZZ-bilirubin is approximately 40%. In conclusion, we demonstrate here that lumirubin can be photo-reconverted to ZZ-bilirubin via exposure to blue light in the presence of UnaG. Utilizing this approach, urinary lumirubin levels can be estimated using an easy-to-perform fluorescence assay.


Assuntos
Icterícia Neonatal , Bilirrubina/metabolismo , Humanos , Recém-Nascido , Icterícia Neonatal/terapia , Luz , Espectrometria de Massas , Fototerapia/métodos
9.
Biomed Chromatogr ; 36(11): e5469, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35904380

RESUMO

Silybin, an active component in the plant Silybum marianum (L.) Gaertn., is commonly used to protect against liver disease. We investigated silybin's protective potential in rat liver against emodin-induced liver injury 4 weeks. It was found that aspartate aminotransferase and direct bilirubin serum biomarkers for liver toxicity significantly increased, and liver histopathology revealed cholestasis and necrosis in rats administered emodin alone, whereas aspartate aminotransferase and total bile acid levels in rats administered emodin and silybin simultaneously were changed compared to rats administered emodin alone. Liver mRNA and protein levels of Cyp7a1-which plays roles in cholesterol metabolism and bile acid synthesis-and Abcb11 (Bsep)-which facilitates bile salt secretion in hepatocyte canaliculi-were significantly altered with emodin, whereas cotreatment with silybin attenuated emodin's adverse effect. Metabolomic analysis using ultra-performance liquid chromatography-quadrupole-time-of-flight-mass spectrometry determined eight potential metabolite biomarkers in serum, urine, and liver tissue. Network analysis was conducted to conceptualize the interplay of genes, metabolites, and metabolic pathways for cholesterol metabolism and bile acid synthesis for liver injury. Overall, rats administered only emodin were shown to be a sound model to investigate fat-associated drug-induced hepatoxicity or liver injury and cotreatment of emodin with silybin prevents fatty liver injury. This metabolomic study revealed that emodin-induced fatty liver injury disrupted bile acid synthesis, vitamin B6 , and glycerophospholipid metabolism pathways and that silybin ameliorates liver injury on these compromised pathways.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Emodina , Fígado Gorduroso , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Animais , Aspartato Aminotransferases , Ácidos e Sais Biliares/metabolismo , Bilirrubina/metabolismo , Bilirrubina/farmacologia , Biomarcadores/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Colesterol , Cromatografia Líquida , Emodina/metabolismo , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Glicerofosfolipídeos/metabolismo , Fígado/metabolismo , Espectrometria de Massas , RNA Mensageiro/metabolismo , RNA Mensageiro/farmacologia , Ratos , Silibina/metabolismo , Silibina/farmacologia , Vitaminas/metabolismo , Vitaminas/farmacologia
10.
Sheng Wu Gong Cheng Xue Bao ; 38(7): 2581-2593, 2022 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-35871626

RESUMO

Biliverdin is an important cellular antioxidant. Traditionally, biliverdin is produced by chemical oxidation of bilirubin, which is a complex process and the final product is of low purity. Here we report an efficient, green and safe process for biotechnological production of biliverdin. A heme oxygenase (HO) gene from Clostridium tetani was screened, and a recombinant strain Escherichia coli BL21/pETDuet-hoCt with the ability of transforming heme into biliverdin was constructed. A biliverdin yield of 32.9 mg/L from 100 mg/L substrate was achieved under pH 7.0 and 35 ℃. In order to improve the supply of reducing power, an NADPH regeneration system using glutamate dehydrogenase (GdhA) was constructed, resulting in a recombinant strain E. coli BL21/pETDuet-gdhAEc-hoCt which was capable of producing 71.5 mg/L biliverdin. Moreover, through introduction of a membrane surface display system, a recombinant strain E. coli BL21/pETDuet-gdhAEc-blc/hoCt was constructed to shorten the transformation time, and the production of biliverdin was further increased to 76.3 mg/L, this is the highest titer of biosynthesized biliverdin reported to date, and the research may thus facilitate the green production of biliverdin.


Assuntos
Biliverdina , Escherichia coli , Bilirrubina/metabolismo , Biliverdina/genética , Biliverdina/metabolismo , Biocatálise , Escherichia coli/genética , Escherichia coli/metabolismo , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo
11.
Int J Mol Sci ; 23(13)2022 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-35806040

RESUMO

Heme oxygenase (HO) has both beneficial and detrimental effects via its metabolites, including carbon monoxide (CO), biliverdin or bilirubin, and ferrous iron. HO-1 is an inducible form of HO that is upregulated by oxidative stress, nitric oxide, CO, and hypoxia, whereas HO-2 is a constitutive form that regulates vascular tone and homeostasis. In brains injured by trauma, ischemia-reperfusion, or Alzheimer's disease (AD), the long-term expression of HO-1 can be detected, which can lead to cytotoxic ferroptosis via iron accumulation. In contrast, the transient induction of HO-1 in the peri-injured region may have regenerative potential (e.g., angiogenesis, neurogenesis, and mitochondrial biogenesis) and neurovascular protective effects through the CO-mediated signaling pathway, the antioxidant properties of bilirubin, and the iron-mediated ferritin synthesis. In this review, we discuss the dual roles of HO-1 and its metabolites in various neurovascular diseases, including age-related macular degeneration, ischemia-reperfusion injury, traumatic brain injury, Gilbert's syndrome, and AD.


Assuntos
Heme Oxigenase (Desciclizante) , Heme Oxigenase-1 , Bilirrubina/metabolismo , Biliverdina/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Ferro/metabolismo
12.
Braz J Biol ; 84: e258234, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35830129

RESUMO

The present work was showed to assess the effect of administration of rosemary extract on etoposide-induced toxicity, injury and proliferation in male rats were investigated. Forty male albino rats were arranged into four equal groups. 1st group, control; 2nd group, etoposide; 3rd group, co-treated rosemary & etoposide; 4th group, rosemary alone. In comparison to the control group, etoposide administration resulted in a significant increase in serum ALT, AST, ALP, total bilirubin, total protein, and gamma GT. In contrast; a significant decrease in albumin level in etoposide group as compared to G1. G3 revealed a significant decrease in AST, ALT, ALP, total protein and total bilirubin levels and a significant rise in albumin level when compared with G2. Serum levels of urea, creatinine, potassium ions, and chloride ions significantly increased; while sodium ions were significantly decreased in G2 when compared with G1. Also, there was an increase of MDA level for etoposide treated group with corresponding control rats. However, there was a remarkable significant decrease in SOD, GPX and CAT levels in G2 as compared to G1. There was a significant increase in serum hydrogen peroxide (H2O2) and Nitric oxide (NO) levels in group treated with etoposide when compared to control group. It was noticeable that administrated by rosemary alone either with etoposide had not any effect on the levels of H2O2 and Nitric oxide. Serum level of T3 and T4 was significantly increased in etoposide-administered rats in comparison with G1. The administration of rosemary, either alone or with etoposide, increased the serum levels of T3 and T4 significantly when compared to control rats. The gene expression analysis showed significant downregulation of hepatic SOD and GPx in (G2) when compared with (G1). The treatment with rosemary extract produced significant upregulation of the antioxidant enzymes mRNA SOD and GPx. MDA gene was increased in (G2) when contrasted with (G1). Treatment of the etoposide- induced rats with rosemary extract delivered significant decrease in MDA gene expression when compared with etoposide group. Rats treated with etoposide showed significant decline in hepatic Nrf2 protein expression, when compared with G1. While, supplementation of Etoposide- administered rats with the rosemary produced a significant elevation in hepatic Nrf2 protein levels. Additionally, the liver histological structure displayed noticeable degeneration and cellular infiltration in liver cells. It is possible to infer that rosemary has a potential role and that it should be researched as a natural component for etoposide-induced toxicity protection.


Assuntos
Rosmarinus , Albuminas/metabolismo , Albuminas/farmacologia , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Bilirrubina/metabolismo , Bilirrubina/farmacologia , Etoposídeo/metabolismo , Etoposídeo/toxicidade , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico/farmacologia , Estresse Oxidativo , Extratos Vegetais/farmacologia , Ratos , Rosmarinus/química , Rosmarinus/metabolismo , Superóxido Dismutase/metabolismo , Superóxido Dismutase/farmacologia
13.
Front Public Health ; 10: 888331, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757614

RESUMO

Background: Sleep deprivation and poor sleep quality contribute to increases in oxidative stress, antioxidant imbalance, and a pro-inflammatory state which may predispose to a higher risk of diabetes. Our objective was to estimate the contributions of C-reactive protein (CRP), gamma glutamyl transferase (GGT), and micronutrient antioxidants (bilirubin, carotenoids, uric acid, vitamins A, C-E?) to the relationships between sleep-fasting insulin concentration and -glycosylated hemoglobin (HbA1c). Methods: Data from the 2005/06 US National Health and Nutritional Examination Survey were used (N = 1,946; 20 y+). Sleep quality and quantity was assessed by the Sleep Disorders Questionnaire, and fasting blood was collected to quantify CRP, GGT, antioxidant micronutrients, insulin concentration, and HbA1c. The bootstrap method was used to estimate the amount of mediation or contribution of these mediators to the sleep-insulin concentration and -HbA1c relationships, which were quantified as large (≥0.25) or moderate (≥0.09). Results: The sleep duration-fasting insulin relationship was mediated by GGT, carotenoids, uric acid, and vitamins C and D, whereas CRP and bilirubin were non-significant mediators of a moderate effect size. Similarly, the sleep quality-fasting insulin relationship was mediated by CRP, bilirubin and vitamin C, whereas GGT, carotenoids, uric acid, and vitamin D were non-significant large-to-moderate mediators. To a lesser degree, these micronutrients mediated for the relationship between sleep-HbA1c levels. Conclusion: Several factors related to inflammation, oxidative stress, and antioxidant status were found to lie on the pathway of the sleep-insulin and -glycemic control relationships. Sleep hygiene, reduced systemic inflammation/oxidative stress, and optimal antioxidants intake are potentially beneficial targets for managing diabetes risk.


Assuntos
Diabetes Mellitus , Resistência à Insulina , Antioxidantes/metabolismo , Bilirrubina/metabolismo , Proteína C-Reativa , Carotenoides/metabolismo , Hemoglobina A Glicada/metabolismo , Humanos , Inflamação , Insulina/metabolismo , Micronutrientes , Estresse Oxidativo , Sono , Ácido Úrico , Vitaminas
14.
Am J Chin Med ; 50(5): 1331-1348, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35729506

RESUMO

The pathological mechanism of cholestatic hepatic injury is associated with oxidative stress, hepatocyte inflammation, and dysregulation of hepatocyte transporters. Paeonia lactiflora Pall. and its compound can improve hepatic microcirculation, dilate bile duct, and promote bile flow, which is advantageous to ameliorate liver damage. Paeoniflorin (PEA), as the main efficacy component of Paeonia lactiflora Pall., has multiple pharmacological effects. PEA improves liver injury, but it remains obscure whether the protective action on [Formula: see text]-naphthalene isothiocyanate (ANIT)-induced cholestatic liver injury is dependent on the NF-E2 p45-related Factor 2 (Nrf2) signaling pathway. In this study, C57BL/6 mice were administrated with 80 mg⋅kg[Formula: see text]⋅d[Formula: see text] ANIT followed by PEA (75, 150, and 300 mg⋅kg[Formula: see text]⋅d[Formula: see text]) orally for 10 days, respectively. Tissue histology and liver function were detected, including serum enzymes, gallbladder (GB) weight, phenobarbital-induced sleeping time (PEN-induced ST), hepatic uridine di-phosphoglucuronosyltransferase (UDPG-T), malondialdehyde (MDA), and glutathione (GSH). The expressions of protein Nrf2, sodium taurocholate cotransporting polypeptide (Ntcp), and NADPH oxidase 4 (Nox4) were evaluated. Nrf2 plasmid or siRNA-Nrf2 transfection on LO2 cells and Nrf2-/- mice were used to explore the liver protective mechanism of PEA. Compared to ANIT-treated mice, PEA decreased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), direct bilirubin (DBIL), total bile acid (TBA), and phenobarbital-induced sleeping time. The bile secretion, hepatic UDPG-T, MDA, GSH, and liver histology were improved. The expressions of protein Nrf2 and Ntcp in liver tissues increased, but Nox4 decreased. After Nrf2 plasmid or small interfering RNA (siRNA)-Nrf2 transfection, the protective effects of PEA on LO2 cells were, respectively, strengthened or weakened. Moreover, PEA had no significant effects on ANIT-treated Nrf2-/- mice. Our results suggest that Nrf2 is essential for PEA protective effects on ANIT-induced liver injury.


Assuntos
Colestase , Paeonia , 1-Naftilisotiocianato/toxicidade , Animais , Bilirrubina/metabolismo , Colestase/metabolismo , Glucosídeos , Glutationa/metabolismo , Isotiocianatos/farmacologia , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Monoterpenos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fenobarbital/efeitos adversos , RNA Interferente Pequeno/metabolismo , Uridina Difosfato Glucose/metabolismo , Uridina Difosfato Glucose/farmacologia , Uridina Difosfato Glucose/uso terapêutico
15.
Acta Histochem ; 124(6): 151918, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35724482

RESUMO

BACKGROUND AND PURPOSE: Hyperbilirubinemia is a common condition in neonates that is associated with poor neurodevelopmental outcomes. Although studies have proposed that calycosin has a neuroprotective effect, the exact molecular mechanism underlying calycosin treatment of hyperbilirubinemia remains elusive. To fill this gap, we analyzed the mechanism of calycosin treatment in hyperbilirubinemia model mice. METHOD: Thirty neonatal mice were randomly divided into wide type (WT), Ugt1-/- and calycosin treatment group. Neuronal damage was observed with Nissl staining. Immunofluorescence staining were carried out to determine DNA damage repair and neurodegeneration. Oxidative stress was investigated by immunostaining with 4-hydroxynonenal (4-HNE). Western blot (WB) and Qpcr were used to detect relative protein and mRNA expression levels. Mitochondrial CI/CII activity of mitochondria was analyzed with a spectrophotometer. RESULT: The total bilirubin concentration was significantly higher in Ugt1-/- group compared with WT, but calycosin treatment reduced concentration of bilirubin. The total bilirubin and bilirubin/albumin ratio were significantly higher at postnatal day 4 compared with day 2. Calycosin treatment reduced serum bilirubin concentration and bilirubin/albumin ratio. After calycosin treatment, Nissl body count increased, apoptosis-related protein was downregulated and 4-HNE level decreased. Compared with Ugt-/- group, calycosin treatment increased neurons (NeuN+) and calbindin positive cells and decreased fluorojade C(FJC)positive neurons in WT group. In mitochondria, calycosin alleviated mitochondrial electron transport chain dysfunction in Ugt1-/- mice. CONCLUSION: We demonstrated that the mechanism of calycosin treatment on hyperbilirubinemia-induced Ugt1-/- was associated mainly with antioxidant effects, antiapoptosis and inhibition of normal mitochondrial function.


Assuntos
Glucuronosiltransferase , Hiperbilirrubinemia , Albuminas/metabolismo , Albuminas/farmacologia , Animais , Apoptose , Bilirrubina/metabolismo , Bilirrubina/farmacologia , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Glucuronosiltransferase/farmacologia , Hiperbilirrubinemia/complicações , Hiperbilirrubinemia/metabolismo , Isoflavonas , Camundongos , Mitocôndrias/metabolismo , Estresse Oxidativo
16.
Int J Mol Sci ; 23(11)2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35682565

RESUMO

Sallow and/or dull skin appearance is greatly attributable to the yellow components of skin tone. Bilirubin is a yellow chromophore known to be made in the liver and/or spleen and is transported throughout the body via the blood stream. Recent publications suggest bilirubin may be synthesized in other cells/organs, including the skin. We found human keratinocytes express the transcripts involved in bilirubin biosynthesis. In parallel, we also found human keratinocytes could indeed synthesize bilirubin in monolayer keratinocytes and in a 3D human skin-equivalent model. The synthesized amount was substantial enough to contribute to skin yellowness. In addition, oxidative stress enhanced bilirubin production. Using UnaG, a protein that forms a fluorescent species upon binding to bilirubin, we also visualized the intracellular expression of bilirubin in keratinocytes. Finally, we screened a compound library and discovered that the sucrose laurate/dilaurate (SDL) combination significantly reduced bilirubin levels, as well as bilirubin-mediated yellowness. In conclusion, bilirubin is indeed synthesized in epidermal keratinocytes and can be upregulated by oxidative stress, which could contribute to chronic or transient yellow skin tone appearance. Application of SDL diminishes bilirubin generation and may be a potential solution to mitigate yellowish and/or dull skin appearance.


Assuntos
Bilirrubina , Queratinócitos , Bilirrubina/metabolismo , Bilirrubina/farmacologia , Epiderme/metabolismo , Humanos , Queratinócitos/metabolismo , Pele/metabolismo , Sacarose/análogos & derivados
17.
Trop Anim Health Prod ; 54(4): 217, 2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35759058

RESUMO

The study aimed at determining the effect of Pleurotus tuber-regium-treated cassava root sievate-based diets on haematology and serum biochemistry of West African Dwarf (WAD) goats. Thirty-two WAD goats between 6 and 8 months old were randomly divided into four groups of eight goats each. The four experimental diets were formulated to contain 0, 20, 40 and 60% dietary levels of inclusion of Pleurotus tuber-regium-treated cassava root sievate, respectively. The groups were randomly assigned to the four experiment diets (T1, T2, T3 and T4) for 90 days in a completely randomized design. At the start of the experiment, packed cell volume (PCV) ranged from 24.90 to 29.49% and red blood cell (RBC) 9.42-10.44 × 10 12/L while mean cell haemoglobin significantly (p < 0.05) ranged from 5.44 to 6.41 pg. At the end of the experiment, PCV and RBC showed significant differences (p < 0.05) and were better in T2. At the start of the experiment, cholesterol ranged from 2.15 to 2.29 mmol/l, creatinine from 75.72 to 80.32 µmol/l, urea from 16.39 to 16.72 mg/dl, total bilirubin from 0.25 to 0.28 µmol/l, total protein from 61.73 to 63.16 g/I, globulin from 29.08 to 29.59 g/I and aspartate aminotransferase (AST) from 68.62 to 71.06 U/L. At the end of the trial, cholesterol values were significantly (p < 0.05) higher in T1. Urea was significantly reduced (p < 0.05) with T1 showing significantly higher values than T3 and T4. Total protein, globulin and total bilirubin increased (p < 0.05) linearly from T1 to T4. AST was improved (p < 0.05) at the end of the study. The study revealed that the inclusion of Pleurotus tuber-regium-degraded cassava root sievate in the diets of West African Dwarf goats had no deleterious effects on the haematological and serum biochemical parameters of goats and could be included in goat diets up to 60%.


Assuntos
Hematologia , Manihot , Animais , Bilirrubina/metabolismo , Dieta/veterinária , Cabras/metabolismo , Pleurotus , Ureia/metabolismo
18.
J Complement Integr Med ; 19(3): 599-606, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35751565

RESUMO

OBJECTIVES: Favism is a metabolic disease and this study aimed to compare between olive oil and almond oil to ameliorate blood parameters, liver function, blood and liver antioxidants and DNA, and liver histology in favism rats. METHODS: Animals were 36 male albino rats. They classified to 2 equal (normal and favism) groups. Normal group classified to 3 equal subgroups; Control, Olive oil, and Almond oil subgroups: normal rats orally administrated with 1 mL/100 g of saline, olive oil, and almond oil, respectively. Favism group was subdivided into 3 equal subgroup; favism, favism + olive oil, and favism + almond oil subgroups: favism rats orally administrated with no treatment, 1 mL/100 g olive oil, and 1 mL/100 g almond oil, respectively. All treatments were administrated orally by oral gavage once a day for 1 month. RESULTS: The hemoglobin, hematocrite, the blood cells, glucose and glucose-6-phosphate dehydrogenase, aspartate and alanine aminotransferase, total proteins, albumin, and globulin in serum were decreased in favism. The glutathione, superoxide dismutase, and glutathione peroxidase in blood and liver were decreased in favism while alkaline phosphatase and total bilirubin in serum were increased in favism. The blood and liver malondialdehyde was increased in favism. Furthermore, oral administration with both oils in favism rats restored all these parameters to be approached the control levels. Also, both oils preserved blood and liver DNA and liver histology. CONCLUSIONS: Almond oil restored blood parameters, liver function, blood and liver antioxidants and DNA, and liver histology more efficiently than olive oil in favism.


Assuntos
Antioxidantes , Favismo , Alanina Transaminase , Albuminas/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Ácido Aspártico/metabolismo , Bilirrubina/metabolismo , DNA/metabolismo , Glucose/metabolismo , Glucosefosfato Desidrogenase/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Azeite de Oliva/metabolismo , Estresse Oxidativo , Óleos Vegetais/farmacologia , Superóxido Dismutase/metabolismo
19.
Fluids Barriers CNS ; 19(1): 47, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35672829

RESUMO

BACKGROUND: Severe neonatal jaundice resulting from elevated levels of unconjugated bilirubin in the blood induces dramatic neurological impairment. Central oxidative stress and an inflammatory response have been associated with the pathophysiological mechanism. Cells forming the blood-brain barrier and the choroidal blood-CSF barrier are the first CNS cells exposed to increased plasma levels of unconjugated bilirubin. These barriers are key regulators of brain homeostasis and require active oxidative metabolism to fulfill their protective functions. The choroid plexus-CSF system is involved in neuroinflammatory processes. In this paper, we address the impact of neonatal hyperbilirubinemia on some aspects of brain barriers. We describe physiological changes in the neurovascular network, blood-brain/CSF barriers integrities, and CSF cytokine levels during the postnatal period in normobilirubinemic animals, and analyze these parameters in parallel in Gunn rats that are deficient in bilirubin catabolism and develop postnatal hyperbilirubinemia. METHODS: Gunn rats bearing a mutation in UGT1a genes were used. The neurovascular network was analyzed by immunofluorescence stereomicroscopy. The integrity of the barriers was evaluated by [14C]-sucrose permeability measurement. CSF cytokine levels were measured by multiplex immunoassay. The choroid plexus-CSF system response to an inflammatory challenge was assessed by enumerating CSF leukocytes. RESULTS: In normobilirubinemic animals, the neurovascular network expands postnatally and displays stage-specific regional variations in its complexity. Network expansion is not affected by hyperbilirubinemia. Permeability of the blood-brain and blood-CSF barriers to sucrose decreases between one- and 9-day-old animals, and does not differ between normobilirubinemic and hyperbilirubinemic rats. Cytokine profiles differ between CSF and plasma in all 1-, 9-, and 18-day-old animals. The CSF cytokine profile in 1-day-old animals is markedly different from that established in older animals. Hyperbilirubinemia perturbs these cytokine profiles only to a very limited extent, and reduces CSF immune cell infiltration triggered by systemic exposure to a bacterial lipopeptide. CONCLUSION: The data highlight developmental specificities of the blood-brain barrier organization and of CSF cytokine content. They also indicate that a direct effect of bilirubin on the vascular system organization, brain barriers morphological integrity, and inflammatory response of the choroid plexus-CSF system is not involved in the alteration of brain functions induced by severe neonatal jaundice.


Assuntos
Barreira Hematoencefálica , Icterícia Neonatal , Animais , Bilirrubina/metabolismo , Barreira Hematoencefálica/metabolismo , Líquido Cefalorraquidiano/metabolismo , Plexo Corióideo/metabolismo , Citocinas/metabolismo , Humanos , Hiperbilirrubinemia/metabolismo , Recém-Nascido , Icterícia Neonatal/metabolismo , Ratos , Ratos Gunn , Sacarose
20.
J Tissue Viability ; 31(3): 474-484, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35595596

RESUMO

AIM OF THE STUDY: The study was performed to understand the detailed mechanism of diabetic wound healing by bilirubin-deferoxamine (DFO) combination on topical application. MATERIALS AND METHODS: There were two study groups, control, and treatment. The granulation tissues collected on different days (3, 7, 14, and 19) were studied in detail for inflammatory mediators, angiogenesis markers, epithelialization, and oxidative stress parameters. RESULTS: A significant increase in wound contraction percentage was observed from day 7 in the bilirubin-DFO treatment group. The combinatorial treatment significantly reduced tumour necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß), and enhanced IL-10 levels. Upregulated mRNAs of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 alpha (HIF-1 α) along with CD31 immunohistochemistry showed the pro-angiogenesis potential of the combination. Hematoxylin and Eosin (H and E) staining and Masson's trichrome staining showed reduced inflammatory cell infiltration, enhanced fibroblast proliferation, well-organized collagen fibers, and the development of new blood vessels. Collagen deposition is further supported by immunohistochemistry studies and Masson's trichrome staining. Bilirubin-DFO combination also reduced lipid peroxidation and elevated antioxidative enzymes. CONCLUSION: Topical application of bilirubin-DFO showed immense potential in augmenting skin wound regeneration in diabetes by upregulating the antioxidant status as well as increasing angiogenesis, collagen deposition, and modulating cytokines.


Assuntos
Desferroxamina , Diabetes Mellitus Experimental , Animais , Antioxidantes , Bilirrubina/metabolismo , Colágeno/farmacologia , Colágeno/uso terapêutico , Desferroxamina/metabolismo , Desferroxamina/farmacologia , Desferroxamina/uso terapêutico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Estresse Oxidativo , Ratos , Pele , Fator A de Crescimento do Endotélio Vascular , Cicatrização
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