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Background. Anti-vascular endothelial growth factor (anti-VEGF) therapy via intravitreal injection is an effective treatment for patients with abnormal ocular neovascularization, such as age-related macular degeneration (AMD) and diabetic macular edema (DME). However, prolonged and frequent anti-VEGF treatment is associated with a risk of local and systemic adverse events, including geographic atrophy, cerebrovascular disease, and death. Furthermore, some patients do not adequately respond to anti-VEGF therapy. Hypoxia-inducible factor (HIF) is a transcription factor that controls the expression of hypoxia-responsive genes involved in angiogenesis, inflammation, and metabolism. The HIF/VEGF pathway plays an important role in neovascularization, and the inhibition of HIF activation could be an effective biomolecular target for neovascular diseases. The demand for disease prevention or treatment using functional foods such as superfoods has increased in recent years. Few reports to date have focused on the antineovascular effects of superfoods in the retinal pigment epithelium (RPE). In light of the growing demand for functional foods, we aimed to find novel HIF inhibitors from superfoods worked in RPE cells, which could be an adjuvant for anti-VEGF therapy. Methods. Seven superfoods were examined to identify novel HIF inhibitor candidates using luciferase assay screening. We used the human RPE cell line ARPE-19 and fetal human RPE (fhRPE) to investigate the biomolecular actions of novel HIF inhibitors using quantitative PCR and western blotting. Results. Under CoCl2-induced pseudohypoxic condition and 1% oxygen hypoxic incubation, camu-camu (Myrciaria dubia) showed HIF inhibitory effects determined by luciferase assays. Camu-camu downregulated HIF-1α and VEGFA mRNA expressions in a concentration-dependent manner. Camu-camu also inhibited HIF-1α protein expressions, and its inhibitory effect was greater than that of vitamin C, which is present at high levels in camu-camu. Conclusion. The camu-camu extract suppressed the activation of HIF and VEGF in RPE cells. This could assist anti-VEGF therapy in patients with abnormal ocular neovascularization. [ABSTRACT FROM AUTHOR]

Background. Podocarpus gracilis is an evergreen, dioecious tree found in Ethiopia and other African nations. It can reach a height of 60 meters. Without any scientific validation, ethnobotanical studies conducted in Ethiopia revealed that the Podocarpus gracilis plant's leaf is consumed orally to treat diabetes mellitus. Hence, this study aims to evaluate the in vivo blood glucose level lowering, lipid-lowering, and in vitro-free radical scavenging responses of Podocarpus gracilis leaf extract and fractions on experimental mice induced with diabetes. Methods. The in vitro antioxidant activity of PGC (Podocarpus gracilis) leaf extract was assessed by using a diphenyl-2-picrylhydrazyl (DPPH) assay. The oral glucose-loaded, normoglycemic, and streptozotocin- (STZ-) induced diabetic mouse models were employed. In the STZ-induced mice model, the leaf extract and solvent fractions activity on serum lipid and weight were also measured. The extract and fractions were tested at 100, 200, and 400 mg/kg dosages. One-way ANOVA was used to determine the statistical significance of BGL (blood glucose level) changes within and between groups, and Tukey's post hoc multiple comparisons were then performed. Results. In the acute toxicity study of Podocarpus gracilis leaf extract and fractions, there was no evidence of animal mortality at the maximum dose of 2 g/kg during the observation period. The extract-treated group with normoglycemia revealed a significant lowering in BGL at the 4-hour mark of 27.4% (p < 0.001) and 25.2% (p < 0.01) at doses of 200 mg/kg and 400 mg/kg, respectively, compared to that in negative control. In the oral glucose tolerance test (OGTT) model, only 400 mg/kg treated groups at 120 min after exposure showed a BGL reduction of 31.17% which was statistically significant (p < 0.05) in comparison to the negative control. In the single-dose STZ-induced model, eighth-hour BGL measurements from CE 100, CE 200, CE 400, and GLC5 showed drops in BGL of 43.1%, 44.1%, 45%, and 47.3% from baseline fasting BGL values. In the repeated streptozotocin (STZ)-induced model, at all doses of leaf extract and fractions, the fasting BGL was significantly (p < 0.001) reduced. Moreover, the leaf extract and solvent fractions have shown a significant (p < 0.001) reduction of serum lipids such as LDL, TC, and VLDL, and at the same time, it increases HDL at 14 days with body weight gained. In the test for antioxidant activity, the half-maximal inhibitory concentrations (IC50) for leaf extract and the standard medication (ascorbic acid) were 8.2 μg/ml and 3.3 μg/ml, respectively. The IC50 value denotes the concentration of the sample required to scavenge 50% DPPH radicals. Conclusion. The 80% hydromethanolic leaf extract and fractions of Podocarpus gracilis exhibited blood glucose lowering, lipid-lowering activity in normoglycemic, oral glucose tolerance test (OGTT) mode, and STZ-induced diabetic mice with weight gains. There is scientific support for the alleged traditional use as an antidiabetic, lipid-lowering, and antioxidant activity. The results need to be confirmed by future studies. [ABSTRACT FROM AUTHOR]

One of the most often utilized nanoparticles (NPs) in several technologies is zinc oxide (ZnO) NPs. However, these NPs are said to have harmful effects on the reproductive system. Thus, we designed this study to specify the potential preventive activity of vitamins (Vits) A, C, and E, as antioxidants, against toxicity of ZnO NPs in the testes of rats. A total of 54 Wistar rats were arranged in 9 groups of 6 and then orally received water (control 1), olive oil (control 2), Vit A (1000 IU/kg), Vit C (200 mg/kg), Vit E (100 IU/kg), ZnO (200 mg/kg), ZnO+Vit A, ZnO+Vit C, and ZnO+Vit E. To determine the amount of testicular injury, sperm analysis and histological evaluation were performed. In addition, oxidative stress status was examined using colorimetric and qRT-PCR methods. Our findings suggest that ZnO NPs cause adverse effects on sperm parameters and testicular histology. Furthermore, oxidative biomarkers (malondialdehyde and total oxidant capacity) were enhanced in the ZnO group. By contrast, the gene expression and activities of antioxidant enzymes (SOD, GPx, and CAT) noted a remarkable decrease in the ZnO group regarding control (p < 0.05). However, oxidative markers were remarkably mitigated after combined treatment of ZnO NPs and Vits A, C, or E compared to the rats given ZnO NPs (p < 0.05). Additionally, compared to the ZnO NP group, the rats receiving Vits+ZnO NPs exhibit increased antioxidant enzyme activity and mRNA expression (p < 0.05). The findings demonstrate the abovementioned Vits' ameliorative effects on toxicity incurred by ZnO NPs. [ABSTRACT FROM AUTHOR]

Background. Kirsten rat sarcoma (KRAS) protein is an essential contributor to the development of pancreatic ductal adenocarcinoma (PDAC). KRAS G12D and G12V mutant tumours are significant challenges in cancer therapy due to high resistance to the treatment. Objective. To determine how effective is the ATO/D-VC combination in suppression of PDAC the mouse transgenic model. This study investigated the antitumour effect of a novel combination of arsenic trioxide (ATO) and D-ascorbic acid isomer (D-VC). Such a combination can be used to treat KRAS mutant cancer by inducing catastrophic oxidative stress. Methods. In this study, we examined the effectiveness of ATO and D-VC on xenograft models—AK192 cells transplanted into mice. Previously, it has been shown that a high concentration of Vitamin C (VC) selectively can kill the cells expressing KRAS. Results. The results of this study demonstrated that the combination of VC with a low dose of the oxidizing drug ATO led to the enhancement of the therapeutic effect. These findings suggest that the combined treatment using ATO and D-VC is a promising approach to overcome the limitation of drug selectivity and efficacy. [ABSTRACT FROM AUTHOR]

Habb-e-Suranjan (HES), an Unani formulation, has been studied for its anti-inflammatory properties in both in vitro and in vivo experiments. HES is recommended for arthritis, gout, and joint pain. The current endeavor is an attempt to put it to the test and verify its efficacy scientifically. It was tested for DPPH, hydroxyl, and nitric oxide scavenging activities. It was shown that HES had the greatest TAC and FRAC values when compared to catechin and ascorbic acid. HES exhibited DPPH and hydroxyl radical scavenging activity that was dose-dependent. Incubation of sodium nitroprusside solutions in PBS at 25°C for 150 min resulted in the production of nitric oxide. Nitric oxide production was effectively decreased by HES. Anti-inflammatory medications boosted the migration of PMN cells toward the chemoattractant FMLP in an agarose experiment of PMN chemotaxis. In carrageenan-induced rat paw edema, in the HES-treated group, paw thickness was 3.021 ± 0.084 at t = 0 , but it showed an increase in paw inflammation after one hour, i.e., 3.195 ± 0.082 cm which again showed a decrease in paw thickness up to 4th hour, i.e., 3.018 ± 0.078 , 2.98 ± 0.032 , and 2.684 ± 0.061 at t = 2 , 3, and 4, respectively. It showed again getting back to the normal thickness of paw at t = 24 hrs, i.e., 3.029 ± 0.118 cm. It is concluded that the formulation is potent enough and can be used effectively for the treatment of inflammation and associated health issues. Moreover, there is much scope to evaluate its effectiveness using different in vitro and in vivo models. [ABSTRACT FROM AUTHOR]

The lowering blood pressure effect of vitamin C (VC) has been evaluated in various models. As VC has a fast degradation rate in the body after consumption, a study of the frequency-dependent manner of VC is essential for the sustained antihypertension effect of VC. In this study, we investigated the frequency and dose dependency of vitamin C (VC) on blood pressure reduction in spontaneously hypertensive rats (SHRs). Wistar–Kyoto rats (WKYs) and SHRs were orally administered tap water or VC (250, 500, 1000, and 2000 mg/60 kg/day). Blood pressures were measured using the tail-cuff method, and thoracic aortas, liver, and blood were harvested from sacrificed rats after 8 weeks to measure angiotensinogen, angiotensin-converting enzyme (ACE) I, endothelial nitric oxide synthase (eNOS), and total nitric oxide (NOx) concentration. VC decreased blood pressure from the fourth week with no significant differences between doses. The twice-a-day administration of VC decreased blood pressure from the second week, and the blood pressure in these groups was close to that of the WKY group in the eighth week. Treatment with once a day VC decreased ACE I production which was further significantly reduced in twice a day groups. Angiotensinogen and eNOS production were increased upon VC treatment but were not significant among groups. The NOx content was decreased by VC treatment. These results suggest that VC lowers blood pressure in SHRs by directly targeting ACE I production in a frequency-dependent manner and may improve endothelial function depending on the frequency of administration. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) is the main cause of liver damage mediated by the excretion of toxic active drug metabolites. Omega-3 fatty acids and vitamin C have potent antioxidant, anti-inflammatory, and antiapoptotic effects that could offer protection against oxidative stress and liver damage. This study evaluated the hepatoprotective effect of omega-3 and vitamin C alone as well as in a combined form in methotrexate- (MTX-) induced acute liver injury in mice. Male ICR mice of seven groups (7 mice per group) were used. Groups 1 (control group) and 2 (MTX) received 0.9% saline/day (po) for 9 days. Groups 3 and 4 received 100 and 200 mg/kg bw/day omega-3 (po), respectively, for 9 days. Groups 5 and 6 received 100 and 200 mg/kg bw/day vitamin C (po), respectively, for 9 days, while group 7 received omega-3 (100 mg/kg bw/day) and vitamin C (100 mg/kg bw/day) (po) for 9 days. All animals in groups 2 to 7 received 20 mg/kg/day MTX (I.P.) once on the 10th day. Our results revealed that MTX significantly induced the elevation of transaminases, alkaline phosphates (ALP), lactate dehydrogenase (LDH), and malonaldehyde (MDA) while depleting the levels of superoxide dismutase (SOD) and glutathione (GSH) when compared to the control group. Treatment with omega-3 fatty acids or vitamin C significantly attenuated the antioxidants and biochemical alterations in a dose-independent manner. Our molecular docking study of ligand-receptor interaction revealed that both ascorbic acid and omega-3 docked well to the binding cavity of LDH with high binding affinities of –5.20 and –4.50 kcal/mol, respectively. The histopathological features were also improved by treatment with omega-3 and vitamin C. The combined form of omega-3 and vitamin C showed a remarkable improvement in the liver enzymes, oxidative stress biomarkers, and the histopathological architecture of the mice. Conclusively, the combination of omega-3 and vitamin C demonstrated a synergistic therapeutic effect against MTX-intoxicated mice, hence representing a potential novel strategy for the management of drug-induced liver disorders. [ABSTRACT FROM AUTHOR]

Balanites aegyptiaca L. Delile (B. aegyptiaca) is used in traditional medicine for the treatment of memory impairment. This work aims to evaluate the antioxidant and anticholinesterase potential of BA fruit pulp extract on excitotoxicity induced by monosodium glutamate (MSG). MSG was administered 30 minutes after treatment with B. aegyptiaca aqueous fruit pulp extract (50, 125, 250, and 500 mg/kg) and vitamin C (100 mg/kg) for 30 days. The negative control group received only MSG, while the control group was given distilled water daily. Behavioral tests parameters (using the novel object recognition, Y-maze, and Barnes maze tests), oxidative stress biomarkers (malondialdehyde, superoxide dismutase, and catalase), nitric oxide, and acetylcholinesterase activity and hippocampal architecture were evaluated. Results obtained revealed that different doses of B. aegyptiaca significantly reversed the deleterious effect of MSG on memory. This was displayed by a significant (p < 0.05) increment in the percentage of spontaneous alternation in the Y-maze test and a significant (p < 0.001) increase in discrimination index in novel object recognition observed with 500 mg/kg extract dose. Moreover, the extract (250 and 500 mg/kg doses) significantly (p < 0.001) increased direct search strategy and significantly decreased (p < 0.01) the time taken to find the target hole in the Barnes maze. A modulation of hyperactivity was observed after administration of all extract doses compared to the negative control group in the open arena. Furthermore, the highest dose of the extract caused a significant (p < 0.001) improvement in antioxidant enzymes activity, associated with a significant (p < 0.001) decrement in nitric oxide and malondialdehyde concentrations and a significant (p < 0.01) decrease in acetylcholinesterase activity. Treatment with the extract also restored normal hippocampal cell architecture. B. aegyptiaca fruit pulp extract could thus confer neuroprotection through its antioxidant and anticholinesterase potential. [ABSTRACT FROM AUTHOR]

Background. Vitamin C (Vc) has been found to promote corneal wound healing after alkali burns. However, the specific mechanism and functional modes are still unclear. The present study sought to assess the mechanisms of Vc function on corneal alkali burns. Methods. Eighty BALB/c mice were divided into four groups: a normal group without alkali injury (n = 10), an alkali injury group without any treatment (1-day group, n = 10), a Vc group treated with topical 10% Vc (Vc group, n = 30), and a control group treated with topical sterile water (control group, n = 30). Except in the blank control group, the alkali injuries were induced in one eye of each mouse. The mice in the treatment group were given Vc by topical application (q 1 h for 6 days), while those in the control group were given topical sterile water. The clinical evaluations, including corneal fluorescent staining, corneal opacity, and neovascularization, were assessed on days 1, 4, 7, and 10 using slit-lamp microscopy. Ten mice at each time point were sacrificed. The protein expressions in the corneas of p63, PCNA, CK3, MPO, CD31, and α-SMA were detected by immunohistochemistry to examine the corneal epithelial stem cells, corneal epithelium wound healing, corneal stroma inflammation, neovascularization, and fibrosis. Results. The scores of the corneal epithelium defects, corneal neovascularization, and corneal opacities in the Vc group were significantly decreased compared to the control group on day 10. We found that Vc promoted the activation of the corneal epithelial stem cells as shown by a higher number of p63-positive and PCNA-positive cells and an increased CK3 expression when compared with the control group p < 0.001 . The central corneal re-epithelialization was completed by day 10. Moreover, Vc inhibited MPO, CD31, and α-SMA expressions. These results first indicated that the frequent use of topical Vc in the first 6 days of corneal alkali burns alleviated corneal inflammatory cell infiltration, activated corneal epithelial stem cell activity, and reduced corneal neovascularization and fibrosis within 10 days. Conclusions. The study, therefore, showed the therapeutic benefits of Vc on corneal alkali burns and provided new insight into the mechanisms of Vc regulation on corneal wound healing. [ABSTRACT FROM AUTHOR]

Malaria is a life-threatening disease caused by Plasmodium and represents one of the main public health problems in the world. Among alterations associated with the disease, we highlight the hepatic impairment resulting from the generation of oxidative stress. Studies demonstrate that liver injuries caused by Plasmodium infection are associated with unbalance of the antioxidant system in hepatocytes, although little is known about the role of antioxidant molecules such as glutathione and vitamin C in the evolution of the disease and in the liver injury. To evaluate disease complications, murine models emerge as a valuable tool due to their similarities between the infectious species for human and mice. Herein, the aim of this study is to evaluate the effect of antioxidants glutathione and vitamin C on the evolution of murine malaria and in the liver damage caused by Plasmodium berghei ANKA infection. Mice were inoculated with parasitized erythrocytes and treated with glutathione and vitamin C, separately, both at 8 mg/kg during 7 consecutive days. Our data showed that during Plasmodium infection, treatment with glutathione promoted significant decrease in the survival of infected mice, accelerating the disease severity. However, treatment with vitamin C promoted an improvement in the clinical outcomes and prolonged the survival curve of infected animals. We also showed that glutathione promoted increase in the parasitemia rate of Plasmodium-infected animals, although treatment with vitamin C has induced significant decrease in parasitemia rates. Furthermore, histological analysis and enzyme biochemical measurement showed that treatment with glutathione exacerbates liver damage while treatment with vitamin C mitigates the hepatic injury induced by the infection. In summary, the current study provided evidences that antioxidant molecules could differently modulate the outcome of malaria disease; while glutathione aggravated the disease outcome and liver injury, the treatment with vitamin C protects the liver from damage and the evolution of the condition. [ABSTRACT FROM AUTHOR]