Protective effects of gallic acid against nickel-induced kidney injury: impact of antioxidants and transcription factor on the incidence of nephrotoxicity.

Nickel (Ni) is a common metal with a nephrotoxic effect, damaging the kidneys. This study investigated the mechanism by which gallic acid (GA) protects mice kidneys against renal damage induced by Nickel oxide nanoparticles (NiO-NPs). Forty male Swiss albino mice were randomly assigned into four groups, each consisting of ten mice (n = 10/group): Group I the control group, received no treatment; Group II, the GA group, was administrated GA at a dosage of 110 mg/kg/day body weight; Group III, the NiO-NPs group, received injection of NiO-NPs at a concentration of 20 mg/kg body weight for 10 consecutive days; Group IV, the GA + NiO-NPs group, underwent treatment with both GA and NiO-NPs. The results showed a significant increase in serum biochemical markers and a reduction in antioxidant activities. Moreover, levels of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), phosphorylated nuclear factor kappa B (p65), and protein carbonyl (PC) were significantly elevated in group III compared with group I. Furthermore, the western blot analysis revealed significant high NF-κB p65 expression, immunohistochemistry of the NF-κB and caspase-1 expression levels were significantly increased in group III compared to group I. Additionally, the histopathological inspection of the kidney in group III exhibited a substantial increase in extensive necrosis features compared with group I. In contrast, the concomitant coadministration of GA and NiO-NPs in group IV showed significant biochemical, antioxidant activities, immunohistochemical and histopathological improvements compared with group III. Gallic acid has a protective role against kidney dysfunction and renal damage in Ni-nanoparticle toxicity.

Anti-angiogenic and anti-proliferative activity of ziziphus leaf extract as a novel potential therapeutic agent for reducing hepatic injury in experimental hamster schistosomiasis.

BACKGROUND: Schistosomiasis is one of the most prevalent helminthic infections worldwide. Praziquantel (PZQ) resistance poses a possible danger to the disease's ability to be controlled. Little is known about the role of Ziziphus spina-christi leaf extract (ZLE) in the treatment of hepatic schistosomiasis. However, no study has explored ZLE's anti-angiogenic and anti-proliferative activity as a possible mechanism for reducing hepatic injury in this context. Therefore, this study aimed to evaluate the therapeutic potential of ZLE as an anti-angiogenic, and anti-proliferative agent in hamsters infected with S. mansoni. METHODS: Fifty hamsters were used and divided into 5 groups (10 hamsters each); noninfected untreated (controls), noninfected treated with ZLE, infected untreated, infected treated with PZQ- and infected treated with ZLE. Anti-angiogenic and anti-fibrotic effects of the drugs were assessed pathologically through the immunohistochemical expression of VEGF, Ki-67, and TGF ß1 in liver sections. Some oxidative stress parameters were measured in hepatic homogenates (NO, GSH, GST, and SOD), and serum liver enzymes were also assessed. RESULTS: A significant decrease in worm burden, granuloma size, granuloma area, and numbers in the ZLE- and PZQ-treated groups compared to the infected untreated group, and the decrease in granulomas number and tissue egg load was significantly lower in PZQ treated group compared to ZLE treated group (p<0.05). ZLE exhibited significant anti-angiogenic and anti-fibrotic effects on granulomas, illustrated by significantly lower expression of VEGF and TGF-ß1 than infected untreated and PZQ-treated groups. ZLE exhibits antiproliferative activity evidenced by a significant reduction of positive Ki-67 hepatocytes percentage compared to the infected untreated group. Moreover, ZLE exhibits potent antioxidant effects evidenced by a significantly lowered NO and conservation of hepatic GSH, GST, and SOD in hepatic homogenates compared to infected untreated and PZQ-treated groups (p<0.05). CONCLUSION: Our results point to ZLE as a promising hepatoprotective therapeutic tool in the treatment of schistosome hepatic fibrosis as it has anti-angiogenic, anti-proliferative, anti-fibrotic, and antioxidant effects in hamsters infected with S. mansoni, providing scientific support for its use in conventional medicine.

Fagonia indica ameliorates chromium-induced nephrotoxicity: Role of antioxidant activity and pro-inflammatory cytokines in in-vivo renoprotection.

Chromium (Cr) is an environmental pollutant, has high redox potential, and can exist in various oxidation states, possibly leading to nephrotoxicity. As a potential treatment option, Fagonia indica (F. indica) is an herb remedy traditionally used as a phytomedicine to cure ailments. However, efficient validation of its protective effect and molecular mechanisms has not yet been established. As such, this study aims to investigate the protective effect of F. indica against Cr-induced nephrotoxicity in Swiss mice. Mice were divided into five groups: group I (negative control), group II (F. indica), group III (potassium dichromate [PDC]-treated), group IV (PDC + saline), and group V (PDC + F. indica). Our results demonstrate that group III exhibited decreases in superoxide dismutase (SOD), glutathione s-transferases (GST), glutathione peroxidase (GSH-Px), catalase (CAT), and thioredoxin peroxidase (TPX) levels. Meanwhile, protein carbonyl (PCO) and malondialdehyde (MDA) levels increased in kidney homogenates, increasing the expression of the pro-inflammatory cytokine interleukin-6 (IL-6). This was followed by elevated NF-κB, blood urea nitrogen (BUN), and creatinine serum levels in group III compared with group I. Moreover, histopathological and immunohistochemical examinations demonstrated severe damage to the renal tubular epithelial cells, as well as marked congestion and expressions of caspase-3 and NF-κB. Further, group V showed an improvement in antioxidant activity parameters and reductions in the IL-6, caspase-3, and NF-κB expressions, followed by significant decreases in NF-κB, BUN, and creatinine serum levels. Furthermore, fewer histopathological disturbances were observed compared with untreated group III. Such alterations may be attributed to the antioxidant and anti-inflammatory effects of F. indica. Therefore, our exploration reveals that F. indica is effective in protecting against Cr-induced nephrotoxicity, and it could be applied in the future to human kidney diseases caused by environmental pollutants.

Fagonia indica attenuates chromium-induced nephrotoxicity via antioxidant and anti-inflammatory activities in mice.

Chromium (Cr) is a common environmental pollutant that has wide-ranging toxic manifestations. Fagonia indica (F. indica) is an herbal medicine with anti-inflammatory properties and antioxidant activity. This study aims to evaluate the protective role of F. indica (whole plant) in attenuating Cr-induced nephrotoxicity in Swiss mice. Swiss albino mice were divided into five groups (10 mice in each): group I (control); group II (F. indica-treated); group III (Cr-intoxicated); group IV (Cr- and saline-intoxicated); and group V (Cr-intoxicated and F. indica-treated). Blood samples were drawn after sacrifice for biochemical examinations. Kidney specimens were collected to examine antioxidant activities and conduct histological and immunohistochemical studies for all groups. Mice intoxicated with Cr at 15 mg/kg/b.wt showed a decrease in superoxide dismutase (SOD), glutathione S-transferase (GST), and glutathione peroxidase (GSH-Px) levels compared to the control group, followed by an elevation in the serum IL-6 level. The data revealed severe damage to the renal tubular epithelial cells as well as marked congestion and positive, diffuse, and strong expression of caspase-3 in the dilated tubules. Additionally, the data disclosed an increase in the serum level of blood urea nitrogen (BUN) and creatinine in group III compared with group I. Group V, treated with F. indica at a selected dose of 120 mg/kg/b.wt, showed an improvement in antioxidant activity, attenuation of the IL-6 level, fewer histopathological disturbances, and a statistically significant decrease in the serum level of BUN and creatinine compared with group III. Such changes may be attributed to the antioxidant and anti-inflammatory effects of F. indica. Therefore, our investigation revealed that F. indica effectively protects against Cr-induced nephrotoxicity.

Caffeic acid phenethyl ester mitigates infertility: A crucial role of metalloproteinase and angiogenic factor in cadmium-induced testicular damage.

Cadmium (Cd) is expected to cause deleterious effects on most organs, especially on the male reproductive system. The current study was performed to assess the effect of Cd on fertility in Swiss mice and to evaluate the protective role of caffeic acid phenethyl ester (CAPE) in relieving the detrimental effect of Cd. The mice were divided into four groups of 10: normal Group I received distilled water. Group II, III, and IV were injected 3 mg/kg body weight with Cd intraperitoneally for four consecutive days. Group III received saline. Group IV was treated with 3 mg/kg/day CAPE intraperitoneally for 6 days. Results indicated that CAPE brings about a highly significant improvement in fertility parameters, spermatogenesis, and reduced apoptotic percent. Moreover, metalloprotease-3 (MMP-3) and vascular endothelial growth factor reduced significantly. Overall, our results strongly suggest that CAPE has a protective effect, counteracts the toxic effects of Cd, and prevents testicular injury.

Protective effects of caffeic acid phenethyl ester on cadmium-induced testicular injury: A crucial role of antioxidant enzymes in male mice infertility.

Infertility in men is referred to inability to achieve pregnancy in fertile females after at least one year of regular intercourse. The lack of oxygen in the environment may lead to an imbalance of testes production. Swiss mice were alienated into four groups 10 mice/each. This included one negative normal control group I. The induction of infertility was achieved with injection of cadmium chloride at dose 3 mg/kg body weight for four consecutive days for the rest groups. Group III received vehicle (saline) from the second day of induction for the similar period during the experiment. Infertile mice determined depending on alterations in morphology, motility, and reduced sperm count. Group IV was treated with 3 mg/kg of caffeic acid phenethyl ester (CAPE) per day, for 6 days from the second day of cadmium intoxication. Data showed effectiveness of CAPE significantly through improving the antioxidant enzymes SOD, GST and GSH in testes homogenate and GSH-Px in mice serum that were treated compared to those in the untreated group II (P˂0.001). The histopathology, DNA analysis showed marked improvement in spermatogenesis and DNA intact pattern in treated mice testis. Overall, the results demonstrated the ability of CAPE to improve spermatogenic cells. The data analysis indicated the possibility for the future use of CAPE as an inhibitory agent of infertility. Clinical trials and further studies are required to evaluate the definite medical effects of CAPE based on abundant experimental studies, with predictive future applications in human clinical trials.

In-vivo antioxidant and anti-inflammatory activity of rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists in animal model of bronchial asthma.

OBJECTIVES: Peroxisome proliferator activated receptor-gamma (PPAR-γ) has been shown to play an important role in the control of immunological and inflammatory responses. This study aims at investigating the potential role of rosiglitazone, a strong PPAR-γ agonist in a murine model of bronchial asthma. METHODS: Adult male guinea pigs were administered ovalbumin 100 mg/kg subcutaneous (SC) and 100 mg/kg intraperitoneal (IP). Treatment with rosiglitazone [5 mg/kg/day, per oral (PO)] was assessed for 21 days. On day 21, the animals were challenged with the same dose of ovalbumin. The forced expiratory volume in 1 s (FEV1 ) to forced vital capacity (FVC), FEV1 /FVC, was measured using a spirometer to diagnosis lung obstruction. Serum levels of interleukin-5 (IL-5) and immunoglobulin E (IgE) were assessed. The activity of superoxide dismutase (SOD) and catalase and the level of reduced glutathione (GSH) were determined in lung tissue homogenates. KEY FINDINGS: Our results demonstrated that treatment with rosiglitazone resulted in a statistically significant improvement in lung function and histopathological features. Significant decrease in the serum levels of IL-5 and IgE were observed. The activity of SOD and catalase as well as the GSH level were significantly increased in the lung tissues of treated animals compared with untreated asthmatic animals. Serum IgE concentrations and IL-5 levels were directly correlated to each other and inversely correlated to the SOD, GSH and catalase levels in the all studied guinea pigs. CONCLUSIONS: Our results provide evidence that the PPAR-γ agonist rosiglitazone may have potential in the development of therapies for bronchial asthma.

Alternative Medicine in Diabetes - Role of Angiogenesis, Oxidative Stress, and Chronic Inflammation.

Diabetes is a chronic metabolic disorder that is characterized by hyperglycemia due to lack of or resistance to insulin. Patients with diabetes are frequently afflicted with ischemic vascular disease and impaired wound healing. Type 2 diabetes is known to accelerate atherosclerotic processes, endothelial cell dysfunction, glycosylation of extracellular matrix proteins, and vascular denervation. Herbal medicines and naturally occurring substances may positively affect diabetes management, and could thus be utilized as cost-effective means of supporting treatment in developing countries. Natural treatments have been used in these countries for a long time to treat diabetes. The present review analyses the features of aberrant angiogenesis, abnormalities in growth factors, oxidative stress, and metabolic derangements relevant to diabetes, and how herbal substances and their active chemical constituents may counteract these events. Evidence for possible biochemical effectiveness and limitations of herbal medicines are given, as well as details regarding the role of cytokines and nitric oxide.

Protective and anti-angiopathy effects of caffeic acid phenethyl ester against induced type 1 diabetes in vivo.

OBJECTIVE: This study aims at investigating the anti-diabetic effects of caffeic acid phenethyl ester (CAPE) against induced immunoregulated diabetes in vivo. METHODS: Swiss mice were administered cyclosporine (CsA) 20mg/kg/day, s.c. for 10 days and simultaneously received multiple low doses of streptozotocin (MLDSTZ) 40mg/kg/day, i.p. for 5 consecutive days. RESULTS: Our results showed that administering CAPE (5µM/kg i.p./every 2 days) to diabetic mice led to a time-dependent decrease in blood glucose levels to 137.1±7.2 from 229.1±12.6mg/dl and induced a significant increase in serum insulin levels by 93.8% compared with untreated ones. An in vivo anti-inflammatory effect of CAPE treated diabetic mice was observed, based on a significant decrease in IL-1ß and IFN-γ (P<0.01) levels and a highly significant reduction in NO (P<0.001). An anti-angiogenic effect of CAPE was observed, as determined by a significant serum matrix metalloproteinase (MMP-9) reduction, angiopoietin (Ang-2) reduction and activation of endostatin serum level in the CAPE treated diabetic mice. Furthermore, histopathological examination showed that destroyed pancreatic islets were regenerated and became free of cell infiltration after treatment. CONCLUSION: CAPE has a significant anti-diabetic effect on mice in vivo. This anti-diabetic effect may be related to its anti-inflammatory and angiostatic effects. It also reduced angiogenic factors which may shift the equilibrium to the angiostatic effect of CAPE. These findings provide the validity of CAPE as anti-diabetic agent in the special model of CsA/STZ and could be relevant in the future for human diabetes.

Inhibitory effect of caffeic acid phenethyl ester on mice bearing tumor involving angiostatic and apoptotic activities.

UNLABELLED: This study aims at investigating the anti-tumor effect of caffeic acid phenethyl ester (CAPE) against animal carcinogenesis. In order to substantiate this fact implanted tumor Ehrlich carcinoma cells were assessed in vivo to Swiss mice strain. We found that administrating of CAPE (15 mg/kg S.C.) showed that the tumor volume decreased significantly by 51%. As a result, it improved animal chances of survival and they became healthier. An anti-angiogenic effect of CAPE in vivo was observed, as determined by a significant serum matrix metalloproteinase (MMP-9) reduction (142.1 ng/ml), activation of endostatin serum level (1.9 ng/ml), as well as DNA fragmentation in tumor treated mice when compared with untreated ones. CONCLUSION: CAPE has a significant inhibitory effect on tumor in vivo. This inhibition may be related to its angiostatic and apoptotic effects. It also reduced angiogenic factors which may shift the equilibrium to the angiostatic effect of CAPE. These findings provide the possibility for the future use of CAPE as tumor therapy in human clinical trials.

Snake venom inhibits the growth of mouse mammary tumor cells in vitro and in vivo.

Crude preparations as well as purified components of venoms isolated from American, Asian and European snakes have been shown to inhibit the growth of some mouse and human cancer cell lines. However, it is not known if Cerastes cerastes venom (CCV) obtained from the Egyptian desert possesses any anti-tumor activity. In the present study we examined in vitro the effect of CCV on the growth rate and morphology of a mouse mammary tumor virus-induced mammary tumor cell line (RIII/Sa-MT). In addition, the effect of the venom on the growth of RIII/Sa-MT cells transplanted into syngeneic mice was investigated. Our results show that CCV at a concentration of 7 microg/ml kills in vitro a significant number of cells (approximately 55%) within a period of 48 h. CCV (1 microg/mouse), administered once per week directly into growing tumors for a period of 4 weeks, was found to reduce tumor load by 54%, and as a consequence the CCV-treated mice lived for more than 35 days longer than untreated mice. Histological and ultrastructural examination of the cells and tumors, as well as nuclear staining of the cells and DNA fragmentation studies, led us to conclude that necrosis is most likely the underlying mechanism by which CCV inhibited the growth of mouse mammary tumor cells both in vitro and in vivo.

Prognostic implication of N-RAS gene mutations in Egyptian adult acute myeloid leukemia.

The pathogenesis of acute myeloid leukemia (AML) involves the cooperation of mutations promoting proliferation/survival and those impairing differentiation. Point mutations of the N-RAS gene are the most frequent somatic mutations causing aberrant signal-transduction in acute myeloid leukemia (AML). The aim of the present work is to study the frequency and prognostic significance of N-RAS gene mutations (N-RASmut) in de novo Egyptian adult AML. Bone marrow specimens from 150 patients with de novo acute myeloid leukemia and controls were analyzed by genomic PCR-SSCP at codons 12, 13 (exon 1), and 61 (exon 2) for N-RAS mutations. In 12.7% (19/150) AML cases, N-RAS gene mutations were found and were observed more frequently in the FAB subtype M4eo (P = 0.028) and with codon 12, 13 (14 of 19; 73.7%). Patients with N-RAS mutation had a significant lower peripheral and marrow blasts (P = 0.004, P = 0.03) and clinical outcome did not improve more than in patients without mutation. In patients with N-RAS gene mutation vs. those without, complete remission rate was (63.2% vs. 56.5%; P = 0.46), resistant disease (15.8% vs. 23.6%; P = 0.51), three years overall survival (44% vs 42%; P= 0.85) and disease free survival (42.1% vs. 38.9%, P = 0.74). Multivariate analysis showed that age was the strongest unfavorable factor for overall survival (relative risk [RR], 1.9; P = 0.002), followed by cytogenetics (P = 0.004). FAB types, N-RAS mutation and leukocytosis were the least important. In conclusion, the frequency and spectrum of N-RAS gene mutation differ between biologically distinct subtypes of AML but do not significantly influence prognosis and clinical outcome in patients with AML.