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1.
Biofactors ; 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38344831

RESUMO

The prevalence of testicular dysfunction is increasing as it is a common diabetes mellites (DM) complication. The objective of this study is to explore the potential protective effect of sulbutiamine against testicular hypofunction associated with streptozotocin (STZ)-induced DM in rats. Sulbutiamine was administered orally (60 mg/kg) to male Wistar rats for 8 weeks starting 72 h after a single injection of STZ (45 mg/kg, i.p.). Blood glucose level (BGL), serum testosterone level, sperm number, and motility were determined. Testicular tissue was examined histopathologically, and the Johnson score was evaluated. Levels of malondialdehyde (MDA), protein kinase C (PKC), nuclear factor erythroid-derived 2-like 2 (Nrf2), and proliferating cell nuclear antigen (PCNA) were measured. Apoptosis was evaluated by immunohistochemical determination of B-cell lymphoma protein 2 (Bcl-2), Bcl-2 associated X-protein (Bax), and caspase-3. Sulbutiamine administration managed to reduce BGL and boost testicular function as manifested by increased testicular weight, testosterone level, sperm number, and motility compared to the STZ group. Additionally, histopathological examination revealed an improved histological picture and Johnson score of testicular tissue after sulbutiamine treatment. Sulbutiamine administration reduced testicular PKC, MDA, and PCNA levels and increased Nrf2 compared to the untreated group. Moreover, sulbutiamine treatment suppressed apoptosis triggered by STZ as evidenced by elevated Bcl-2, decreased Bax and reduced caspase-3. The present work revealed for the first time a promising protective role of sulbutiamine against STZ-induced testicular dysfunction which may add to the clinical utility of sulbutiamine. The underlying mechanisms involve reducing BGL and PKC, activating Nrf2 and inhibiting apoptosis.

2.
ACS Chem Neurosci ; 14(17): 3047-3058, 2023 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-37585620

RESUMO

Multiple sclerosis (MS) is a progressive neuro-inflammatory and neuro-autoimmune disease. Although hydrogen sulfide has recently shown potential therapeutic impacts in different neurological diseases, its effects on MS are still obscure. MiR-146a is considered a vital target for different therapeutic approaches in treating MS. The present study is directed to explore the therapeutic effects of NaHS (hydrogen sulfide donor) on cuprizone-induced MS and to explore whether NaHS can mediate its effects via regulating miR-146a expression. A total of 28 male C57Bl/6 mice were divided into 4 groups; control, cuprizone-intoxicated, NaHS control (100 µmol/kg/day, i.p), and NaHS-treated groups. Intriguingly, NaHS treatment managed to improve locomotor coordination and curb neuronal inflammation and demyelination as evidenced by hematoxylin & eosin, and Luxol fast blue staining and the increased myelin basic protein (MBP) content. Additionally, NaHS reduced interleukin-1 receptor-associated kinase-1 (IRAK-1), nuclear transcription factor kappa B (NF-κB), interleukin (IL)-17, and IL-1ß brain levels along with downregulation of miR-146a expression compared with the untreated cuprizone-intoxicated group. Furthermore, NaHS-treated animals revealed much less oxidative stress compared to the untreated animals as evidenced by elevated glutathione and reduced malondialdehyde contents. Altogether, the current work reported that NaHS could improve motor dysfunction and reduce axonal demyelination, oxidative stress, as well as neuro-inflammation in mice with MS. Thus, using H2S-releasing compounds could be a promising approach in MS treatment strategies. The mechanism of these beneficial effects may involve the regulation of miR-146a/NF-κB/IL-1ß axis.


Assuntos
Sulfeto de Hidrogênio , MicroRNAs , Esclerose Múltipla , Masculino , Camundongos , Animais , Sulfeto de Hidrogênio/farmacologia , Esclerose Múltipla/tratamento farmacológico , NF-kappa B/metabolismo , Cuprizona , Inflamação , Camundongos Endogâmicos C57BL
3.
J Zhejiang Univ Sci B ; 24(8): 723-733, 2023 Jul 01.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-37551558

RESUMO

Ivermectin is a US Food and Drug Administration (FDA)-approved antiparasitic agent with antiviral and anti-inflammatory properties. Although recent studies reported the possible anti-inflammatory activity of ivermectin in respiratory injuries, its potential therapeutic effect on pulmonary fibrosis (PF) has not been investigated. This study aimed to explore the ability of ivermectin (0.6 mg/kg) to alleviate bleomycin-induced biochemical derangements and histological changes in an experimental PF rat model. This can provide the means to validate the clinical utility of ivermectin as a treatment option for idiopathic PF. The results showed that ivermectin mitigated the bleomycin-evoked pulmonary injury, as manifested by the reduced infiltration of inflammatory cells, as well as decreased the inflammation and fibrosis scores. Intriguingly, ivermectin decreased collagen fiber deposition and suppressed transforming growth factor-|ß1 (TGF-|ß1) and fibronectin protein expression, highlighting its anti-fibrotic activity. This study revealed for the first time that ivermectin can suppress the nucleotide-binding oligomerization domain (NOD)|-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, as manifested by the reduced gene expression of NLRP3 and the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), with a subsequent decline in the interleukin|-|1ß (IL|-|1ß) level. In addition, ivermectin inhibited the expression of intracellular nuclear factor-|κB (NF|-|κB) and hypoxia­inducible factor­1α (HIF|-|1α) proteins along with lowering the oxidative stress and apoptotic markers. Altogether, this study revealed that ivermectin could ameliorate pulmonary inflammation and fibrosis induced by bleomycin. These beneficial effects were mediated, at least partly, via the downregulation of TGF-|ß1 and fibronectin, as well as the suppression of NLRP3 inflammasome through modulating the expression of HIF­1α and NF-|κB.


Assuntos
Inflamassomos , Fibrose Pulmonar , Animais , Ratos , Anti-Inflamatórios , Bleomicina/toxicidade , Fibronectinas/metabolismo , Fibrose , Inflamassomos/metabolismo , Ivermectina/efeitos adversos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico
4.
ACS Chem Neurosci ; 14(11): 2035-2048, 2023 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-37196197

RESUMO

Patients with hyperthyroidism are commonly diagnosed with mood disorders. Naringin, (4',5,7-trihydrocyflavanone-7-O-rhamnoglucoside), a natural bioflavonoid, has many neurobehavioral activities including anxiolytic and antidepressant properties. The role of Wingless (Wnt) signaling in psychiatric disorders is considered substantial but debatable. Recently, regulation of Wnt signaling by naringin has been reported in different disorders. Therefore, the present study aimed to investigate the possible role of Wnt/GSK-3ß/ß-catenin signaling in hyperthyroidism-induced mood disturbances and explore the therapeutic effects of naringin. Hyperthyroidism was induced in rats by intraperitoneal injection of 0.3 mg/kg levothyroxine for 2 weeks. Naringin was orally administered to rats with hyperthyroidism at a dose of 50 or 100 mg/kg for 2 weeks. Hyperthyroidism induced mood alterations as revealed by behavioral tests and histopathological changes including marked necrosis and vacuolation of neurons in the hippocampus and cerebellum. Intriguingly, hyperthyroidism activated Wnt/p-GSK-3ß/ß-catenin/DICER1/miR-124 signaling pathway in the hippocampus along with an elevation in serotonin, dopamine, and noradrenaline contents and a reduction in brain-derived neurotrophic factor (BDNF) content. Additionally, hyperthyroidism induced upregulation of cyclin D-1 expression, malondialdehyde (MDA) elevation, and glutathione (GSH) reduction. Naringin treatment alleviated behavioral and histopathological alterations and reversed hyperthyroidism-induced biochemical changes. In conclusion, this study revealed, for the first time, that hyperthyroidism could affect mental status by stimulating Wnt/p-GSK-3ß/ß-catenin signaling in the hippocampus. The observed beneficial effects of naringin could be attributed to increasing hippocampal BDNF, controlling the expression of Wnt/p-GSK-3ß/ß-catenin signaling as well as its antioxidant properties.


Assuntos
MicroRNAs , Via de Sinalização Wnt , Ratos , Animais , Glicogênio Sintase Quinase 3 beta/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , beta Catenina/metabolismo
5.
Chem Biol Interact ; 381: 110544, 2023 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-37224990

RESUMO

One of the serious complications of diabetes mellitus is diabetic nephropathy (DN) which may finally lead to renal failure. The current study aimed to explore the effect of sulbutiamine, a synthetic derivative of vitamin B1, in streptozotocin (STZ)-induced DN and related pathways. Experimental DN was successfully induced 8 weeks after a single low dose of STZ (45 mg/kg, I.P.). Four groups of rats were used in this study and divided randomly into: control group, diabetic group, sulbutiamine control (control + sulbutiamine) group, and sulbutiamine-treated (60 mg/kg) (diabetic + sulbutiamine) group. The fasting blood glucose level (BGL), the levels of kidney injury molecule-1 (Kim-1), urea and creatinine in serum, as well as the renal content of malondialdehyde (MDA), protein kinase C (PKC), toll-like receptor-4 (TLR-4) and nuclear factor kappa B (NF-κB) were determined. Additionally, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and transforming growth factor-ß1 (TGF-ß1) contents were evaluated immunohistochemically. Sulbutiamine treatment decreased fasting BGL and improved the kidney function tests compared to diabetic rats. Moreover, TLR-4, NF-κB, MDA and PKC contents were substantially reduced following sulbutiamine treatment compared to the diabetic group. Sulbutiamine managed to obstruct the production of the pro-inflammatory TNF-α and IL-1ß and suppressed TGF-ß1 level, in addition to attenuating the histopathological changes associated with DN. This study revealed, for the first time, the ability of sulbutiamine to ameliorate STZ-induced diabetic nephropathy in rats. This nephroprotective outcome of sulbutiamine against DN may be attributed to glycemic control in addition to its anti-oxidative, anti-inflammatory and anti-fibrotic effects.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Animais , Ratos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Rim , NF-kappa B/metabolismo , Estresse Oxidativo , Estreptozocina , Tiamina/farmacologia , Tiamina/uso terapêutico , Receptor 4 Toll-Like/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
6.
J Biochem Mol Toxicol ; 36(9): e23129, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35673973

RESUMO

Despite the extensive therapeutic uses of diclofenac, it may cause several adverse effects, including hepatorenal injury. The antioxidant and anti-inflammatory properties of resveratrol, a polyphenolic compound, make the agent effective in ameliorating a variety of drug-induced injuries. This study investigated the potential beneficial effects of resveratrol on diclofenac-induced hepatorenal toxicity and explored the role of miR-144 and its relationship to oxidative stress and inflammation triggered by diclofenac. Rats were divided into four groups: control; diclofenac group received diclofenac (10 mg/kg/day, intraperitoneal [ip]) for 7 days; prevention group received resveratrol concomitantly with diclofenac for 7 days; and the treatment group received diclofenac for 7 days followed by resveratrol (20 mg/kg/day, per oral) for another 7 days. Diclofenac administration induced a significant increase in serum hepatorenal biomarkers and histopathological aberrations. In addition, diclofenac upregulated miR-144 while reducing nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels and glutathione (GSH) content. Moreover, diclofenac induced tissue inflammation and apoptosis as evidenced by increased protein expression of nuclear factor kappa B (NF-κB), tumor necrosis factor α (TNF-α), and caspase-3. Intriguingly, resveratrol prevention or treatment significantly mitigated the toxic effects of diclofenac as manifested by normalization of the hepatorenal functions and amelioration of the histopathological changes. Resveratrol also triggered miR-144 downregulation with Nrf2 upregulation. Consequently, resveratrol showed hepatorenal antioxidant, anti-inflammatory, and antiapoptotic activities as manifested by improvement in the antioxidant markers along with a decline in NF-κB, TNF-α, and caspase-3 expressions. In conclusion, this study demonstrates a potential therapeutic role of resveratrol in mitigating diclofenac-induced hepatorenal insult, possibly via modulating miR-144/Nrf2/GSH axis.


Assuntos
MicroRNAs , Fator 2 Relacionado a NF-E2 , Animais , Antioxidantes/uso terapêutico , Biomarcadores/metabolismo , Caspase 3/metabolismo , Diclofenaco/toxicidade , Glutationa/metabolismo , Inflamação/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo , Ratos , Resveratrol/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
7.
J Biochem Mol Toxicol ; 35(11): e22899, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34435724

RESUMO

Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide. Lutein (LU) possesses numerous pharmacological activities, including anti-inflammatory, antioxidant, and antiapoptotic effects. This study aimed to investigate the cardioprotective potential of LU in isoprenaline (ISO)-induced MI and to explore its molecular mechanisms of action. AMI was induced by two consecutive subcutaneous doses of ISO (65 mg/kg; s.c.). The LU group was pretreated with LU (20 mg/kg; p.o.) for 30 days followed by ISO injections on Days 29 and 30. ISO group showed elevated serum creatine kinas-MB (CK-MB) and considerable electrocardiographic changes along with reduced ejection fraction compared to the normal group. LU pretreatment could decrease serum CK-MB activity, normalize QRS and QTc intervals and restore ejection fraction compared to the untreated group. The ISO group demonstrated infarcted-like lesions, which were ameliorated in the LU-pretreated group. Immunohistochemical investigation revealed upregulated cardiac troponin T (cTn T) and desmin expressions in the LU-pretreated group. LU pretreatment also enhanced cardiac thioredoxin (Trx) and glutathione (GSH) contents as well as reduced lipid peroxidation, compared to the untreated group. Importantly, LU pretreatment could downregulate long noncoding MI associated transcript (lncRNA MIAT) and thioredoxin-interacting protein (TXNIP) and augment micro RNA (miR)-200a and nuclear factor erythroid 2-related factor 2 (Nrf2) expressions compared to the ISO group. Moreover, a significant inverse correlation between MIAT and miR-200a was observed. In conclusion, this study revealed that LU could ameliorate ISO-induced MI in rats by modulating MIAT/miR-200a/Nrf2 pathway.


Assuntos
Isoproterenol/toxicidade , Luteína/farmacologia , Infarto do Miocárdio/induzido quimicamente , Transdução de Sinais , Animais , Cardiotônicos/farmacologia , Modelos Animais de Doenças , MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , RNA Longo não Codificante/metabolismo , Ratos
8.
Biomed Pharmacother ; 112: 108584, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30784910

RESUMO

Stem cell therapy represents a promising therapeutic avenue for cardiac disorders, including heart failure. Although stem cell transplantation showed encouraging preliminary results, the outcomes of clinical studies are still unsatisfactory. This study aimed to compare the outcomes of two therapeutic approaches, in vivo co-delivery of sodium hydrogen sulfide (NaHS) concomitant with bone marrow-derived mesenchymal stem cell (BMSC) transplantation and in vitro preconditioning of BMSCs with NaHS, both of which are intended to promote the success of stem cell therapy in rats with isoprenaline-induced heart failure. Heart failure developed 4 weeks after the subcutaneous injection of isoprenaline (170 mg/kg) for 4 consecutive days. The in vivo approach involved the co-delivery of intraperitoneally administered NaHS concomitant with BMSC transplantation for a period of 14 days. The in vitro approach involved preconditioning BMSCs with NaHS for 30 min before transplantation. Compared to treatment with BMSCs alone, in vitro preconditioning of BMSCs with NaHS improved left ventricular function as measured by echocardiography and electrocardiography and enhanced stem cell homing, proliferation and differentiation as manifested by higher cardiac expression of GATA-4 and myocyte enhancer factor 2. Moreover, the measurement of cardiac transforming growth factor beta 1 levels and histopathological investigation revealed mitigated fibrosis and myocardial injury scores. Compared with BMSC therapy alone, the in vivo approach enhanced stem cell homing and differentiation, alleviated fibrosis and augmented vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) expression. In conclusion, NaHS can potentiate the efficiency of BMSC therapy for heart failure by in vitro preconditioning or in vivo co-delivery. The in vitro approach is superior with regard to improving cardiac function in addition to enhancing stem cell proliferation, while the in vivo approach is superior with regard to increasing cardiac VEGF and eNOS expression.


Assuntos
Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/terapia , Sulfeto de Hidrogênio/administração & dosagem , Precondicionamento Isquêmico Miocárdico/métodos , Animais , Terapia Combinada , Insuficiência Cardíaca/fisiopatologia , Masculino , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/fisiologia , Distribuição Aleatória , Ratos , Ratos Wistar , Resultado do Tratamento
9.
Stem Cell Res Ther ; 6: 172, 2015 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-26369808

RESUMO

INTRODUCTION: Activation of endogenous stem cell mobilization can contribute to myocardial regeneration after ischemic injury. This study aimed to evaluate the possible role of Avemar or Echinacea extracts in inducing mobilization and homing of CD34(+) stem cells in relation to the inflammatory and hematopoietic cytokines in rats suffering from acute myocardial infarction (AMI). METHODS: AMI was developed by two consecutive subcutaneous injections of isoprenaline (85 mg/kg). AMI rats were either post-treated or pre- and post-treated daily with oral doses of Avemar (121 mg/kg) or Echinacea (130 mg/kg). In whole blood, the number of CD34(+) cells was measured by flow cytometry and their homing to the myocardium was immunohistochemically assessed. Serum creatine kinase, vascular endothelial growth factor, interleukin-8 and granulocyte macrophage colony stimulating factor were determined on days 1, 7 and 14 after AMI. Sections of the myocardium were histopathologically assessed. RESULTS: Rats pre- and post-treated with Avemar or Echinacea exhibited substantial increases in the number of circulating CD34(+) cells, peaking on the first day after AMI to approximately 13-fold and 15-fold, respectively, with a decline in their level on day 7 followed by a significant increase on day 14 compared to their corresponding AMI levels. Only post-treatment with Echinacea caused a time-dependent increase in circulating CD34(+) cells on days 7 and 14. Such increases in circulating CD34(+) cells were accompanied by increased homing to myocardial tissue 14 days after AMI. Interestingly, pre- and post-treatment with Avemar or Echinacea substantially increased serum creatine kinase on day 1, normalized its activity on day 7 and, on continued treatment, only Echinacea markedly increased its activity on day 14 compared to the corresponding AMI values. Moreover, both treatments modified differently the elevated serum vascular endothelial growth factor and the lowered granulocyte macrophage colony stimulating factor levels of the AMI group but did not affect the level of interleukin-8. These results were supported histopathologically by reduced inflammatory reactions and enhanced neovascularization. CONCLUSION: Avemar and Echinacea extracts can effectively induce mobilization and homing of CD34(+) stem cells to the myocardial tissue and thus may help in stem cell-based regeneration of the infarcted myocardium.


Assuntos
Antígenos CD34/metabolismo , Movimento Celular , Infarto do Miocárdio/tratamento farmacológico , Extratos Vegetais/farmacologia , Células-Tronco/efeitos dos fármacos , Animais , Antígenos CD34/genética , Echinacea/química , Masculino , Infarto do Miocárdio/sangue , Miocárdio/citologia , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Células-Tronco/metabolismo , Células-Tronco/fisiologia
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