Mitigative impact of bradykinin potentiating factor isolated from Androctonus amoreuxi scorpion venom and low doses of γ-irradiation on doxorubicin induced hepatotoxicity through ang II/AMPK crosstalk.

In this study, the mitigative impact of bradykinin potentiating factor (BPF) and low doses of γ-irradiation (LDR) were evaluated against doxorubicin (DOX) hepatotoxicity through Ang II/AMPK crosstalk. Rats have received a single dose of DOX (10 mg/kg, i.p.). BPF administration at a dose of 1 µg/g (b.wt./twice a week) was started one week before the administration of DOX and followed throughout the study for another consecutive week where LDR rats were subjected to two low fractions of γ-irradiation; 0.5 Gy/fraction/week up to the cumulative dose of 1 Gy at 7 days before and after doxorubicin administration. DOX produced a remarkable disturbance in serum hepatic enzymes activities, hepatic oxidative stress indices, as well as hepatic inflammatory and fibrotic markers in response to a marked elevation in hepatic angiotensin II (Ang II) together with marked depression in hepatic AMP-activated protein kinase (AMPK) expressions. The combination of BPF and LDR produced a significant improvement in all examined parameters as well as mitigates hepatic toxicity through inhibition of Ang II induced by DOX, which might also be mediated by AMPK activation. Furthermore, histopathological and immunohistochemical examination reinforced the previous results. In conclusion, these findings shed new light on the mechanism underlying the anti-inflammatory and anti-fibrosis consequence of our remedy and support the potential use of it as a preventive and therapeutic candidate against hepatic toxicity through Ang II/AMPK crosstalk.

Concerted hepatoprotective effect of bradykinin potentiating factor and low dose of γ- radiation on Naja haje envenomed rats via Bax/Bcl2 pathway.

This study investigates the concerted hepatoprotective effects for three doses of bradykinin potentiating factor (BPF) and/or followed by exposure to a low dose of γ-radiation (LDR) against Naja haje envenoming in rats. Male rats were injected with three consecutive doses of BPF (1 µg/g i.p. for 3 days), followed by exposure to a low dose of gamma radiation (0.5 Gy), and then rats were injected with a dose of Naja haje venom (250 µg/kg i.p.). Results showed that Naja haje causes liver damage, significant elevation of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), cytochrome c, Nitric oxide (NO), malondialdehyde (MDA) and significant depletion in glutathione peroxidase (GPx) contents. In addition, significant depletion in B-cell lymphoma 2 (Bcl-2) and significant elevation in BcL-2 associated X (Bax protein), nuclear factor kappa B (NF-κB), interleukin-1ß (IL-1ß) in hepatocytes. Bradykinin potentiating factor and/or low dose of γ-radiation caused improvement in liver damage caused by Naja haje venom by a significant decrease in ALT, AST, ALP levels, Bax, cytochrome c, NF-κB, IL-1ß, NO and MDA contents, BPF alone or combined with low dose radiation caused a significant increase in Bcl2 and GPx contents. In conclusion, the concerted impact of BPF and LDR may provide an effective venom detoxification tool that helps to reduce hepatic toxicity and extends the lifespan.

Scorpion bradykinin potentiating factor mitigates lung damage induced by γ-irradiation in rats: Insights on AngII/ACE/Ang(1-7) axis.

The goal of this research is to study the mitigating impact of bradykinin potentiating factor (BPF) found in scorpion Androctonus bicolor venom on irradiation-induced lung damage as a new functional target for angiotensin-converting enzyme inhibitors (ACEIs). Male rats were exposed to 7 Gy of γ-radiation as a single dose, with a biweekly intraperitoneal injection of 1 µg/g BPF. Gamma irradiation not only boosted the ACE activity and angiotensin II (Ang II) level, in lung tissue but also significantly depressed the angiotensin (1-7) (Ang (1-7)) that, lead to lung toxicity through a significant elevation of pulmonary levels of CXC-chemokine receptor 4 (CXCR4), toll-like receptor 4 (TLR4), nitric oxide (NO) and lactate dehydrogenase (LDH) activity with a marked disruption in oxidative stress markers, via a reduction in the level of total thiol (tSH) and superoxide dismutase (SOD) activity associated with an elevation in protein carbonyl (PCO) contents. In addition, apoptotic consequences of gamma irradiation were evidenced by raising the levels of mitogen-activated protein kinase (MAPK), C-Jun N-Terminal Kinases (JNK), and cleaved caspase-3. BPF administration leads to ACE inhibition, consequently sustaining decreased Ang II alongside increased Ang (1-7) production. Those sensitive molecules reduce irradiated lung issues. In conclusion, BPF significantly diminished the biochemical and histopathological consequences of radiation through renin-angiotensin system (RAS) control and ACE suppression in the lung.

Concerted outcome of metformin and low dose of radiation in modulation of cisplatin induced uremic encephalopathy via renal and neural preservation.

AIM: The therapeutic expediency of cisplatin was limited due to its nephrotoxic side effects, so this study planned to assess the nephrotic and neuroprotective impact of metformin (MET) and low-dose radiation (LDR) in cisplatin-prompted kidney injury and uremic encephalopathy (UE). METHODS: The effect of the 10-day MET treatment (200 mg/kg, orally) and/or fractionated LDR (0.25 Gy, of the total dose of 0.5 Gy, 1st and 7th day, respectively) on (5 mg/kg, intraperitoneally) cisplatin as a single dose was administered at the 5th day. Serum urea, creatinine and renal kidney injury molecule-1 were measured for the assessment of kidney function. Furthermore, the antioxidant potential in the renal and brain tissues was evaluated through, malondialdehyde and reduced glutathione estimation. Moreover, renal apoptotic markers: AMP-activated protein kinase, lipocalin, B-cell lymphoma 2 associated X protein, B-cell lymphoma 2, P53 and beclin 1 were estimated. UE was evaluated through the determination of serum inflammatory markers: nuclear factor kappa B, tumor-necrosis factor-α and interleukin 1 beta likewise, the cognitive deficits were assessed via forced swimming test, gamma-aminobutyric acid, n-methyl-d-aspartate and neuronal nitric oxide synthases besides AMP-activated protein kinase, light chain 3 and caspase3 levels in rats' cerebella. KEY FINDINGS: The obtained results revealed a noticeable improvement in the previously mentioned biochemical factors and behavioral tasks that was reinforced by histopathological examination when using the present remedy. SIGNIFICANCE: metformin and low doses of radiation afforded renoprotection and neuroprotection against cisplatin-induced acute uremic encephalopathy.

Diminazene aceturate extenuate the renal deleterious consequences of angiotensin-II induced by γ-irradiation through boosting ACE2 signaling cascade.

AIM: This work aims to explore the role of diminazene aceturate (DIZE) in the enhancement of angiotensin-converting enzyme-2 (ACE2) to prevent the inflammatory and fibrotic response induced by γ-irradiation through activating the protective axis ACE2/angiotensin (1-7)/Mas receptor (ACE2/Ang(1-7)/Mas). METHODS: Male rats were injected i.p. with 15 mg/kg DIZE daily for 7 days pre and post-irradiation, where 7.5 Gy of γ-radiation as a single dose was used. KEY FINDINGS: Gamma radiation induced a significant elevation of renal biochemical parameters: urea, creatinine and blood urea nitrogen (BUN) in serum with a significant disturbance in oxidative stress markers: elevation in malondialdehyde (MDA) associated with a depletion of reduced glutathione (GSH) and superoxide dismutase (SOD). Beside elevation in the level of angiotensin II (AngII) that lead to remarkably increases in the levels of the renal inflammatory mediators: tumor necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB) and interleukin-1ß (IL-1ß) as well as renal fibrogenic markers: transforming growth factor-ß1 (TGF-ß1), connective tissue growth factor (CTGF), and hydroxyproline content in the renal tissues. DIZE caused marked expansion in the expression of ACE2 consequently decreased the expression of AngII and increased the expression of Ang(1-7) which through its Mas receptor ameliorates the biochemical and histopathological damage induced by radiation. SIGNIFICANCE: DIZE-induced stimulation of ACE2 subdues the renal deleterious consequences induced by γ-radiation via activation of ACE2/Ang(1-7)/Mas axis in rats.

Bradykinin-potentiating factor isolated from Leiurus quinquestriatus scorpion venom alleviates cardiomyopathy in irradiated rats via remodelling of the RAAS pathway.

The objective of this work was to evaluate the effect of a bradykinin-potentiating factor (BPF) isolated from Leiurus quinquestriatus scorpion venom as a natural modulator of radiation-induced cardiac damage. Four groups of rats were treated as follows; control group, group receiving BPF (1 µg/g b.wt i.p./biweekly) for 4 weeks, group irradiated at 6 Gy, group receiving BPF post-irradiation for 4 weeks. Irradiation induced a significant elevation of myocardial parameters: atrial natriuretic peptide (ANP), cardiac troponin I (cTnI), potassium (K+ ) and creatine kinase (CK); vascular indices: lactate dehydrogenase (LDH), inducible nitric oxide synthase (iNOS) and endothelin I; oxidative stress indices: malondialdehyde (MDA) associated with a significant depletion of both reduced glutathione (GSH) in the cardiac tissue homogenate and serum ferric reducing antioxidant power (FRAP) depletion and significantly reinforced elevation of Renin Angiotensin Aldosterone System (RAAS) indices: serum angiotensin II (AngII) and aldosterone, and also protein expression of cleaved caspase-3 and cyclophilin A. BPF administration altered the biochemical damage of radiation, specifically inhibited AngII formation, aldosterone release and prevented the histopathological and immunohistochemical alterations which were observed in cardiac tissue with significant reduction in mean arterial blood pressure (MAP) caused by irradiation. In conclusion, biochemical assays, histopathological and immunohistochemical findings of the present study demonstrated that exogenous BPF isolated from scorpion venom reduced the cardiomyopathy alterations induced by irradiation via remodelling of the RAAS pathway.

Synergistic effect of cranberry extract and losartan against aluminium chloride-induced hepatorenal damage associated cardiomyopathy in rats.

The present study was designed to evaluate the effect of cranberry extract (CRAN) and/or losartan (LOS) against aluminium chloride (AlCl3) induced hepatorenal damage associated cardiomyopathy in rats. To induce hepatorenal and cardiotoxicity, animals were received (AlCl3; 70 mg/kg i.p.) for 8 weeks day after day and treated with CRAN (100 mg/kg b.wt.) orally daily for 4 weeks started after 4 weeks from AlCl3 injection accompanied with an administration of LOS (5 mg/kg i.p.) three times weekly for 4 weeks. Our data revealed that, compared to AlCl3, administration of CRAN extract and LOS produced a significant improvement which was evidenced by a significant amelioration in myocardial and vascular indices, kidney and liver markers, lipid profile and oxidative stress indices. Furthermore, histopathological and immunohistochemical examination reinforced the previous results. It could be concluded that combination of CRAN extract and LOS hindered AlCl3 induced hepatorenal damage complicated cardiomyopathy in rats.

Cholinergic and cytoprotective signaling cascades mediate the mitigative effect of erythropoietin on acute radiation syndrome.

The present investigation aimed to evaluate the radiomitigative efficacy of the recombinant human erythropoietin (EPO) against acute radiation syndrome (ARS) in a rat model. Rats were irradiated with a single sublethal dose of γ-radiation (7 Gy; total body irradiation; TBI) on the 1st day of experimental course, then received EPO (5000 IU/kg; i.p.) 24 h after irradiation, and rats were observed for 30 days of survival analysis. Administration of EPO improved 30-day survival, alleviated TBI-induced myelosuppression and pancytopenia, by augmenting lymphocytes and other white blood cells in the peripheral blood of rats, while bone marrow and spleen cellularity were restored. EPO post-exposure treatment alleviated hepatotoxicity biomarkers and restored splenic function. EPO abrogated radiation-induced oxidative stress through the upregulation of the cholinergic anti-inflammatory nicotinic acetylcholine receptor (α-7-nAChR) and the pro-survival Janus kinase-2 and signal transducers and activators of transcription JAK-2/STAT-3 signaling mediated via enhancing nuclear factor erythroid-2 related factor-2 (Nrf-2) cytoprotective machinery in liver and spleen of irradiated rats. Moreover, EPO treatment prevented hepatic and splenic apoptosis. The present study establishes the implication of α-7-nAChR-JAK-2/STAT-3-Nrf-2 signaling cascade in the radiomitigative potential of EPO against ARS.

Diosmin attenuates radiation-induced hepatic fibrosis by boosting PPAR-γ expression and hampering miR-17-5p-activated canonical Wnt-ß-catenin signaling.

BACKGROUND: Liver fibrosis is one of the major complications from upper right quadrant radiotherapy. MicroRNA-17-5p (miR-17-5p) is hypothesized to act as a regulator of hepatic stellate cell (HSCs) activation by activation of the canonical Wnt-ß-catenin pathway. Diosmin (Dios), a citrus bioflavonoid, is known to possess potent antioxidant, anti-inflammatory, and anti-apoptotic properties. PURPOSE: To explore the molecular mechanisms that underlie radiation-induced liver fibrosis, and to evaluate the possible influence of Dios on the miR-17-5p-Wnt-ß-catenin signaling axis during fibrogenesis provoked by irradiation (IRR) in rats. Also, the effect of Dios on hepatic peroxisome proliferator activated receptor-γ (PPAR-γ) expression as a regulator for HSC activation was considered. METHODS: We administered 100 mg·(kg body mass)-1·day-1 (per oral) of Dios were administered to IRR-exposed rats (overall dose of 12 Gy on 6 fractions of 2 Gy each) for 6 successive weeks. RESULTS: Data analysis revealed that Dios treatment mitigated oxidative stress, enhanced antioxidant defenses, alleviated hepatic inflammatory responses, abrogated pro-fibrogenic cytokines, and stimulated PPAR-γ expression. Dios treatment repressed the miR-17-5p activated Wnt-ß-catenin signaling induced by IRR. Moreover, Dios treatment restored the normal hepatic architecture and reversed pathological alterations induced by IRR. CONCLUSION: We hypothesize that the stimulation of PPAR-γ expression and interference with miR-17-5p activated Wnt-ß-catenin signaling mediates the antifibrotic properties of Dios.

The Evolving Role of Erythropoietin in Lung of Irradiated Rats

ABSTRACT The aim of the present study is to evaluate the possible curative effect of erythropoietin (EPO) on radiation-induced damage to the lung and its renin angiotensin system. EPO (200 U/100g) was i.p. injected to male rats one hour post 6 Gy whole body gamma irradiation. The animals were sacrificed after 14 days post irradiation. Irradiation induced significant drop of haematological values, bone marrow (BM) count, lung oxidative stress markers, glutathione (GSH) and superoxide dismutase(SOD) associated with significant elevation of malondialdehyde (MDA), advanced oxidation protein product (AOPP) and nitric oxide (NO) besides serum inflammatory markers, tumor necrosis factor alpha (TNF-α) and lactate dehydrogenase (LDH). Also serum and lung renin angiotensin system markers, sodium (Na) and potassium (K) were elevated whereas calcium (Ca) was decreased. EPO treatment post irradiation has significantly ameliorated blood parameters and BM count also lung oxidative stress markers were improved associated with decreased serum Na, TNF-α, and LDH levels. Lung K and Ca showed no change compared to irradiated group. The findings of the present study suggest that EPO might contribute to enhance recovery of the lungs from radiation-induced damage due to its erythropoietic, anti-oxidative and anti-inflammatory effects.