RESUMO
Even while accelerated cardiomyocyte apoptosis is one of the primary causes of cardiac damage, the underlying mechanism is still mostly unknown. In addition to examining potential protective effects of bisoprolol and diosmin against CoCl2-induced cardiac injury, the goal of this study was to identify potential mechanisms regulating the hypoxic cardiac damage caused by cobalt chloride (CoCl2). For a period of 21 days except Cocl2 14 days from the first day of the experiment, rats were split into the following groups: Normal control group, rats received vehicle only (2 ml/kg/day, p.o.), (Cocl2, 150 mg/kg/day, p.o.), bisoprolol (25 mg/kg/day, p.o.); diosmin (100 mg/kg/day, p.o.) and bisoprolol + diosmin + Cocl2 groups. At the end of the experimental period, serum was taken for estimation of cardiac function, lipid profile, and pro/anti-inflammatory cytokines. Moreover, tissue samples were collected for evaluation of oxidative stress, endothelial dysfunction, α-SMA, PKC-α, MiR-143-3P, MAPK, ERK5, MCP-1, CXCR4, Orai-1, and STIM-1. Diosmin and bisoprolol, either alone or in combination, enhance heart function by reducing abnormalities in the electrocardiogram and the hypotension brought on by CoCl2. Additionally, they significantly ameliorate endothelial dysfunction by downregulating the cardiac expressions of α-SMA, PKC-α, MiR-143-3P, MAPK, ERK5, MCP-1, CXCR4, Orai-1, and STIM-1. Bisoprolol and diosmin produced modulatory activity against inflammatory state, redox balance, and atherogenic index concurrently. Together, diosmin and bisoprolol, either alone or in combination, significantly reduced all the cardiac alterations brought on by CoCl2. The capacity to obstruct hypoxia-induced α-SMA, PKC-α, MiR-143-3P/MAPK/MCP-1, MiR-143-3P/ERK5/CXCR4, Orai-1/STIM-1 signaling activation, as well as their anti-inflammatory, antioxidant, and anti-apoptotic properties, may be responsible for these cardio-protective results.
Assuntos
Bisoprolol , Cardiotoxicidade , Cobalto , Diosmina , MicroRNAs , Proteína ORAI1 , Receptores CXCR4 , Transdução de Sinais , Animais , Cobalto/toxicidade , Masculino , Receptores CXCR4/metabolismo , Receptores CXCR4/genética , Cardiotoxicidade/tratamento farmacológico , Ratos , Bisoprolol/farmacologia , Bisoprolol/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , MicroRNAs/metabolismo , MicroRNAs/genética , Diosmina/farmacologia , Diosmina/uso terapêutico , Proteína ORAI1/metabolismo , Proteína ORAI1/genética , Ratos Wistar , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Quimiocina CCL2RESUMO
BACKGROUND: Vancomycin (VCM) is used clinically to treat serious infections caused by multi-resistant Gram-positive bacteria, although its use is severely constrained by nephrotoxicity. This study investigated the possible nephroprotective effect of febuxostat (FX) and/or fenofibrate (FENO) and their possible underlying mechanisms against VCM-induced nephrotoxicity in a rat model. METHODS: Male Wistar rats were randomly allocated into five groups; Control, VCM, FX, FENO, and combination groups. Nephrotoxicity was evaluated histopathologically and biochemically. The oxidative stress biomarkers (SOD, MDA, GSH, total nitrite, GPx, MPO), the apoptotic marker, renal Bcl-2 associated X protein (Bax), and inflammatory and kidney injury markers (IL-1ß, IL-6, TNF-α, Nrf2, OH-1, kappa-light-chain-enhancer of activated B cells (NF-κB), NADPH oxidase, Kim-1, COX-II, NGAL, Cys-C were also evaluated. RESULTS: VCM resulted in significant elevation in markers of kidney damage, oxidative stress, apoptosis, and inflammatory markers. Co-administration of VCM with either/or FX and FENO significantly mitigated nephrotoxicity and associated oxidative stress, inflammatory and apoptotic markers. In comparison to either treatment alone, a more notable improvement was observed with the FX and FENO combination regimen. CONCLUSION: Our findings show that FX, FENO, and their combination regimen have a nephroprotective impact on VCM-induced kidney injury by suppressing oxidative stress, apoptosis, and the inflammatory response. Renal recovery from VCM-induced injury was accomplished by activation of Nrf2/HO-1 signaling and inhibition of NF-κB expression. This study highlights the importance of FX and FENO as effective therapies for reducing nephrotoxicity in VCM-treated patients.
Assuntos
Injúria Renal Aguda , Febuxostat , Fator 2 Relacionado a NF-E2 , NF-kappa B , Ratos Wistar , Transdução de Sinais , Vancomicina , Animais , Masculino , Ratos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Injúria Renal Aguda/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Antibacterianos/farmacologia , Antibacterianos/toxicidade , Ciclo-Oxigenase 2/metabolismo , Febuxostat/farmacologia , Heme Oxigenase (Desciclizante)/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama , Transdução de Sinais/efeitos dos fármacos , Vancomicina/toxicidade , Vancomicina/farmacologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Solenostemma argel is widely distributed in Africa & Asia with traditional usage in alleviating abdominal colic, aches, & cramps. This plant is rich in phytochemicals, which must be explored for its pharmacological effects. PURPOSE: Peptic Ulcer Disease (PUD) is the digestion of the digestive tube. PUD not only interferes with food digestion & nutrient absorption, damages one of the largest defensive barriers against pathogenic micro-organisms, but also impedes drug absorption & bioavailability, rendering the oral route, the most convenient way, ineffective. Omeprazole, one of the indispensable cost-effective proton-pump inhibitors (PPIs) extensively prescribed to control PUD, is showing growing apprehensions toward multiple drug interactions & side effects. Hence, finding a natural alternative with Omeprazole-like activity & limited side effects is a medical concern. STUDY DESIGN: Therefore, we present Stemmoside C as a new gastroprotective phytochemical agent isolated from Solenostemma argel to be tested in upgrading doses against ethanol-induced gastric ulcers in mice compared to negative, positive, & reference Omeprazole groups. METHODS: We carried out in-depth pharmacological & histopathological studies to determine the possible mechanistic pathway. RESULTS: Our results showed that Stemmoside C protected the stomach against ethanol-induced gastric ulcers parallel to Omeprazole. Furthermore, the mechanistic studies revealed that Stemmoside C produced its effect using an orchestrated array of different mechanisms. Stemmoside C stimulates stomach defense by increasing COX-2, PGE-2, NO, & TFF-1 healing factors, IL-10 anti-inflammatory cytokine, & Nrf-2 & HO-1 anti-oxidant pathways. It also suppresses stomach ulceration by inhibiting leucocyte recruitment, especially neutrophils, leading to subsequent inhibition of NF-κBp65, TNF-α, IL-1ß, & iNOS pro-inflammatory cytokines & JAK-1/STAT-3 inflammation-induced carcinogenicity cascade in addition to MMP-9 responsible for tissue degradation. CONCLUSION: These findings cast light on Stemmoside C's clinical application against gastric ulcer progression, recurrence, & tumorigenicity & concurrently with chemotherapy.
Assuntos
Antiulcerosos , Úlcera Gástrica , Camundongos , Animais , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/patologia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/metabolismo , Antiulcerosos/farmacologia , Antiulcerosos/uso terapêutico , Omeprazol/farmacologia , Omeprazol/uso terapêutico , Etanol/farmacologia , Citocinas/metabolismo , Mucosa GástricaRESUMO
Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related deaths worldwide. Current treatment strategies include surgical resection, liver transplantation, liver-directed therapy, and systemic therapy. Sorafenib (Sor) is the first systemic drug authorized by the US Food and Drug Administration (FDA) for HCC treatment. Nevertheless, the conventional oral administration of Sor presents several limitations: poor solubility, low bioavailability, drug resistance development, and off-target tissue accumulation, leading to numerous adverse effects. Nano-emulsion, a nano-delivery system, is a viable carrier for poorly water-soluble drugs. It aims to enhance drug bioavailability, target organ accumulation, and reduce off-target tissue exposure, thus improving therapeutic outcomes while minimizing side effects. This study formulated Sor nano-emulsion (Sor NanoEm) using the homogenization technique. The resultant nano-emulsion was characterized by particle size (121.75 ± 12 nm), polydispersity index (PDI; 0.310), zeta potential (-12.33 ± 1.34 mV), viscosity (34,776 ± 3276 CPs), and pH (4.38 ± 0.3). Transmission Electron Microscopy exhibited spherical nano-droplets with no aggregation signs indicating stability. Furthermore, the encapsulation of Sor within the nano-emulsion sustained its release, potentially reducing the frequency of therapeutic doses. Cytotoxicity assessments on the HepG2 cell line revealed that Sor NanoEm had a significantly (P < 0.05) more potent cytotoxic effect compared to Sor suspension. Subsequent tests highlighted superior pharmacokinetic parameters and reduced dosage requirements of Sor NanoEm in mice. It exhibited an enhanced safety profile, particularly in behavior, brain, and liver, compared to its suspended form. These findings underscore the enhanced pharmacological and toxicological attributes of Sor Nano-emulsion, suggesting its potential utility in HCC treatment.
RESUMO
Di-(2-ethylhexyl) phthalate (DEHP) is the most abundant phthalate threatening public health-induced neurotoxicity. This neurotoxicity is associated with behavioral and biochemical deficits in male rats. Our study investigated the neuroprotective effect of ferulic acid (FA) on male rats exposed to DEHP. Thirty-two male Wistar rats were assigned to four groups. Group I control rats received corn oil, group II intoxicated rats received 300 mg/kg of DEHP, group III received 300 mg/kg of DEHP + 50 mg/kg of FA, and group IV received 50 mg/kg of FA, all agents administrated daily per os for 30 days. Anxiety-like behavior, spatial working memory, and recognition memory were assessed. Also, brain oxidative stress biomarkers, including brain malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), superoxide dismutase (SOD), brain-derived neurotrophic factor (BDNF) as well as heme oxygenase-1 (HO-1) were measured. Moreover, brain histopathology examinations associated with immunohistochemistry determination of brain caspase-3 were also evaluated. Furthermore, docking simulation was adapted to understand the inhibitory role of FA on caspase-3 and NO synthase. Compared to DEHP-intoxicated rats, FA-treated rats displayed improved cognitive memory associated with a reduced anxious state. Also, the redox state was maintained with increased BNDF levels. These changes were confirmed by restoring the normal architecture of brain tissue and a decrement in the immunohistochemistry caspase-3. In conclusion, FA has potent antioxidant and antiapoptotic properties that confirm the neuroprotective activity of FA, with a possible prospect for its therapeutic capabilities and nutritional supplement value.
RESUMO
BACKGROUND: Sodium butyrate (SB) is a short-chain fatty acid and a safe antibiotic alternative. During 35 days, this study compared the impact of coated SB (Butirex C4) and lincomycin (Lincomix) on broiler growth, gut health, and litter hygiene in 1200 one-day-old Ross-308 broiler chicks that were randomly assigned into 5-dietary groups with 5-replications each. Groups divided as follows: T1: Basal diet (control), T2: Basal diet with buffered SB (1 kg/ton starter feed, 0.5 kg/ton grower-finisher feeds), T3: Basal diet with 100 g/ton lincomycin, T4: Basal diet with buffered SB (0.5 kg/ton starter feed, 0.25 kg/ton grower-finisher feeds) + 50 g/ton lincomycin, and T5: Basal diet with buffered SB (1 kg/ton starter feed, 0.5 kg/ton grower-finisher feeds) + 50 g/ton lincomycin. Birds were housed in a semi-closed deep litter house, where feed and water were available ad libitum. Results were statistically analyzed using ANOVA and Tukey's post hoc tests. RESULTS: Combined dietary supplementation with SB and lincomycin (T4 and T5) significantly enhanced body weights, weight gains, feed conversion ratio, and profitability index. Also, carcasses in T4 and T5 exhibited the highest dressing, breast, thigh, and liver yields. T5 revealed the best blood biochemical indices, while T3 showed significantly elevated liver and kidney function indices. T4 and T5 exhibited the highest expression levels of IGF-1 and TLR4 genes, the greatest villi length of the intestinal mucosa, and the lowest levels of litter moisture and nitrogen. Clostridia perfringens type A alpha-toxin gene was confirmed in birds' caeca, with the lowest clostridial counts defined in T4. CONCLUSIONS: Replacing half the dose of lincomycin (50 g/ton) with 0.5 or 1 kg/ton coated SB as a dietary supplement mixture showed the most efficient privileges concerning birds' performance and health.
Assuntos
Galinhas , Receptor 4 Toll-Like , Animais , Ácido Butírico/metabolismo , Lincomicina/farmacologia , Fator de Crescimento Insulin-Like I/genética , Dieta/veterinária , Suplementos Nutricionais , Ração Animal/análiseRESUMO
Plants belonging to the Launaea genus have been extensively utilized ethnopharmacologically to treat a variety of diseases, including kidney disorders. Chromium is a common industrial pollutant that has been linked to kidney disease. The present work was designed for the investigation of the UPLC-QTOF-MS/MS metabolite profile of the L. mucronate ethanolic extract (LME), along with assessing the mechanistic protective actions of LME and its nano-silver formulation (LMNS) against K2Cr2O7-induced nephrotoxicity in rats. LMNE was successfully biosynthesized and confirmed using UV-Visible (UV-Vis) spectroscopy and transmission electron microscopy (TEM). The nephroprotective effects of LME and LMNE was assessed in rats exposed to potassium dichromate (K2Cr2O7, 15 mg/kg BW) to cause nephrotoxicity. LME and LMNS, separately, were administered twice daily for 14 days at doses of 200 and 400 mg/kg BW, respectively. The kidney function, catalase, UGT, Nrf2, PGE2, Cox-2, ERK, and MAPK levels in renal tissue were all assessed, along with histopathological examinations for exploring their ameliorative effects. Forty-five bioactive metabolites were annotated belonging to flavonoids, phenolic and organic acids, coumarins, and fatty acids. Metabolite profiling revealed that chlorogenic acid, apigenin, and luteolin glycosides were the main phenolics, with chlorogenic acid-O-hexoside reported for the first time in LME. The findings revealed that the serum kidney function indicators (urea and creatinine) were markedly elevated in K2Cr2O7-intoxicated rats. Furthermore, inflammatory indicators (COX-2 and PGE2), MAPK, and ERK were all markedly elevated in kidney tissue, whereas catalase, UGT, and Nrf2 levels were downregulated. Histological and immunohistochemical assays confirmed the toxic effects of K2Cr2O7 in the kidneys. In contrast, the administration of LME and LMNS prior to K2Cr2O7 considerably improved the architecture of the renal tissue, while also restoring levels of most biochemical markers. Functioning via the inhibition of the MAPK/ERK pathway, activating Nrf2, and modifying the antioxidant and metabolic enzymes, LME and LMNS exerted their nephroprotective effects against K2Cr2O7-induced toxicity.
RESUMO
Hexavalent chromium salt, like potassium dichromate (PD), is chromium's most precarious valence state in industrial wastes. Recently, there has been increasing interest in ß-sitosterol (BSS), a bioactive phytosterol, as a dietary supplement. BSS is recommended in treating cardiovascular disorders due to its antioxidant effect. Trimetazidine (TMZ) was used traditionally for cardioprotection. Through the administration of BSS and TMZ, the cardiotoxic effects of PD were to be countered in this study, in addition to examining the precise mechanism of PD-induced cardiotoxicity. Thirty male albino rats were divided into five groups; the control group: administered normal saline daily (3 mL/kg); the PD group: administered normal saline daily (3 mL/kg); BSS group: administered BSS daily (20 mg/kg); TMZ group: administered TMZ daily (15 mg/kg); and the BSS + TMZ group: administered both BSS (20 mg/kg) and TMZ (15 mg/kg) daily. All experimental groups, except the control, received on the 19th day a single dose of PD (30 mg/kg/day, S.C.). Normal saline, BSS, and TMZ were received daily for 21 consecutive days p.o. The exposure to PD promoted different oxidative stresses, pro-inflammatory, and cardiotoxicity biomarkers. BSS or TMZ succeeded solely in reducing these deleterious effects; however, their combination notably returned measured biomarkers close to normal values. The histopathological investigations have supported the biochemical findings. The combination of BSS and TMZ protects against PD cardiotoxicity in rats by reducing oxidative stress and apoptotic and inflammatory biomarkers. It may be promising for alleviating and protecting against PD-induced cardiotoxicity in people at an early stage; however, these findings need further clinical studies to be confirmed. HIGHLIGHTS: ⢠Potassium dichromate induces cardiotoxicity in rats through the upregulation of oxidative stress, proinflammatory, and apoptotic pathways biomarkers. ⢠ß-Sitosterol possesses a possible cardioprotective effect by modulating several signaling pathways. ⢠Trimetazidine, the antianginal agent, has a potential cardioprotective impact on PD-intoxicated rat model. ⢠The combination of ß-Sitosterol and trimetazidine was the best in modulating different pathways involved in PD cardiotoxicity in rats via the interplay between NF-κB/AMPK/mTOR/TLR4 and HO-1/NADPH signaling pathways.
Assuntos
Trimetazidina , Masculino , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/farmacologia , Biomarcadores , Cardiotoxicidade/tratamento farmacológico , NADP/metabolismo , NADP/farmacologia , NF-kappa B/metabolismo , Dicromato de Potássio , Solução Salina/farmacologia , Transdução de Sinais , Receptor 4 Toll-Like , Serina-Treonina Quinases TOR/metabolismo , Trimetazidina/farmacologia , Trimetazidina/uso terapêutico , Animais , RatosRESUMO
Acute lung injury (ALI) is a life-threatening condition usually associated with poor therapeutic outcomes and a high mortality rate. Since 2019, the situation has worsened due to the COVID-19 pandemic. ALI had approximately 40% of deaths before COVID-19, mainly due to the dysfunction of the blood-gas barrier that led to lung edema, failure of gas exchange, and dyspnea. Many strategies have been taken to mitigate the disease condition, such as diuretics, surfactants, antioxidants, glucocorticoids, heparin, and ventilators with concomitant sedatives. However, until now, there is no available effective therapy for ALI. Thus, we are presenting a new compound termed Arabincoside B (AR-B), recently isolated from Caralluma arabica, to be tested in such conditions. For that, the lipopolysaccharide (LPS) mice model was used to investigate the capability of the AR-B compound to control the ALI compared to standard dexamethasone. The results showed that AR-B had a significant effect on retrieving ALI. A further mechanistic study carried out in the serum, lung homogenate, histological, and immunohistochemistry sections revealed that the AR-B either in 50 mg/kg or 75 mg/kg dose inhibited pro-inflammatory cytokines such as IL-6, IL-13, NF-κB, TNFα, and NO and stimulated regulatory cytokines IL-10. Moreover, AR-B showed a considerable potential to protect the pulmonary tissue against oxidative stress by decreasing MDA and increasing catalase and Nrf2. Also, the AR-B exhibited an anti-apoptotic effect on the lung epithelium, confirmed by reducing COX and BAX expression and upregulating Bcl-2 expression. These results pave its clinical application for ALI.
Assuntos
Lesão Pulmonar Aguda , Apocynaceae , COVID-19 , Pneumonia , Camundongos , Animais , Humanos , Lipopolissacarídeos/farmacologia , Transdução de Sinais , Pandemias , COVID-19/metabolismo , Pulmão , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , NF-kappa B/metabolismo , Pneumonia/metabolismo , Citocinas/metabolismo , Apocynaceae/metabolismoRESUMO
BACKGROUND: With the recent growth in the applications of silver nanoparticles (Ag-NPs), worries about their harmful effects are increasing. Selenium plays a vital role in the antioxidant defense system as well as free radical scavenging activity. OBJECTIVES: This study aims to inspect the neuroprotective effect of selenium-loaded chitosan nanoparticles (CS-SeNPs) against the adverse impact of Ag-NPs on brain tissue in adult rats. DESIGN: Rats were divided into four groups: group I (control) was administered distilled water (0.5 mL/kg), group II was administered Ag-NPs (100 mg/kg), group III was administered Ag-NPs (100 mg/kg) and CS- SeNPs (0.5 mg/kg) and group IV received only CS- SeNPs (0.5 mg/kg) daily by oral gavage. After 60 days, rats were subjected to behavioral assessment and then euthanized. Brain tissues were obtained for estimation of total antioxidant capacity (TAC), malondialdehyde (MDA), 8-hydroxy-2-deoxy Guanosine (8-OHdG), and Nuclear Factor Erythroid 2 Like Protein 2 (Nrf2). Also, histological examination of the brain and immunohistochemical detection of glial fibrillary acidic protein (GFAP) were investigated RESULTS: exposure to Ag-NPs induced marked neurotoxicity in the brain tissue of rats that was manifested by decreased levels of TAC and Nrf2 with increased levels of MDA and 8-OHdG. Also, various pathological lesions with an increase in the number of GFAP immunoreactive cells were detected. While brain tissue of rats received Ag-NPs plus CS-SeNPs group (III) revealed significantly fewer pathological changes. CONCLUSION: Co-administration of CS-SeNPs significantly ameliorates most of the Ag-NPs-induced brain damage.
Assuntos
Quitosana , Nanopartículas Metálicas , Nanopartículas , Fármacos Neuroprotetores , Selênio , Ratos , Animais , Selênio/farmacologia , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Fármacos Neuroprotetores/farmacologia , Quitosana/farmacologia , Prata/toxicidade , Nanopartículas Metálicas/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Estresse OxidativoRESUMO
In this study, the anti-inflammatory effects of the methanolic extract (TE) of Plumeria obtusa L. (aerial parts) and its fractions were evaluated in vitro, and active fraction was evaluated in vivo. Among tested extracts, dichloromethane fraction (DCM-F) exhibited the strongest inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) in RAW 264.7 macrophages. The effect of DCM-F on LPS-induced acute lung injury (ALI) in mice was studied. The animals were divided into five groups (n = 7) randomly; Gp I: negative control, GP II: positive control (LPS group), GP III: standard (dexamethasone, 2 mg/kg b.wt), GP IV and V: DCM-F (100 mg/kg), and DEM-F (200 mg/kg), respectively. DCM-F at a dose of 200 mg/kg suppressed the ability of LPS to increase the levels of nitric oxide synthase (iNOS), NO, tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6), as measured by ELISA. In addition, the expression of cyclooxygenase-2 (COX-2) was reduced (determined by immunohistochemistry) and the level of malondialdehyde (MDA) was decreased while that of catalase was restored to the normal values. Furthermore, the histopathological scores of inflammation induced by LPS were reduced. Twenty-two compounds were tentatively identified in DCM-F using LC/ESI-QToF with iridoids, phenolic derivatives and flavonoids as major constituents. Identified compounds were subjected to two different molecular docking processes against iNOS and prostaglandin E synthase-1 target receptors. Notably, protoplumericin A and 13-O-coumaroyl plumeride were the most promising members compared to the co-crystallized inhibitor in each case. These findings suggested that DCM-F attenuates the LPS-induced ALI in experimental animals through its anti-inflammatory and antioxidant potential.
Assuntos
Lesão Pulmonar Aguda , Lipopolissacarídeos , Camundongos , Animais , Lipopolissacarídeos/farmacologia , Simulação de Acoplamento Molecular , Extratos Vegetais/uso terapêutico , NF-kappa B/metabolismo , Inflamação/metabolismo , Macrófagos , Anti-Inflamatórios/uso terapêutico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismoRESUMO
Aluminum oxide nanoparticles (Al2O3 NPs) have been widely used in vaccine manufacture, food additives, human care products, and cosmetics. However, they also have adverse effects on different organs, including the liver, kidneys, and testes. Melatonin is a potent antioxidant, particularly against metals by forming melatonin-metal complexes. The present study aimed to investigate the protective effects of melatonin against Al2O3 NP-induced toxicity in the rat brain. Forty adult male Wistar rats were allocated to four groups: the untreated control (received standard diet and distilled water), Al2O3 NP-treated (received 30 mg/kg body weight Al2O3 NPs), melatonin and Al2O3 NP-treated (received 30 mg/kg body weight Al2O3 NPs + 10 mg/kg body weight melatonin), and melatonin-treated (received 10 mg/kg body weight melatonin) groups. All treatments were by oral gavages and administered daily for 28 days. Afterward, the rats were sacrificed, and samples from various brain regions (cerebrum, cerebellum, and hippocampus) were subjected to biochemical, histopathological, and immunohistochemical analyses. Al2O3 NPs substantially increased malondialdehyde, ß-amyloid 1-42 peptide, acetylcholinesterase, and ß-secretase-1 expression, whereas they markedly decreased glutathione levels. Furthermore, Al2O3 NPs induced severe histopathological alterations, including vacuolation of the neuropil, enlarged pericellular and perivascular spaces, vascular congestion, neuronal degeneration, and pyknosis. Al2O3 NP treatment also resulted in an intense positive caspase-3 immunostaining. Conversely, the administration of melatonin alleviated the adverse effects induced by Al2O3 NPs. Therefore, melatonin can diminish the neurotoxic effects induced by Al2O3 NPs.
Assuntos
Melatonina , Nanopartículas , Humanos , Masculino , Ratos , Animais , Óxido de Alumínio/toxicidade , Ratos Wistar , Melatonina/farmacologia , Acetilcolinesterase/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Cerebelo/metabolismo , Hipocampo/metabolismo , Peso Corporal , Estresse OxidativoRESUMO
Bisphenol A (BPA) used in plastic industry. This study evaluate ameliorative effect of vitamin E and selenium in combating BPA toxicity in spinal cord (SC) and submandibular glands (SMGs). Thirty rats divided into three groups [Group I, controls; Group II, BPA orally (25 mg/kg) three times a week, 60 days; Group III, BPA (25 mg/kg) plus vitamin E and selenium in water (1 ml/L/day)]. By histopathological, immunohistochemical, and biochemical investigations. Bisphenol A group showed degenerative alterations. SC gray matter showed pyknotic nuclei and white matter revealed neuropil degeneration. Myelinated fibers showed dispersed myelin. SMGs, exhibited vacuolated cytoplasm in acinar cells. Intense glial fibrillary acidic protein in SC and strong proliferating cell nuclear antigen in acinar and ductal cell nuclei of SMGs. Malondialdehyde elevated in SC and catalase decreased in SMG. Group III, SC and SMG revealed partial recovery. Vitamin E and selenium displayed protective effects against BPA toxicity in SC and SMGs.
BPA had a neurotoxic effect on spinal cord of albino rats.BPA causing degeneration of nerve fibers with axonal disappearance of white matter.BPA caused GFAP proliferation and high MDA level in spinal cord.BPA caused degeneration of submandibular gland's acinar cells and duct system.Both vitamin E and Selenium had a protective effect against BPA toxicity.
Assuntos
Selênio , Vitamina E , Ratos , Masculino , Animais , Vitamina E/farmacologia , Selênio/farmacologia , Glândula Submandibular , Compostos Benzidrílicos/toxicidade , Medula Espinal , Estresse OxidativoRESUMO
Atrazine (ATZ) is a widely used herbicide; however, it has deleterious effects. The current study aimed to investigate the potential toxic effect of ATZ as a neuroendocrine disruptor on the cerebellum and thyroid gland and on the liver as a detoxifying organ. We examined the ability of ATZ to induce oxidative stress and subsequent apoptosis in these organs. Moreover, we investigated the potential protective effect of Acacia nilotica, because of its potent antioxidant activity. Thus, our study was carried out on 40 adult male albino rats that were divided equally into 4 groups (10 rats/each group). The first group received distilled water, while the second group received ATZ dissolved in corn oil at 200 mg/kg body weight/day by stomach gavage. The third group was treated orally by ATZ (200 mg/kg body weight/day) plus Acacia nilotica (400 mg/kg/day). Group IV received Acacia nilotica only at a dose (400 mg/kg/day). After successive 30 days of the experiment, blood and tissue samples were collected from all groups. Our findings revealed the ability of ATZ to induce toxic effects was observed microscopically in the form of degenerated neurons and vacuolated neuropil of the cerebellum, degenerated hepatocytes, and vacuolation of the follicular cells of the thyroid gland. Furthermore, ATZ significantly elevated AST, ALT, and ALP serum levels and TB concentration, while decreased GSH. DNA fragmentation% and activated caspase-3 expression significantly increased after ATZ exposure. Interestingly, Acacia nilotica administration was able to partially protect the examined organs against the toxic effect of ATZ exposure.
Assuntos
Acacia , Atrazina , Ratos , Animais , Acacia/química , Atrazina/toxicidade , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Estresse Oxidativo , Peso CorporalRESUMO
This study was conducted to explore the potential cardioprotective and anti-depressive effects of dichloromethane (DCM) fractions of Morus macroura leaves (L) and stem branches (S) on post-myocardial infarction (MI) depression induced by isoprenaline (ISO) in rats in relation to their metabolites. The study was propped with a UPLC-ESI-MS/MS profiling and chromatographic isolation of the secondary metabolites. Column chromatography revealed the isolation of lupeol palmitate (6) that was isolated for the first time from nature with eight known compounds. In addition, more than forty metabolites belonging, mainly to flavonoids, and anthocyanins groups were identified. The rats were injected with ISO (85 mg kg-1, s.c) in the first two days, followed by the administration of M. macroura DCM-L and DCM-S fractions (200 mg kg-1 p.o) for 19 days. Compared with the ISO exposed rats, the treated rats displayed a reduction in cardiac biomarkers (LDH and CKMB), anxiety, and depressive-like behaviour associated with an increase in the brain defense system (SOD and GSH), neuronal cell energy, GABA, serotonin, and dopamine, confirmed by histopathological investigations. In conclusion, DCM-L and DCM-S fractions' cardioprotective and anti-depressive activities are attributed to their metabolite profile. Therefore, they could serve as a potential agent in amending post-MI depression.
RESUMO
Two new series of coumarin and benzofuran derivatives were designed, synthesized, and assessed for their in vitro and in vivo antitumor activities against breast cancer. Compounds 8, 9, 14, 15, and 17 exhibited the best antiproliferative activities (IC50 : 0.07-2.94 µM) against the MCF-7 cell line, compared with lapatinib (IC50 : 4.69 µM). Compound 14, with the most potent cytotoxic activity against MCF-7 cells, was capable of enhancing preG1 apoptosis and triggering cell cycle arrest at the G2/M phase. The kinase inhibitory activity of compound 14 against a panel of 22 kinases was examined to reveal multikinase inhibition within -39% to -97%. Furthermore, compound 14 exhibited potent in vivo Ehrlich (mammary adenocarcinoma) tumor regression, positive caspase-3, and negative EGFR immunoreaction, and was capable of elevating the catalase level. The physicochemical properties and pharmacokinetic parameters of compound 14 were investigated in silico for its druglikeness.
Assuntos
Antineoplásicos , Benzofuranos , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose , Benzofuranos/química , Benzofuranos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Cumarínicos/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-AtividadeRESUMO
Atrazine (ATZ) is herbicide that has been widely used for different crops. This extensive use has resulted in severe deleterious effects in different species. In this work, we investigated the potentially harmful effect of atrazine herbicide on the brain and submandibular salivary gland. Our investigation was carried out on 20 adult male albino rats that were equally divided into two groups. The first group received distilled water as control, while the second group received ATZ at 200 mg/kg body weight/ day via stomach gavage for 30 successive days of the experiment; the oral LD50 for ATZ is 3090 mg/kg. Our findings revealed the ability of ATZ to cause damage to the cerebrum, hippocampus, and submandibular salivary gland. This damage resulted from the induced oxidative stress, which was indicated by a significant elevation in malondialdehyde (MDA) concentration, DNA fragmentation, tumor necrotic factor-alpha (TNF-α) expression, with a significant decrease in reduced glutathione (GSH) level and reduction of B cell lymphoma 2 (BCL2), dopamine receptor D1 (Drd1), cAMP-responsive element-binding protein 1 (Creb1) genes expression after ATZ exposure. Moreover, degeneration of cells, cytoplasmic vacuolation, congestion of blood vessels, a strong immune reaction to caspase 3, and negligible immune expression of a glial fibrillary acidic protein (GFAP) were also noticed in the ATZ-treated group. We concluded that ATZ induces oxidative stress and has a toxic and apoptotic effects on the cerebrum, hippocampus, and salivary gland of adult male albino rats.
Assuntos
Atrazina , Herbicidas , Animais , Atrazina/toxicidade , Encéfalo/metabolismo , Herbicidas/toxicidade , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo , RatosRESUMO
Polystyrene Nanoparticles (PS-NPs) used for packaging foam, disposable cups, and food containers. Therefore, this study aimed to evaluate PS- NPs toxic effects on kidney of adult male albino rats. A total of 30 rats divided into three groups (n = 10): group I negative control group; group II orally administered 3% PS-NPs (3 mg/kg body weight/day) and group III orally administered 3% PS-NPs (10 mg/kg body weight/day) for 35 days. Blood and kidney samples collected and processed for biochemical, histopathological, and immunohistochemical examinations. Results showed that low and high doses PS-NPs had significantly increased serum blood urea nitrogen (BUN), creatinine, malondialdehyde, significantly further reduced glutathione, downregulation of nuclear factor erythroid 2-related factor 2 and glutathione peroxidase, upregulation of caspase-3 and Cytochrome-c. Histopathological examination revealed several alterations. Low dose of PS-NPs exhibited dilated glomerular capillaries, hypotrophy of some renal corpuscles significantly decreases their diameter to 62 µm. Some proximal convoluted tubules and distal convoluted tubules showed loss of cellular architecture with pyknotic nuclei. Hyalinization and vacuolation in renal medulla. In high dose PS-NPs, alterations increased in severity. A significant increase in percentage area of cyclooxygenase-2 in low and high-doses. In conclusion, PS-NPs are a nephrotoxic causing renal dysfunction.
Assuntos
Nefropatias , Nanopartículas , Animais , Rim/metabolismo , Nefropatias/metabolismo , Masculino , Malondialdeído/metabolismo , Nanopartículas/toxicidade , Estresse Oxidativo , Poliestirenos/análise , Poliestirenos/metabolismo , Poliestirenos/toxicidade , RatosRESUMO
Chemotherapeutic-related toxicity exacerbates the increasing death rate among cancer patients, necessitating greater efforts to find a speedy solution. An in vivo assessment of the protective effect of the C. macrocarpa leaves polar fraction of hydromethanolic extract against doxorubicin (Dox)-induced neurotoxicity was performed. Intriguingly, this fraction ameliorated Dox-induced cognitive dysfunction; reduced serum ROS and brain TNF-α levels, upregulated the brain nerve growth factor (NGF) levels, markedly reduced caspase-3 immunoexpression, and restored the histological architecture of the brain hippocampus. The in vivo study results were corroborated with a UPLC-ESI-MS/MS profiling that revealed the presence of a high percentage of the plant polyphenolics. Molecular modeling of several identified molecules in this fraction demonstrated a strong binding affinity of flavan-3-ol derivatives with TACE enzymes, in agreement with the experimental in vivo neuroprotective activity. In conclusion, the C. macrocarpa leaves polar fraction possesses neuroprotective activity that could have a promising role in ameliorating chemotherapeutic-induced side effects.