Fischer's oligopeptide ratio in ischemic hypoxia: prophylactic amendment of sophoretin and melatonin supplementation.

Aim: The fundamental pathophysiology of ischemic-hypoxia is oxygen depletion. Fischer's ratio is essential for monitoring hypoxia intensity. Methods: the current study highlighted the prophylactic role of sophoretin (QRC) and/or melatonin (MLN) versus sodium nitrite (SN) brain hypoxia. Results: Prophylactic treatment with sophoretin and MLN, was preceded with hypoxia-induction via sodium nitrite (60 mg/kg, S.C.). SN decreased hemoglobin (Hb), elevated HIF-α, HSP-70, IL-6 and TNF-α. Sophoretin and/or MLN restored the ameliorated inflammatory biomarkers, modulated norepinephrine, dopamine, serotonin and gamma-aminobutyric acid (GABA). Similarly, single-cell gel electrophoresis (SCGE or COMET) DNA damage assay confirmed this finding. Conclusion: Treatment via sophoretin and MLN was the most effective therapy for improving sodium nitrite-induced brain injury.

Sodium nitrite is utilized as a preservative, food colorant and in medicine. However, misusage can affect human health, leading to brain injury, cyanosis, hypotension and hypoxia. Therefore, its toxic effect on the brain was investigated in addition to the potential protective impact of sophoretin and/or melatonin was also monitored. Sophoretin and melatonin revealed a positive impact on certain factors. They regulated hemoglobin level, hypoxia biomarker hypoxia inducible factor (HIF-α), inflammatory biomarkers such as TNF-α and IL-6 and heat shock protein-70 (HSP-70) and DNA damage. When these antioxidants were combined, they had a superior protective impact against brain injury and mutations.

Impact of HIF1-α/TGF-ß/Smad-2/Bax/Bcl2 pathways on cobalt chloride-induced cardiac and hepatorenal dysfunction.

Background: Cobalt chloride (CoCl2) is a ferromagnetic ubiquitous trace element extensively dispersed in the environment. Nevertheless, it may merit human hazard. Aim: Excess cobalt can harm vital organs this paves the way to elucidate the toxic impact of CoCl2 on the liver, kidney and heart. Method: CoCl2 was injected in a dose of (60 mg/kg, S.C.) proceeded via Carnosine (200 mg/kg) and/or Arginine (200 mg/kg) treatment 1 month, 24 and 1 h, prior to CoCl2-intoxication. Results: CoCl2 significantly alleviated hemoglobin concentration and BCl2; meanwhile, protein expression of transforming growth factor (TGF-ß), hypoxia-inducible factor (HIF-1α), Mothers against decapentaplegic (Smad-2), AKT protein expression and Bax/Bcl2 ratio was noticeably elevated. Conclusion: The combination of the aforementioned antioxidants exerted a synergistic anti-apoptotic impact in all target tissues.

Cobalt chloride (CoCl₂) is commonly found in the environment and used in medicine. However, it can be harmful to our health, particularly when consumed in excessive amounts, leading to damage in important organs. Therefore, we investigated the toxic effects of CoCl₂ on the liver, kidney, and heart. We also explored potential treatments using substances like Carnosine and Arginine. We discovered that Arginine and carnosine had a positive effect on certain factors related to the health of the organs. They helped regulate the levels of hemoglobin and BCl2, as well as the expression of proteins such as transforming growth factor (TGF-ß), hypoxia-inducible factor (HIF-1α), Mothers against decapentaplegic (Smad-2), AKT, and apoptotic biomarkers like the Bax/Bcl2 ratio. When these antioxidants were combined, they had a stronger protective effect against cell death and mutations in all the organs studied.

Inhibition of NF-κB and the oxidative stress -dependent caspase-3 apoptotic pathway by betaine supplementation attenuates hepatic injury mediated by cisplatin in rats.

BACKGROUND: Cisplatin is a major anti-cancer drug commonly used in the treatment of various cancers; nevertheless, the associated hepatotoxicity has limited its clinical application. The aim of this investigation is to test the impact of betaine supplementation on cisplatin-induced hepatotoxicity. METHODS: Animals were allocated into four groups; normal control group (control betaine group (250 mg/kg/day, po for twenty six days), cisplatin group (single injection of 7 mg/kg, ip) and betaine + cisplatin group (received betaine for twenty one days before cisplatin injection and daily after cisplatin for five days). RESULTS: Cisplatin-induced liver injury was confirmed by increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Cisplatin elevated lipid peroxides, and reduced the concentrations of reduced glutathione (GSH), glutathione peroxidase (GSH-Px), catalase and superoxide dismutase (SOD) in hepatic tissues. Cisplatin increased the inflammatory mediators; nitrite and tumor necrosis factor-α (TNF- α) in hepatic tissues. Increased gene expressions of the apoptotic marker, caspase-3 and nuclear factor-kappa B (NF-κB) were observed in hepatic tissues of cisplatin-treated rats. All these changes were further confirmed by histopathological findings in cisplatin group. Pre-treatment with betaine reduced serum aminotransferases (ALT and AST), and lowered hepatic concentrations of lipid peroxides, nitrite and TNF-α while increased SOD, GSH, catalase, and GSH-Px concentrations. Moreover, the histological and immunohistochemical changes were improved. CONCLUSION: The suppression of NF-κß-mediated inflammation, oxidative stress, and caspase-3 induced apoptosis are possible mechanisms to the observed hepatoprotective effect of betaine.

Roles of some antioxidants in modulation of cardiac myopathy induced by sodium nitrite via down-regulation of mRNA expression of NF-κB, Bax, and flt-1 and suppressing DNA damage.

The underlying pathology of cardiac damage involves various molecular and signaling pathways. Therefore, this study aimed to explore the role of Quercetin (Querc), alone or in combination with Melatonin (Melat) against cardiac damage induced by sodium nitrite (Sod nit), as well as to elucidate different signaling pathways. Querc and Melat were injected intraperitoneally (i.p.), followed by induction of hypoxia in rats by using a single dose of Sod nit (60 mg/kg, s.c.). Treatment with Sod nit significantly decreased hemoglobin (Hb) levels in blood. Pretreatment of hypoxic rats with Querc and/or Melat elevated the declined Hb concentration. The forementioned antioxidants also successfully ameliorated the alteration of heat shock protein 70 (HSP-70) and markers of cardiac injury, including troponin T (Trop. T), creatine kinase-MB (CK-MB), tumor necrosis factor-α (TNF α), and C-reactive protein (CRP) in the rats serum. Furthermore, RT-PCR revealed that these antioxidants successfully modulated mRNA expression of NF-κB, Bax, Bcl-2, and flt-1. They also regulated vascular endothelial growth factor (VEGF), the apoptosis marker caspase 3, and oxidative DNA damage in cardiac tissue, compared to Sod nit-intoxicated rats. The present biochemical results are reinforced by histopathological examination. IN CONCLUSION: The results reflected that treatment with Querc in combination with Melat was most effective in improving Sod nit-toxicity induced cardiac damage, thus confirming the promising role of this combination as an effective treatment for cardiac damage induced by other cardio-toxic agents.

Mitigative role of garlic and vitamin E against cytotoxic, genotoxic, and apoptotic effects of lead acetate and mercury chloride on WI-38 cells.

BACKGROUND: Lead acetate (Led) and mercury chloride (Mer) represent important ecological and public health concerns due to their hazardous toxicities. Naturally found products play a vital role in chemopreventive agent innovation. The current study aimed to assess the modifying effect of garlic (Gar) and/or vitamin E (Vit E) against the half-maximal inhibitory concentration (IC50) Led and/or Mer-induced cytotoxic, genotoxic and apoptotic effects. METHODS: Human lung cells (WI-38) were pretreated with Gar and/or Vit E for 24h and then treated with Led and/or Mer either alone or with their combination for 24h. Cytotoxicity of Led and Mer and the viability of Gar and Vit E were assessed using MTT assay. The alkaline comet assay was used to assess DNA damage, whereas QRT-PCR was performed to evaluate p53, Bax, and Bcl2 mRNA-expression. RESULTS: The results of this study showed that IC50 of Led was (732.72µg/mL) and for Mer was (885.83µg/mL), while cell viability effective dose for Gar was (300µg/mL) and for Vit E was (26,800µg/mL). Treating cells with the IC50-concentration of Led or Mer or their combination using half IC50 of both of them induced severe DNA-damage. Bax-expression was increased, while p53 and Bcl2-expressions were decreased. Pretreatment of cells with Gar and/or Vit E ameliorated the previous alternations. CONCLUSIONS: Led and Mer can induce oxidative stress and change the expressions of apoptosis-related proteins in WI-38 cells. Gar and Vit E may be promising protective candidate agent against the toxic effect of heavy metals.

Downregulation of flt-1 and HIF-1α Gene Expression by Some Antioxidants in Rats Under Sodium Nitrite-Induced Hypoxic Stress.

This study assessed the effect of L-arginine (L-argin), carnosine (carno), or their combination in the amelioration of certain biochemical indices induced in the liver of hypoxic rats. Hypoxia was induced via sodium nitrite (S.nit) injection at a dose of 75 mg/kg. Rats were administered L-argin (250 mg/kg) or carno (250 mg/kg), either alone or in combination, 24 hours and 1 hour prior to S.nit intoxication. Hypoxia significantly elevated serum alanine aminotransferase, in addition to a significant upregulation of hepatic heat shock protein 70 with concurrent reduction in the level of vascular endothelial growth factor. Moreover, hepatic vascular endothelial growth factor 1 (flt-1), hypoxia inducible factor-1α gene expression, and cytochrome P450 levels were elevated, compared with the normoxic group. The antioxidants, administered either alone or in combination, markedly downregulated all of the previously mentioned biomarkers, compared to the hypoxic rats. Histopathological examination revealed hepatocellular degeneration and nuclear pyknosis, in addition to inflammatory cellular infiltration in the hypoxic rats, whereas treatment with the studied antioxidants improved the liver architecture. The present data revealed the efficacy of L-argin and carno in ameliorating the hepatic damage induced via angiogenic markers in response to hypoxia, the combination regimen showing the superior effect.

Prophylactic administration of carnosine and melatonin abates the incidence of renal toxicity induced by an over dose of titanium dioxide nanoparticles.

The alleviative effects of two antioxidants, carnosine (Car) and melatonin (Mel), against titanium dioxide nanoparticles (TiO2 -NPs) toxicity-induced oxidative and inflammatory renal damage were examined in rats. Administration of these antioxidants along with TiO2 -NPs effectively reduced serum urea, uric acid, creatinine, glucose, tumor necrosis factor-α, interleukin-6, C-reactive protein, immunoglobulin G, vascular endothelial growth factor, and nitric oxide, as well as a significant amelioration of the decrease in glutathione levels in renal tissue was observed, compared to those in rats treated with TiO2 -NPs alone. The renoprotective properties of the antioxidants were confirmed by reduced intensity of renal damage as demonstrated by histological findings. In conclusion, Car and Mel play protective roles against TiO2 -NPs-induced renal inflammation and oxidative injury, likely due to their antioxidant and anti-inflammatory properties.

Alterations in Biomarkers Associated with Sterility in Pectinophora gossypiella (Saunders) Induced by Gamma Irradiation

ABSTRACT Nowadays, radiation technology is widely used to produce changes in Biosystems. The goal of this work is to determine the variation induced male Pectinophora gossypiella in gamma-irradiated as pupae using 50Gy and 150Gy. Comparing elements composition and DNA (using RAPD-PCR) between substerile 50Gy and the sterile dose 150Gy in P. gossypiella showed variation between them. Potassium (K) was the most abundant elements in unirradiated and irradiated males followed by magnesium (Mg). The percentage of heavy metals as copper, zinc, and cadmium concurrent with K was directly proportional to the radiation dose. While the percentage of Mg, Phosphorous and calcium decreased as the radiation dose increased. The results also revealed that some extra bands appeared and others disappeared, as a result of irradiation. The appearance of extra bands may be due to the repair mechanism of the irradiation damaged DNA. The banding patterns obtained and the dendrograms drawn on the basis of presence and absence of bands revealed that 150Gy irradiated pupae are more different from the unirradiated pupae than the 50Gy irradiated pupae. It was concluded that the sterile male technique could be used as a benefit tool in controlling P. gossypiella.

Attenuation of DNA damage and mRNA gene expression in hypoxic rats using natural antioxidants.

This study aimed to explore the efficiency of carnosine (Cs) and/or l-arginine (Agn) in the downregulation of apoptotic and inflammatory molecule expression and DNA damage caused hepatic injury in response to sodium nitrite (Sd)-induced hypoxia in rats. Rats were injected with Sd; Agn or/and Cs were administrated prior to Sd intoxication. Sd significantly decreased hemoglobin concentration and Bcl-2 mRNA expression, while increased expressions of apoptotic markers (Bax and caspase), tumor necrosis factor-α, nuclear factor kappa B, and C-reactive protein and the oxidative DNA damage in hepatic tissue. Moreover, administration of Agn or/and Cs exhibited a modulation of the previous parameters. However, concurrent treatment with the forementioned antioxidants modulated these levels. It was concluded that the treatment with the combination of Agn and Cs was the most effective regimen in ameliorating Sd toxicity accompanied by hypoxic stress.

Downregulation of HIF1-α, Smad-2, AKT, and Bax gene expression in sodium nitrite-induced lung injury via some antioxidants.

The aim of the current study is to evaluate the efficacy of pretreatment with either l-arginine (L-arg) or Carnosine (Car) and their combination in ameliorating some of the biochemical indices induced in the lung of sodium nitrite (NaNO2 )-intoxicated rats. The results revealed that NaNO2 significantly increased serum tumor necrosis factor-α, C-reactive protein, heat shock proteins-70, vascular endothelial growth factor, and Interleukin 6. Moreover, transforming growth factor-ß, hypoxia-inducible factor, Smad-2, Protein Kinase B (AKT), and Bax were overexpressed, whereas Bcl2 protein was downregulated compared with the normoxic group. The administration of the fore mentioned antioxidants, either alone or in combination, markedly downregulated the previously mentioned inflammatory, apoptotic, as well as the fibrotic markers in lung tissue compared with the NaNO2 -intoxicated rats. The histopathological examination reinforced the previous results. In conclusion, the current data revealed the efficacy of l-arg and Car in ameliorating the pulmonary damage via suppression of the inflammatory markers in response to NaNO2 -intoxication. Interestingly the combination regimen showed the most significant effect.

Role of Different Natural Antioxidants in the Modulation of mRNA-expression of Apoptotic Molecules in the Livers of Carbon Tetrachloride-Intoxicated Rats.

Overexpression of nuclear factor (NF-κB) or activation of Smad3 by transforming growth factor ß (TGF-ß1) induced by oncogenes results in overexpression of fibrotic processes and hence cell death. The objective of this study is to examine whether Silymarin (Sil) alone or in combination with Vitamin E (Vit E) and/or Curcumin (Cur) plays a modulatory role against the overexpression of NF-κB, and TGF-ß that induced in response to carbon tetrachloride (CCl4) administration. The present work revealed that CCl4 induced elevation of in serum alanine aminotransferase (ALT), Apoptosis regulator (Bax), Smad3, TGF-ß, and NF-kB hepatic mRNA expression (using Real-time PCR), administration of Sil alone downregulated these expressions. Treatment with Vit E acid and/ or Cur along with Sil produced best results in this concern. B-cell lymphoma 2 (Bcl-2) expressions were downregulated by CCl4; whereas concurrent treatment of Vit E and/or Cur along with Sil increased its expression. On conclusion, the use of Vit E and/or Cur could potentiate the antiapoptotic action of Sil.

Quercetin inhibits sodium nitrite-induced inflammation and apoptosis in different rats organs by suppressing Bax, HIF1-α, TGF-ß, Smad-2, and AKT pathways.

The objective of this work is to study the protective effects of Quercetin against sodium nitrite-induced hypoxia on liver, lung, kidney and cardiac tissues, also to explore novel mechanism of this compound. Male albino rats were injected with sodium nitrite (75 mg/kg). Quercetin (200 mg kg-1 ,- i.p.) was administrated 24 and 1 h respectively prior to sodium nitrite intoxication, hypoxia significantly decreased hemoglobin concentration, while increased expressions of HIF, Bax, Smad-2, TGF-ß, and AKT. However, administration of Quercetin played a modulatory role against the previous mentioned apoptotic factors protein expressions in all the studied tissues. On the other hand, Bcl-2 was downregulated by NaNO2 , whereas concurrent treatment with Quercetin increased its expression. It was concluded that Quercetin possesses an anti-apoptotic action induced by NaNO2 -intoxication via different mechanisms. Quercetin administration is recommended in areas of high altitudes to combat the hazard effect of hypoxia in different organs and in some diseases accompanied by hypoxic stress.

Alterations in Biomarkers Associated with Sterility in Pectinophora gossypiella (Saunders) Induced by Gamma Irradiation

ABSTRACT Nowadays, radiation technology is widely used to produce changes in Biosystems. The goal of this work is to determine the variation induced male Pectinophora gossypiella in gamma-irradiated as pupae using 50Gy and 150Gy. Comparing elements composition and DNA (using RAPD-PCR) between substerile 50Gy and the sterile dose 150Gy in P. gossypiella showed variation between them. Potassium (K) was the most abundant elements in unirradiated and irradiated males followed by magnesium (Mg). The percentage of heavy metals as copper, zinc, and cadmium concurrent with K was directly proportional to the radiation dose. While the percentage of Mg, Phosphorous and calcium decreased as the radiation dose increased. The results also revealed that some extra bands appeared and others disappeared, as a result of irradiation. The appearance of extra bands may be due to the repair mechanism of the irradiation damaged DNA. The banding patterns obtained and the dendrograms drawn on the basis of presence and absence of bands revealed that 150Gy irradiated pupae are more different from the unirradiated pupae than the 50Gy irradiated pupae. It was concluded that the sterile male technique could be used as a benefit tool in controlling P. gossypiella.

New mechanism in the modulation of carbon tetrachloride hepatotoxicity in rats using different natural antioxidants.

Transforming growth factor-ß (TGF-ß1) enhances the expression of apoptosis induced by certain cytokines and oncogenes. Activation of small mother against decapentaplegic (Smads) by TGF-ß results in fibrotic, apoptotic processes. PI-3/AKT focal adhesion kinase-phosphatidylinositol3-kinase (AKT), the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription-3 (STAT3) pathways are influence in COX-2 and VEGF-stimulating pathways. NF-E2-related factor-2 (Nrf2) is an essential transcription factor that regulates an array of detoxifying and antioxidant defense genes expression in the liver. The objective of this study is to examine whether silymarin alone or in combination with vitamin E and/or curcumin plays a modulatory role against MAPK, STAT3, AKT, Smad-2 and TGF-ß protein expressions that produced apoptotic damage in rat's liver by the administration of carbon tetrachloride (CCl4). The results of the present work revealed that CCl4-induced an elevation of serum alanine aminotransferase (ALT) with concomitant increase in MAPK, STAT3, AKT, Smad-2 and TGF-ß hepatic protein expression, administration of silymarin alone down regulates these expressions. Treatment with vitamin E and/or curcumin along with silymarin produced best results in this concern. On the other hand, Nrf2 protein expression was down regulated by CCl4 whereas concurrent treatment with vitamin E and/or curcumin along with silymarin increased this expression. It was concluded that CCl4-induced protein expression of apoptotic and fibenorgenic factors. Whereas administration of silymarin alone or in combination with vitamin E and/or curcumin plays a modulatory role against the previous aforementioned apoptotic factors expressions. The use of vitamin E and/or curcumin potentiates the anti-apoptotic action of silymarin. So this combination can be used as hepatoprotective agent against other hepatotoxic substances.

Down-Regulation of NFkB, Bax,TGF-β, Smad-2mRNA expression in the Livers of Carbon Tetrachloride Treated Rats using Different Natural Antioxidants

The objective of this study is to examine whether silymarin alone or in combination with chlorogenic acid and/ or melatonin plays a modulatory role against apoptotic damage in rats liver induced by of CCl4. The present work revealed that CCl4 induced elevation of in Bax, Smad, TGF-β and NFkBhepatic mRNA expression, administration of silymarin alone down regulates these expressions. Treatment with chlorogenic acid and/ or melatonin along with silymarin produced best results in this concern. Bcl-2 expression was down regulated by CCl4 whereas concurrent treatment of chlorogenic acid and/ or melatonin along with silymarin increased this expression. On conclusion, the use of chlorogenic acid and/ or melatonin potentiates the anti-apoptotic action of silymarin.