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1.
Int J Mol Sci ; 22(11)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204038

RESUMO

Metabolic syndrome (MetS) is a chronic disease, including abdominal obesity, dyslipidemia, hyperglycemia, and hypertension. It should be noted that the occurrence of MetS is closely related to oxidative stress-induced mitochondrial dysfunction, ectopic fat accumulation, and the impairment of the antioxidant system, which in turn further aggravates the intracellular oxidative imbalance and inflammatory response. As enriched anti-inflammatory and antioxidant components in plants, natural polyphenols exhibit beneficial effects, including improving liver fat accumulation and dyslipidemia, reducing blood pressure. Hence, they are expected to be useful in the prevention and management of MetS. At present, epidemiological studies indicate a negative correlation between polyphenol intake and MetS incidence. In this review, we summarized and discussed the most promising natural polyphenols (including flavonoid and non-flavonoid drugs) in the precaution and treatment of MetS, including their anti-inflammatory and antioxidant properties, as well as their regulatory functions involved in glycolipid homeostasis.


Assuntos
Síndrome Metabólica/tratamento farmacológico , Polifenóis/uso terapêutico , Substâncias Protetoras/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Progressão da Doença , Humanos , Polifenóis/química , Polifenóis/farmacologia , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos
2.
Ecotoxicol Environ Saf ; 221: 112424, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34174736

RESUMO

Nanotechnology is used in a wide range of applications, including medical therapies that precisely target disease prevention and treatment. The current study aimed firstly, to synthesize selenium nanoparticles (SeNPs) in an eco-friendly manner using Moringa oleifera leaf extract (MOLE). Secondly, to compare the protective effects of green-synthesized MOLE-SeNPs conjugate and MOLE ethanolic extract as remedies for melamine (MEL) induced nephrotoxicity in male rats. One hundred and five male Sprague Dawley rats were divided into seven groups (n = 15), including 1st control, 2nd MOLE (800 mg/kg BW), 3rd SeNPs (0.5 mg/kg BW), 4th MOLE-SeNPs (200 µg/kg BW), 5th MEL (700 mg/kg BW), 6th MEL+MOLE, and 7th MEL+MOLE SeNPs. All groups were orally gavaged day after day for 28 days. SeNPs and the colloidal SeNPs were characterized by TEM, SEM, and DLS particle size. SeNPs showed an absorption peak at a wavelength of 530 nm, spherical shape, and an average size between 3.2 and 20 nm. Colloidal SeNPs absorption spectra were recorded between 400 and 700 nm with an average size of 3.3-17 nm. MEL-induced nephropathic alterations represented by a significant increase in serum creatinine, urea, blood urea nitrogen (BUN), renal TNFα, oxidative stress-related indices, and altered the relative mRNA expression of apoptosis-related genes Bax, Caspase-3, Bcl2, Fas, and FasL. MEL-induced array of nephrotoxic morphological changes, and up-regulated immune-expression of proliferating cell nuclear antigen (PCNA) and proliferation-associated nuclear antigen Ki-67. Administration of MOLE or MOLE-SeNPs significantly reversed MEL-induced renal function impairments, oxidative stress, histological alterations, modulation in the relative mRNA expression of apoptosis-related genes, and the immune-expression of renal PCNA and Ki-67. Conclusively, the green-synthesized MOLE-SeNPs and MOLE display nephron-protective properties against MEL-induced murine nephropathy. This study is the first to report these effects which were more pronounced in the MOLE group than the green biosynthesized MOLE-SeNPs conjugate group.


Assuntos
Nefropatias/tratamento farmacológico , Moringa oleifera , Nanopartículas/uso terapêutico , Extratos Vegetais/uso terapêutico , Substâncias Protetoras/uso terapêutico , Selênio/uso terapêutico , Animais , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Folhas de Planta , Ratos Sprague-Dawley , Triazinas , Fator de Necrose Tumoral alfa/metabolismo
3.
Molecules ; 26(9)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066903

RESUMO

The effect of effective microorganisms (EM) on internal organ morphology, intestinal morphometry, and serum biochemical activity in Japanese quails under Clostridium perfringens challenge was determined. After 30 days of EM addition, one group of quails was orally inoculated with Clostridium perfringens. The second group did not receive EM and was inoculated with C. perfringens. In the gut, EM supplementation reduced the number of lesions, enhanced gut health, and protected the mucosa from pathogenic bacteria. EM showed an anti-inflammatory effect and fewer necrotic lesions in villi. In the internal organs, EM showed a protective effect against a typical lesion of C. perfringens infection. Necrosis and degeneration of the hepatocytes, necrosis of bile ducts, and bile duct proliferation were more severe in the infected group without EM. Morphometric evaluation showed significantly higher villi in the jejunum after EM addition. A greater crypt depth was observed in the C. perfringens group. Biochemical analysis of the blood indicated lower cholesterol on the 12th day of the experiment and between-group differences in total protein, lactate dehydrogenase (LDH), and albumin levels in the EM group. Further studies are needed to improve EM activity against pathologic bacteria as a potential alternative to antibiotics and to develop future natural production systems.


Assuntos
Anti-Inflamatórios/uso terapêutico , Doenças das Aves/sangue , Doenças das Aves/dietoterapia , Infecções por Clostridium/sangue , Infecções por Clostridium/dietoterapia , Clostridium perfringens , Enterite/sangue , Enterite/dietoterapia , Mucosa Intestinal/microbiologia , Probióticos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Codorniz/sangue , Codorniz/microbiologia , Ração Animal/microbiologia , Animais , Ductos Biliares/patologia , Doenças das Aves/microbiologia , Colesterol/sangue , Infecções por Clostridium/microbiologia , Enterite/microbiologia , Feminino , Hepatócitos/patologia , Mucosa Intestinal/patologia , Jejuno/microbiologia , Jejuno/patologia , L-Lactato Desidrogenase/sangue , Necrose , Albumina Sérica/análise , Resultado do Tratamento
4.
Inflamm Res ; 70(7): 749-752, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34173853

RESUMO

Coronavirus disease 2019 (COVID-19) pandemic is still a world-class challenge. Inflammation, especially its severe form with excess release of pro-inflammatory cytokines (cytokine storm) which is a life-threatening condition, is among the most important suspects involved in COVID-19 pathogenesis. It has been shown that cytokine storm could cause notable morbidities such as acute respiratory distress syndrome (ARDS) which leads to hypoxia which is significantly associated with mortality of patients with COVID-19. Hypoxia-inducible factor 1α (HIF-1α) which activates following ARDS-induced hypoxia plays a crucial role in pathogenesis of cytokine storm. The expression of tumor necrosis factor α (TNF-α), interleukin 1 ß (IL-1ß), and IL-6 which are key elements of cytokine storm are by nuclear factor κß (NFκB). Interestingly, during the hypoxia, HIF-1α activates NFκB to induce expression of pro-angiogenic and pro-inflammatory factors. These released factors starts a autocrine/paracrine loop and causes deterioration of their etiological pathways of expression: cytokine storm and ARDS. To sum up, it seems HIF-1α is an important target to hit to ameliorate the mentioned pathways. Herein, we suggest perfluorocarbons (PFCs) which are among the organofluorine compounds as a possible co-treatment to reduce hypoxemia and then hypoxia. These substances are known for their high gas solving potential that make them able to be used as a synthetic artificial blood product. Due to the potential of PFCs to affect the fountain of important physiopathological pathway such as inflammation a hypoxia through affecting NFκB, they could be considered as multi-target co-treatment for ARD individuals with COVID-19. It is highly suggested to evaluate this hypothesis in following researches.


Assuntos
COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Fluorcarbonetos/uso terapêutico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/etiologia , Animais , Citocinas/biossíntese , Humanos , Hipóxia/tratamento farmacológico , Hipóxia/etiologia , NF-kappa B/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/etiologia
5.
Life Sci ; 280: 119692, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102189

RESUMO

AIMS: This study investigated the renal protective effects and mechanisms of angiotensin receptor-neprilysin inhibitor LCZ696 in mice with cardiorenal syndrome. MATERIALS AND METHODS: Mice were divided into abdominal aortic ligation alone, or treatment with LCZ696 or valsartan, whilst those undergoing sham surgery served as controls. Rat proximal renal tubular epithelial cells from the NRK-52E line were treated with control solution, LCZ696 or valsartan, in the presence or absence of Ang II for 24 h. KEY FINDINGS: Compared to controls, abdominal aortic ligation significantly increased plasma NT-proBNP and urine neutrophil gelatinase-associated lipocalin (NGAL), which were associated with reduced renal length and velocity time integral on ultrasonography. Histology revealed wrinkling of the glomerular capillary wall and sclerosis of the glomerulus, dilatation of the Bowman's capsule, accompanied by diffuse renal tubular atrophy and fibrosis, accompanied by lower kidney index and higher percentage area of fibrosis. Increases in NGAL and decreased ANP protein and mRNA expression levels were observed. These abnormalities were significantly prevented by LCZ696 and to a lesser extent by valsartan. Cellular experiments demonstrated a central role of Ang II/transforming growth factor-ß1/Smad2/3/connective tissue growth factor-dependent signaling leading to type IV collagen deposition. This upregulation was reversed by LCZ696 in a greater extent than valsartan treatment alone, accompanied by a significant improvement in NGAL. SIGNIFICANCE: LCZ696 can reduce kidney injury to a level beyond valsartan therapy alone in mice with cardiorenal syndrome, which can be speculated by effects on epithelial-mesenchymal transition and fibrosis through downregulating the TGF-ß1/Smad2/3/CTGF/Collagen IV pathway.


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Síndrome Cardiorrenal/tratamento farmacológico , Rim/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Valsartana/uso terapêutico , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Compostos de Bifenilo/farmacologia , Síndrome Cardiorrenal/patologia , Linhagem Celular , Combinação de Medicamentos , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia , Ratos , Valsartana/farmacologia
6.
Life Sci ; 280: 119704, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34111461

RESUMO

AIMS: The present study aimed to evaluate the protective action of thymol towards l-arginine-induced acute pancreatitis (AP) by studying the function of rat peritoneal immune cells. MAIN METHODS: Rat peritoneal exudate cells (PECs), obtained 24 h after the injection of l-arginine (350 mg/100 g of b.w.), were evaluated for mitochondrial activity (MTT assay), adherence capacity (methylene-blue assay), and phagocyte enzyme activity (myeloperoxidase, MPO, assay). The activity of α-amylase and free MPO, as well as the concentration of reactive oxygen species (ROS, i.e. O2-), were determined in the peritoneal exudate fluid. Also, serum α-amylase activity determination and pancreatic tissue pathohistological analysis were performed. KEY FINDING: The administered thymol (50 and 100 mg/kg, per os) caused a significant decrease in the PEC mitochondrial activity and adherence capacity when compared with these functions of PECs isolated from rats with AP. A decrease in cellular MPO activity, as well as in the levels of ROS, α-amylase, and free MPO in peritoneal exudates was found in animals treated with thymol compared to the control animals with AP. Additionally, thymol administration prevented an increase in serum α-amylase activity, accompanied by the decrease in pancreatic tissue damage that follows l-arginine application. SIGNIFICANCE: The present results showed that thymol exerts significant immunomodulatory properties and a potential to silence PEC functions in inflammatory conditions such as the AP induced by l-arginine.


Assuntos
Arginina/efeitos adversos , Imunidade Celular/efeitos dos fármacos , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Timol/uso terapêutico , Animais , Células Cultivadas , Granulócitos/efeitos dos fármacos , Granulócitos/imunologia , Granulócitos/patologia , Masculino , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/imunologia , Pancreatite/patologia , Cavidade Peritoneal/patologia , Ratos , Ratos Wistar
7.
Molecules ; 26(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063148

RESUMO

This study aimed to evaluate the cancer chemopreventive activity of vanillic acid (VA) in diethylnitrosamine- and 1,2-dimethylhydrazine-induced liver and colon carcinogenesis in rats. VA did not induce the formation of hepatic glutathione S-transferase placental form (GST-P) positive foci and colonic aberrant crypt foci, demonstrating no carcinogenic activity. VA (75 mg kg-1 body weight) could significantly reduce the number and areas of hepatic GST-P positive foci when administered before carcinogen injections, but no such effect was seen when it was administered after carcinogen injection. No protection was seen in the colon when VA was treated before or after carcinogen injection. Immunohistochemical studies demonstrated the decreased expression of proliferating cell nuclear antigen and the induction of apoptosis. Mechanistic studies showed that VA significantly induced the expression of GSTA-5 and Nrf-2 genes, which are associated with the detoxification system. Likewise, the antiproliferative effect was noticed by the reduction of Cyclin D1 expression. The apoptotic activity may be due to the upregulation of Caspase-3 and Bad levels and downregulation of the Bcl-2 level. These data suggest that VA exhibited significant protection against diethylnitrosamine- and 1,2-dimethylhydrazine-induced hepatocarcinogenesis, which might be related to the induction of the detoxifying enzyme, the reduction of proliferation and the induction of apoptosis.


Assuntos
Carcinogênese/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Substâncias Protetoras/uso terapêutico , Ácido Vanílico/uso terapêutico , 1,2-Dimetilidrazina , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/sangue , Carcinogênese/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dietilnitrosamina , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/genética , Masculino , Tamanho do Órgão/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos Wistar , Ácido Vanílico/química , Ácido Vanílico/farmacologia
8.
Nutrients ; 13(5)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064981

RESUMO

Alcoholic liver disease (ALD) is one type of liver disease, causing a global healthcare problem and mortality. The liver undergoes tissue damage by chronic alcohol consumption because it is the main site for metabolism of ethanol. Chronic alcohol exposure progresses from alcoholic fatty liver (AFL) to alcoholic steatohepatitis (ASH), which further lead to fibrosis, cirrhosis, and even hepatocellular cancer. Therapeutic interventions to combat ALD are very limited such as use of corticosteroids. However, these therapeutic drugs are not effective for long-term usage. Therefore, additional effective and safe therapies to cope with ALD are urgently needed. Previous studies confirmed that edible food plants and their bioactive compounds exert a protective effect against ALD. In this review article, we summarized the hepatoprotective potential of edible food plants and their bioactive compounds. The underlying mechanism for the prevention of ALD by edible food plants was as follows: anti-oxidation, anti-inflammation, lipid regulation, inhibition of apoptosis, gut microbiota composition modulation, and anti-fibrosis.


Assuntos
Hepatopatias Alcoólicas/terapia , Plantas Comestíveis/química , Polifenóis/uso terapêutico , Substâncias Protetoras/uso terapêutico , Consumo de Bebidas Alcoólicas , Animais , Etanol/efeitos adversos , Etanol/metabolismo , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/terapia , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias Alcoólicas/metabolismo , Neoplasias Hepáticas , Compostos Fitoquímicos/química , Compostos Fitoquímicos/uso terapêutico , Extratos Vegetais/uso terapêutico , Substâncias Protetoras/química
9.
Life Sci ; 280: 119751, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34174321

RESUMO

AIMS: Obesity is associated with a spectrum of hepatic abnormalities that can be experimentally induced by injections of monosodium glutamate (MSG) in neonatal rodents. We investigated the protective actions of the repeated therapy with 4-phenylselenyl-7-chloroquinoline (4-PSQ), a quinoline derivative containing selenium, on damage to the liver triggered by early postnatal administration of MSG in male Wistar rats. MAIN METHODS: Neonatal rats received MSG (4 g/kg, subcutaneous route) or saline (1 ml/kg) from 5 to 14 postnatal day (PND) to induce obesity with consequent damages in the liver. 4-PSQ treatment (5 mg/kg) or canola oil (1 ml/kg) was administered from 60 to 76 PND by the intragastric route. On 76 PND, animals were anesthetized for blood and liver collection. Plasma markers of hepatic function, hepatic lipoperoxidation levels and histology analysis of liver tissue were assessed. KEY FINDINGS: Our data revealed that treatment with 4-PSQ reverted the increase in plasma transaminases activities observed in MSG rats. Treatment with 4-PSQ reduced plasma lactate levels in obese rats. In the liver, MSG elevated the content of lipoperoxidation which was reverted by 4-PSQ administrations. Lastly, 4-PSQ therapy attenuated the histological alterations induced by MSG. SIGNIFICANCE: Together, the results indicate a hepatoprotective action of repeated treatment with 4-PSQ in obese rats.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Aromatizantes/efeitos adversos , Fígado/efeitos dos fármacos , Compostos Organosselênicos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Quinolinas/uso terapêutico , Glutamato de Sódio/efeitos adversos , Animais , Animais Recém-Nascidos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fígado/patologia , Masculino , Ratos Wistar
10.
Life Sci ; 278: 119600, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33984362

RESUMO

Kidney injury is a relatively common complication of the use of aminoglycosides. Inflammation and oxidative stress play a key role in gentamicin (GM) nephrotoxicity. We investigated the protective effect of the melatonergic agonist agomelatine (AGM) on GM nephrotoxicity, emphasizing the involvement of TLR-4 signaling, SIRT1 and PPARγ. Rats received 25 mg/kg AGM for 15 days and 100 mg/kg GM for eight days starting at day 7. Elevated serum creatinine, urea and Kim-1 along with multiple histological alterations in the kidney were observed in GM-intoxicated rats. Malondialdehyde (MDA), TNF-α, IL-1ß, nitric oxide (NO) and myeloperoxidase (MPO) were increased, and GSH, SOD and catalase were decreased in the kidney of GM-intoxicated rats. Treatment with AGM significantly ameliorated the kidney function biomarkers, prevented tissue injury, decreased inflammatory cytokines, MDA, NO and MPO, and boosted antioxidants. In addition, AGM suppressed the expression of TLR-4, NF-κB p65, p38 MAPK, ERK-1, VCAM-1 and iNOS, whereas upregulated SIRT1 and PPARγ in the kidney of GM-intoxicated rats. In conclusion, AGM prevented GM nephrotoxicity in rats by attenuating oxidative injury and inflammation. AGM suppressed TLR-4 signaling, enhanced antioxidants and upregulated SIRT1 and PPARγ in the kidney of GM-induced rats.


Assuntos
Acetamidas/uso terapêutico , Antibacterianos/efeitos adversos , Gentamicinas/efeitos adversos , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , PPAR gama/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Receptor 4 Toll-Like/metabolismo
11.
Life Sci ; 278: 119631, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34022202

RESUMO

AIMS: To investigate the protective effects and underlying mechanisms of diallyl trisulfide (DATS) against acute liver injury induced by concanavalin A (Con A). MATERIALS AND METHODS: DATS (20, 40, 80 mg/kg) were gavaged to ICR mice 1 h before Con A (20 mg/kg) tail vein injection. The survival rate of mice, alterations of serum biochemical markers and liver histopathology were measured to evaluate the protective effects of DATS at 24 h after Con A exposure. The indexes of inflammation, oxidative stress and apoptosis were determined to explore the possible mechanisms. KEY FINDINGS: DATS pretreatment increased survival rate of mice in a dose-dependent manner, inhibited the increase of liver-to-spleen ratio and serum liver injury markers, and attenuated liver pathological damage induced by Con A. Further study showed that DATS pretreatment inhibited the activation of Kupffer cells/macrophages, release of tumor necrosis factor-α (TNF-α) and Caspase-1-dependent inflammation induced by Con A. Moreover, DATS pretreatment alleviated the oxidative stress induced by Con A, which was evidenced by increased superoxide dismutase (SOD) and catalase (CAT) activities and decreased malondialdehyde (MDA) content in DATS and Con A co-treated mice compared with Con A alone group. Finally, DATS pretreatment reduced eosinophilic body formation, TUNEL positive staining and increased Bcl-2/Bax ratio in liver of Con A-injected mice, indicating attenuated apoptosis. SIGNIFICANCE: Collectively, the results suggest that DATS displays potent protective effects against Con A-induced acute liver injury in mice possibly through inhibition of inflammation, oxidative stress and apoptosis.


Assuntos
Compostos Alílicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Sulfetos/uso terapêutico , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Concanavalina A/efeitos adversos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR
12.
Life Sci ; 278: 119638, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34051216

RESUMO

Hepatotoxicity is the main adverse effect of methotrexate (MTX), which limits its clinical use and effectiveness. Both empagliflozin (EMPA) and neohesperidin dihydrochalcone (NHD) have promising criteria for suppressing oxidative stress, inflammation and apoptosis. In this current study, we suggested that EMPA and NHD exhibit protective effects against MTX-triggered liver injury, considering N-acetylcysteine (NAC) as a reference standard. In order to inspect our suggestion, An experimental rat model comprising 70 male adult rats (7 groups, 10 rats in each) was implemented to investigate the effects of MTX (20 mg/kg, i.p. once), alone or with EMPA (10 and 30 mg/kg/day, p.o.), NHD (40 and 80 mg/kg/day, p.o.), and NAC (150 mg/kg/day, p.o.) compared to the normal control animals (1%CMC, p.o.). Pre-treatment with EMPA and NHD showed significant attenuation in liver function abnormalities, pathological tissue deteriorations, hepatic oxidative stress parameters, and the level of expression of pro-inflammatory cytokines TNF-α and IL-6. Also, EMPA and NHD showed significant decreases in NF-κB/Keap1/HSP70/caspase-3 and increases in Nrf2/PPARγ/HO-1 expression levels. In addition, EMPA and NHD showed a marked enhancement of the anti-tumour activity of MTX against HepG2 and lung (A549) cancer cells. This research reveals that both EMPA and NHD can inhibit oxidation, inflammatory reactions, and apoptosis in the liver tissues of MTX-treated rats, mainly through Nrf2/PPARγ/HO-1 signalling initiation and suppression of NF-κB/Keap1/HSP70/caspase-3 axis, considered a unique class of drugs that attenuates or at least delays the onset of MTX-induced toxicity and serves as an innovative therapeutic target for future clinical application in humans.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Compostos Benzidrílicos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Glucosídeos/uso terapêutico , Hesperidina/análogos & derivados , Metotrexato/efeitos adversos , Substâncias Protetoras/uso terapêutico , Animais , Caspase 3/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Proteínas de Choque Térmico HSP72/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Hesperidina/uso terapêutico , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos
13.
Biomed Pharmacother ; 139: 111675, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33965725

RESUMO

We previously profiled the chemical composition of wax apple, Syzygium samarangense, leaf extract using HR-LC-MS/MS and reported its antioxidant, hepatoprotective and antitrypanosomal activities. The plant is widely used in traditional medicine to cure several ailments like bronchitis, asthma, diabetes, fever, pathogenic infections, gut spasms, as well as renal diseases. However, neither the gastroprotective effects nor the underlying mechanisms were explored. Here, we investigated the gastroprotective potential of the leaf extract on indomethacin-induced gastric ulcer in rats and explored the involved mechanism(s) of action. Administration of indomethacin significantly increased the ulcer index, mucosal injury, the gastric levels of the inflammatory markers nuclear factor kabba B-p65(NF-κB p65), myeloperoxidase (MPO), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), lipid peroxidation product, malondialdehyde (MDA) and Caspase-3 expression. It reduced the gastric levels of the endogenous antioxidants glutathione as well peroxidase (GPx), reduced glutathione (GSH) and the gastric mucosal protective factors, mucus secretion and goblet cells. Pretreatment with the leaf extract displayed a prominent decrease in the ulcer index, inflammatory cell infiltration, inflammatory markers, MDA, protein expression of Caspase-3 and a significant increase in the gastric levels of the endogenous antioxidants, mucus content and goblet cell proliferation when compared to the indomethacin group. The individual secondary metabolites of the extract exhibited low binding energy when docked into the prostaglandin receptors EP3 and EP4. This study revealed the gastroprotective effect of S. samarangense on indomethacin-induced gastric ulcer in rats. The gastroprotective effects might be attributed to cytoprotective, antioxidant, anti-inflammatory and antiapoptotic activities with a possible potential of activating EP3 and EP4 receptors. In conclusion, S. samarangense has a promising potential in the prevention of NSAIDs-induced ulcers.


Assuntos
Anti-Inflamatórios não Esteroides , Indometacina , NF-kappa B/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Transdução de Sinais/efeitos dos fármacos , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/prevenção & controle , Syzygium/química , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Biomarcadores , Células Caliciformes/efeitos dos fármacos , Masculino , Simulação de Acoplamento Molecular , Muco/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Ratos , Ratos Wistar
14.
Nat Commun ; 12(1): 2621, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976147

RESUMO

Cullin-RING E3 ligases (CRLs) regulate the turnover of approximately 20% of mammalian cellular proteins. Neddylation of individual cullin proteins is essential for the activation of each CRL. We report herein the discovery of DI-1548 and DI-1859 as two potent, selective and covalent DCN1 inhibitors. These inhibitors selectively inhibit neddylation of cullin 3 in cells at low nanomolar concentrations and are 2-3 orders of magnitude more potent than our previously reported reversible DCN1 inhibitor. Mass spectrometric analysis and co-crystal structures reveal that these compounds employ a unique mechanism of covalent bond formation with DCN1. DI-1859 induces a robust increase of NRF2 protein, a CRL3 substrate, in mouse liver and effectively protects mice from acetaminophen-induced liver damage. Taken together, this study demonstrates the therapeutic potential of selective inhibition of cullin neddylation.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Proteínas Culina/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Substâncias Protetoras/farmacologia , Acetaminofen/administração & dosagem , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cristalografia por Raios X , Modelos Animais de Doenças , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Proteína NEDD8/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Substâncias Protetoras/química , Substâncias Protetoras/uso terapêutico , Processamento de Proteína Pós-Traducional/efeitos dos fármacos
15.
DNA Cell Biol ; 40(6): 748-756, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33983842

RESUMO

Hydrogen sulfide (H2S) has been reported to participate in intestinal mucosal defense and repair. However, the precise regulatory mechanisms of H2S in ulcerative colitis (UC) remain unclear. We explored the effects of sodium hydrosulfide (NaHS), a donor of H2S, in dextran sulfate sodium (DSS)-induced colitis in rats. The pathologic features were determined by analyzing the hematoxylin and eosin-stained samples. Interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α), and myeloperoxidase (MPO) levels were determined using ELISA. The presence of cystathionine-γ-lyase (CSE) and light chain 3B (LC3B) were determined using immunohistochemical and immunofluorescence (IF) approaches, respectively. Next, we investigated the effects of NaHS in lipopolysaccharide (LPS)-stimulated human colonic smooth muscle cells (H2940). The level of reactive oxygen species (ROS) was determined using IF. NOD-like receptor 3 (NLRP3) and CSE were detected using western blot and quantitative real-time polymerase chain reaction. Autophagy was determined using western blot, IF, and electron microscopy. NaHS treatment considerably diminished colitis-induced histological injury and proinflammatory cytokine expressions. MPO, CSE, and H2S were downregulated, whereas LC3B was upregulated after NaHS administration in colitic rats. NaHS remarkably attenuated the levels of ROS, CSE, and NLRP3 in LPS-stimulated cells and enhanced autophagy, as was revealed by increased LC3-II-to-LC3-I ratio, elevated LC3, and decreased p62. Importantly, NaHS promoted autophagosome formation in LPS-treated cells. Exogenous H2S ameliorates intestinal injury by downregulating inflammation and activation of autophagy, suggesting the potential of NaHS as a therapeutic agent for UC.


Assuntos
Autofagia/efeitos dos fármacos , Colite Ulcerativa/tratamento farmacológico , Sulfeto de Hidrogênio , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Substâncias Protetoras , Animais , Linhagem Celular , Colite Ulcerativa/induzido quimicamente , Citocinas/metabolismo , Humanos , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/uso terapêutico , Masculino , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
16.
Pharmacology ; 106(5-6): 233-243, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33849010

RESUMO

BACKGROUND: Our liver has a variety of vital functions including removing poisons, storing energy, immunological roles, and secretory and excretory functions. It may face some kinds of diseases caused by viruses, hepatotoxic chemicals, drugs, alcohol, and inherited disorders. Oxidative stress and inflammation are in the core of mechanisms of liver damages induced by viruses or chemical agents. SUMMARY: Morus nigra (M. nigra), generally known as black mulberry, exhibited wide-spectrum pharmacological effects including antidiabetic, antinociceptive, anticancer, and hepatoprotective activities. Different parts of this plant particularly the fruit and leaf have shown beneficial effects on hepatocytes in cell culture and animal models of liver damages induced by chemicals (e.g., CCl4), drugs (e.g., paracetamol), diet (e.g., high fat), diabetes, etc. The beneficial effects of M. nigra on the liver are attributed to the presence of considerable amounts of phenolic compounds such as anthocyanins, flavonols, and phenolic acids. The present review is aimed to focus on the hepatoprotective activities of M. nigra and its phytochemicals and the mechanisms responsible for these activities. Key Messages: The evidence reviewed in this study can help design clinical trials on M. nigra in patients with liver disorders and develop a hepatoprotective herbal medicine.


Assuntos
Fígado/efeitos dos fármacos , Morus/química , Fenóis/farmacologia , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Animais , Humanos , Hepatopatias/tratamento farmacológico , Hepatopatias/etiologia , Morus/efeitos adversos , Fenóis/efeitos adversos , Fenóis/farmacocinética , Fenóis/uso terapêutico , Compostos Fitoquímicos/efeitos adversos , Compostos Fitoquímicos/farmacocinética , Compostos Fitoquímicos/uso terapêutico , Extratos Vegetais/efeitos adversos , Extratos Vegetais/farmacocinética , Extratos Vegetais/uso terapêutico , Substâncias Protetoras/efeitos adversos , Substâncias Protetoras/farmacocinética , Substâncias Protetoras/uso terapêutico
17.
Pharmacology ; 106(5-6): 332-340, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33849026

RESUMO

INTRODUCTION: The presence of mercury in the environment is a worldwide concern. Inorganic mercury is present in industrial materials, is employed in medical devices, is widely used in batteries, is a component of fluorescent light bulbs, and it has been associated with human poisoning in gold mining areas. The nephrotoxicity induced by inorganic mercury is a relevant health problem mainly in developing countries. The primary mechanism of mercury toxicity is oxidative stress. Trimetazidine (TMZ) is an anti-ischemic drug, which inhibits cellular oxidative stress, eliminates oxygen-free radicals, and improves lipid metabolism. The aim of this study was to evaluate whether the administration of TMZ protects against mercuric chloride (HgCl2) kidney damage. METHODS: Adult male Wistar rats received only HgCl2 (4 mg/kg bw, sc) (Hg group, n = 5) or TMZ (3 mg/kg bw, ip) 30 min before HgCl2 administration (4 mg/kg bw, sc) (TMZHg group, n = 7). Simultaneously, a control group of rats (n = 4) was studied. After 4 days of HgCl2 injection, urinary flow, urea and creatinine (Cr) plasma levels, Cr clearance, urinary glucose, and sodium-dicarboxylate cotransporter 1 (NaDC1) in urine were determined. Lipid peroxidation (MDA) and glutathione (GSH) levels were measured in kidney homogenates. RESULTS: Rats only treated with HgCl2 showed an increase in urea and Cr plasma levels, urinary flow, fractional excretion of water, glucosuria, and NaDC1 urinary excretion as compared with the control group and a decrease in Cr clearance. TMZHg group showed a decrease in urea and Cr plasma levels, urinary flow, fractional excretion of water, glucosuria, NaDC1 urinary excretion, and an increase in Cr clearance when compared to the Hg group. Moreover, MDA and GSH levels observed in Hg groups were decreased and increased, respectively, by TMZ pretreatment. CONCLUSION: TMZ exerted a renoprotective action against HgCl2-induced renal injury, which might be mediated by the reduction of oxidative stress. Considering the absence of toxicity of TMZ, its clinical application against oxidative damage due to HgCl2-induced renal injury should be considered. The fact that TMZ is commercially available should simplify and accelerate the translation of the present data "from bench to bedside." In this context, TMZ become an interesting new example of drug repurposing.


Assuntos
Nefropatias/prevenção & controle , Intoxicação por Mercúrio/prevenção & controle , Substâncias Protetoras/farmacologia , Trimetazidina/farmacologia , Animais , Creatinina/sangue , Transportadores de Ácidos Dicarboxílicos/urina , Glutationa/metabolismo , Glicosúria/induzido quimicamente , Glicosúria/prevenção & controle , Nefropatias/induzido quimicamente , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Cloreto de Mercúrio/efeitos adversos , Transportadores de Ânions Orgânicos Dependentes de Sódio/urina , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Ratos Wistar , Cloreto de Sódio/urina , Simportadores/urina , Trimetazidina/uso terapêutico , Ureia/sangue , Micção/efeitos dos fármacos
18.
Biomed Pharmacother ; 139: 111547, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33831836

RESUMO

Erythropoietin (Epo) is a pleiotropic cytokine, essential for erythropoiesis. Epo and its receptor (Epo-R) are produced by several tissues and it is now admitted that Epo displays other physiological functions than red blood cell synthesis. Indeed, Epo provides cytoprotective effects, which consist in prevention or fight against pathological processes. This perspective article reviews the various protective effects of Epo in several organs and tries to give a proof of concept about its effects in the lung. The tissue-protective effects of Epo could be a promising approach to limit the symptoms of acute and chronic lung diseases.


Assuntos
Eritropoetina/uso terapêutico , Pneumopatias/prevenção & controle , Substâncias Protetoras/uso terapêutico , Animais , Eritropoetina/farmacologia , Humanos , Pneumopatias/patologia , Substâncias Protetoras/farmacologia , Receptores da Eritropoetina , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico
19.
Aging (Albany NY) ; 13(8): 11705-11726, 2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33875618

RESUMO

Hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) can differentiate into all blood lineages to maintain hematopoiesis, wound healing, and immune functions. Recently, cobalt-chromium alloy casting implants have been used extensively in total hip replacements; however, cobalt nanoparticles (CoNPs) released from the alloy were toxic to HSCs and HPCs. We aimed to investigate the mechanism underlying the toxic effect of CoNPs on HSCs/HPCs and to determine the protective effect of selenomethionine (SeMet) against CoNPs in vitro and in vivo. Human and rat CD34+ HSCs/HPCs were isolated from cord blood and bone marrow, respectively. CoNPs decreased the viability of CD34+ HSCs/HPCs and increased apoptosis. SeMet attenuated the toxicity of CoNPs by enhancing the antioxidant ability of cells. The protective effect of SeMet was not completely abolished after adding H2O2 to abrogate the improvement of the antioxidant capacity by SeMet. SeMet and CoNPs stimulated ATM/ATR DNA damage response signals and inhibited cell proliferation. Unlike CoNPs, SeMet did not damage the DNA, and cell proliferation recovered after removing SeMet. SeMet inhibited the CoNP-induced upregulation of hypoxia inducible factor (HIF)-1α, thereby disrupting the inhibitory effect of HIF-1α on breast cancer type 1 susceptibility protein (BRCA1). Moreover, SeMet promoted BRCA1-mediated ubiquitination of cyclin B by upregulating UBE2K. Thus, SeMet enhanced cell cycle arrest and DNA repair post-CoNP exposure. Overall, SeMet protected CD34+ HSCs/HPCs against CoNPs by stimulating antioxidant activity and DNA repair.


Assuntos
Cobalto/toxicidade , Intoxicação por Metais Pesados/prevenção & controle , Células-Tronco Hematopoéticas/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Selenometionina/farmacologia , Administração Oral , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Células Cultivadas , Cobalto/administração & dosagem , Meios de Cultura/toxicidade , Reparo do DNA/efeitos dos fármacos , Modelos Animais de Doenças , Sangue Fetal/citologia , Intoxicação por Metais Pesados/etiologia , Intoxicação por Metais Pesados/patologia , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Humanos , Peróxido de Hidrogênio/farmacologia , Masculino , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Cultura Primária de Células , Substâncias Protetoras/uso terapêutico , Ratos , Selenometionina/uso terapêutico
20.
Eur J Pharmacol ; 901: 174059, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33794215

RESUMO

The role of CXC chemokine ligand 16 (CXCL16), oxidized LDL (ox-LDL), tissue factor (TF) and autophagy-induced beta cell death in type 1 diabetes mellitus (T1DM) pathogenesis is still unclear. We examined the therapeutic potential and mechanism of resveratrol (RES) against T1DM. Diabetes was induced in Balb/c mice by i. p. injection of 55 mg/kg streptozotocin (STZ) for five consecutive days. The control group received vehicles. RES or (RES + STZ) groups received RES (50 mg/kg, i. p.) daily for 12 days starting from the fourth day of buffer or STZ injections, respectively. Blood glucose, serum insulin, beta cell mass, serum lipid profiles, histological changes, oxidative stress biomarkers were determined. Moreover, CXCL16, TF, ox-LDL, P62 and LC3 tissue expression were also analyzed. Diabetic mice showed a marked deterioration in biochemical, physical and oxidative stress parameters. Interestingly, immunofluorescence analysis showed a remarkable elevation in CXCL16 (12 folds), ox-LDL (9 folds), TF (8.3 folds) in pancreatic B-cells. Moreover, western blotting revealed a profound increase in ox-LDL (2.6 folds), TF (3.2 folds), while a significant decline in P62 (0.34) and LC3 (0.25) when compared to control. RES mitigated biochemical, physical, oxidative imbalance and distorted pancreatic architecture in T1DM mice. Intriguingly, CXCL16, ox-LDL, TF and autophagic markers were also restored after RES treatment. Our data give the first direct evidence that beta cell-specific CXCL16/ox-LDL pathway activation is a potential trigger of TF activation and autophagic beta cell death in T1DM. Moreover, RES may have potential therapeutic applications for prevention of T1DM mainly via ameliorating this pathway.


Assuntos
Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Quimiocina CXCL16/efeitos dos fármacos , Diabetes Mellitus Tipo 1/prevenção & controle , Lipoproteínas LDL/efeitos dos fármacos , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tromboplastina/metabolismo , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/prevenção & controle , Teste de Tolerância a Glucose , Células Secretoras de Insulina/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico
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