Ferulic acid exerts a protective effect against cyclosporine-induced liver injury in rats via activation of the Nrf2/HO-1 signaling, suppression of oxidative stress, inflammatory response, and halting the apoptotic cell death.

Drug-induced liver injury is one of the main challenges that leads to the withdrawal of several drugs in the clinical setting. Cyclosporine is one of the drugs that its long-term administration exerts devastating effects on the hepatocytes. In the present study, we aimed to evaluate the effect of ferulic acid, a natural compound found in plants, on cyclosporine-mediated hepatotoxicity. Forty-eight male Wistar rats were treated with cyclosporine and/or ferulic acid to evaluate the function as well as the morphology of liver cells. We found that ferulic acid dose-dependently recovered the functional as well as histopathological parameters of liver cells, as revealed by the improvement of hepatocellular vacuolation, portal fibroplasia, and necrosis. Moreover, this phenolic compound was able to restore the balance of the redox system in cyclosporine-treated rats by activating the nuclear factor (NF) erythroid 2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1) signaling axis. Of note, the protective effects of ferulic acid against cyclosporine-mediated liver toxicity were not restricted only to induction of the potential antioxidant property, as in the presence of this agent, the expression of pro-inflammatory cytokines such as NF-κB, tumor necrosis factor (TNF)-α, and interleukin-1ß was also diminished. Ferulic acid also shifted the equilibrium between the expression levels of proapoptotic to antiapoptotic proteins and thereby prevented the development of cyclosporine-induced liver injury. Overall, these findings highlighted that ferulic acid can reduce cyclosporine-induced liver injury due to its antioxidant properties.

Role of NF-κB/IL-1ß Pathway and Caspase 3 in Mediating the Hepatoprotective Effect of Rutin against Paraquat-Induced Liver Toxicity in Male Rats.

One of the most common bipyridinium herbicides that can lead to liver toxicity is paraquat. Rutin is a bioflavonoid with antioxidant, anti-inflammatory, anti-hepatotoxic, and antimicrobial properties. The effect of rutin on paraquat-induced liver toxicity was examined in this study. 48 male rats were divided into six groups: the control group was given a normal diet; the non-treated group was given paraquat; the positive control group was given paraquat, and silymarin and the treatment groups were given paraquat and rutin at doses of 25, 50, and 100 mg/kg. After fourteen days, the rats were anesthetized by xylazine-ketamine, and fasting blood samples were obtained from their hearts to measure alkaline phosphatase (ALP), aspartate transaminase (AST), alanine transaminase (ALT), malondialdehyde (MDA), creatinine, lipid profile, antioxidant capacity, and carbonyl protein. The liver tissue was removed to measure the levels of catalase (CAT), superoxide dismutase (SOD), total protein, vitamin C, plus NF-κB, IL1ß, and caspase-3 gene expressions. Paraquat gavage in the untreated group (group 2) for 14 days in comparison with the control group induced a significant augmentation (p<0.05) in levels of lipid profile, AST, ALP, ALT, MDA, carbonyl protein, and also NF-κB, IL1ß, Caspase3 expressions. Treatment with rutin reduced the factors as mentioned above. Paraquat poisoning induced a substantial decline (p<0.05) in HDL content, FRAP level, CAT, and SOD activity of the liver compared to the control group. However, rutin oral treatment led to a substantial increase (p<0.05) in the level of these factors compared to the paraquat-only treated group. Based on the findings of the present study, it was found that rutin can be significantly effective in improving hepatotoxicity caused by paraquat.

Inhibitory Effects of Bilirubin on Colonization and Migration of A431 and SK-MEL-3 Skin Cancer Cells Compared with Human Dermal Fibroblasts (HDF).

This study evaluated the inhibitory effects of bilirubin on colony formation and cell migration of melanoma and non-melanoma skin cancer cell lines SK-MEL-3 and A431, compared with normal human dermal fibroblasts (HDF). The IC50 obtained from the MTT assay was 125, 100, and 75 µM bilirubin for HDF, A431, and SK-MEL-3 cells, respectively. The colony formation and cell migration of cancer cells, treated with 100 µM bilirubin, were reduced significantly (p < 0.05). Bilirubin decreased cell adhesion and inhibited cell colonization via inducing apoptosis and cell death. Also by interaction with migration main factors, bilirubin caused inhibition the cell migration.

Serum levels of IL-32 in patients with type 2 diabetes mellitus and its relationship with TNF-α and IL-6.

Type 2 diabetes mellitus (T2DM) is an important public health worldwide. The main underlying mechanism of T2DM is insulin resistance which is associated with chronic inflammation. Interleukin-32 (IL-32) is a pro-inflammatory cytokine which has been implicated in pro-inflammatory responses of several human diseases. Previous studies have reported higher levels of IL-32 in inflammatory disease and obesity. The present study aimed to evaluate the serum concentrations of IL-32 in patients with T2DM and its association with cardio-metabolic parameters. This study was undertaken on 93 patients with TDM and 74 healthy controls. T2DM was diagnosed based on ADA criteria. Serum levels of IL-32, adiponectin, TNF-α, and IL-6 were measured by ELISA technique. Our findings revealed independent elevated levels of IL-32 in T2DM group (1061 (841.9-1601) pg/mL) compared to the control (630.4 (331.1-830.9) pg/mL). Furthermore, it was associated with increased risk of T2DM incidence. IL-32 indicated a positive correlation with body mass index, fasting blood glucose, TNF-α, and IL-6 in patients with T2DM. Furthermore, linear regression showed independent association between IL-32 and IL-6 plus TNF-α in patients' group. The results of the present study revealed higher levels of IL-32 in T2DM patients which have been associated with inflammatory markers. These results suggest the possible role of IL-32 in chronic inflammation in patients with T2DM.

Gallic acid mitigates diclofenac-induced liver toxicity by modulating oxidative stress and suppressing IL-1ß gene expression in male rats.

CONTEXT: Diclofenac (DIC) is an NSAID and consumption of this drug creates side effects such as liver injury. Gallic acid (GA), a natural component of many plants, is used as an antioxidant agent. OBJECTIVE: This study assesses the hepatoprotective effects of GA in the rat model of DIC-induced liver toxicity. MATERIALS AND METHODS: In this research, the male Wistar rats were separated into five groups (n = 6). Group 1, control, received normal saline (1 mL/kg bw, i.p.); Group 2 received DIC-only (50 mg/kg bw, i.p.); Groups 3, received DIC (50 mg/kg bw, i.p.) plus silymarin (100 mg/kg bw, po), groups 4 and 5 received DIC (50 mg/kg bw, i.p.) plus GA (50 and 100 mg/kg, po, respectively). RESULTS: The data demonstrated that the liver levels of the GSH, GPx, SOD, and CAT significantly reduced and the levels of the serum protein carbonyl, AST, ALP, ALT, total bilirubin, MDA, serum IL-1ß, and the liver IL-1ß gene expression were remarkably increased in the second group compared to control group. On the other hand, treatment with GA led to a significant elevation in GSH, GPx, SOD, CAT, and a significant decrease in protein carbonyl, AST, ALP, ALT, total bilirubin, MDA, serum IL-1ß, and gene expression of IL-1ß in comparison with the second group. Histological changes were also ameliorated by GA oral administration. Discussion and Conclusions: The data show that the oral administration of GA could alleviate the noxious effects of DIC on the antioxidant defense system and liver tissue.

miR-342-5p Expression Levels in Coronary Artery Disease Patients and its Association with Inflammatory Cytokines.

BACKGROUND: Atherosclerosis is a progressive inflammatory disease and is the main underlying mechanism of coronary artery disease (CAD). Immune system cells and cytokines play pivotal roles in the development of atherosclerosis. Several studies have shown the role of microRNA in the inflammatory processes of atherosclerosis, and miR-342-5p has been shown to be involved in macrophage activation during atherosclerosis and cytokine secretion. But until now, there has been no data regarding the association of miR-342-5p with CAD and inflammatory cytokines. METHODS: This case control study was conducted on 82 CAD patients and 80 controls. Peripheral blood mononuclear cell (PBMC) miR-342-5p expression and gene expression of IL-6 and TNF-α were evaluated using real timePCR. Also, the serum levels of IL-6 and TNF-α were measured using ELISA kits. RESULTS: The results demonstrated a higher expression of miR-342-5p in CAD patients compared to controls (p < 0.001). Moreover, logistic regression revealed an increased risk of CAD according to the expression of miR342-5p after adjusting for CAD risk factors (OR [CI] = 6.1 [1.0 - 37.2], p = 0.048). Also, serum IL-6 and TNF-α showed higher levels in CAD patients (p = 0.003 and p = 0.004, respectively). Furthermore, there were positive correlations of miR-342-5p with gene expressions and serum levels of IL-6 and TNF-α. CONCLUSIONS: The present study demonstrated higher levels of miR-342-5p in CAD patients and showed positive correlation with inflammatory cytokines. This result is in accordance with a previous study, and suggested a regulatory role for miR-342-5p in atherosclerosis and cytokine secretion, although more studies are required in this direction.

Effects of N-acetyl cysteine on oxidative stress and TNF-α gene expression in diclofenac-induced hepatotoxicity in rats.

The consumption of non-steroidal anti-inflammatory drug, such as diclofenac, can lead to hepatotoxicity. In the present study, protective effect of N-acetyl cysteine (NAC) on diclofenac-induced hepatotoxicity was investigated. Thirty-two male rats were divided into four groups. Group 1 (control group) was treated with normal saline (1 ml/kg, i.p.) for 4 d. Group 2 (test without treatment) received diclofenac only (50 mg/kg, i.p.) for 4 d. Groups 3 and 4 received diclofenac (50 mg/kg, i.p.) plus NAC (150 mg/kg, p.o) and silymarin (100 mg/kg, p.o) for 4 d, respectively. At the end of experiment, serum glutamate pyruvate transaminase (GPT), glutamate oxaloacetate transaminase (GOT), alkaline phosphatase (ALP), lipid profile, uric acid, protein carbonyl content, MDA, liver TNF-α, ferric-reducing antioxidant power, liver catalase, superoxide dismutase, vitamin C, and histopathological examination were done. In group 2, diclofenac caused a significant increase (p < .05) in the levels of serum ALP, GOT, GPT, TNF-α, uric acid, protein carbonyl content, MDA, and liver TNF-α gene expression as opposed to group 1. In treated groups with NAC and silymarin, a significant reduction (p < .05) was seen in all above mentioned parameters as well as improved liver histopathological changes compared with group 2. This study confirmed the protective effect of NAC on diclofenac-induced hepatotoxicity in rats due to not only reduces liver inflammatory cells, TNF-α, serum MDA, and PC but also through increases liver vitamin C, catalase, and superoxide dismutase activities.

The Study of Apoptosis-inducing Effects of Three Pre-apoptotic Factors by Gallic Acid, Using Simulation Analysis and the Comet Assay Technique on the Prostatic Cancer Cell Line PC3.

BACKGROUND: In this study, we demonstrated the effects of the Gallic Acid (GA) molecule on the prostate cancer cells line PC3 using the comet assay (Alkaline electrophoresis) technique and its effects on some important apoptotic factors including BAD (Bcl-2-Associated Death promoter), BAK (Bcl-2 homologous Antagonist/Killer), and BIM (Bcl-2-like protein 11) via simulation analysis by using the Auto Dock and Gromacs software. METHODS: Following the MTT assay on the PC3 cells, and determining IC50, we used three concentrations of GA to around IC50 to treat PC3 cells. 100 comet pictures were obtained by alkaline electrophoresis and have been analysed with the CASP version 1.2.2 software; all the results were thereafter analysed by the SPSS version 21 statistical software. RESULTS: The IC50 value for GA was determined to be 35 µM. The ratio of tail to head in alkaline electrophoresis for the three concentrations below the IC50 of GA in 25, 30, and 35 µM were measured as 24.7 (2.7), 44.5 (1.8), and 57.3 (1.3) percent, respectively. The results of the preapoptotic factors (BAD, BAK, and BIM) in the performed simulation in the absence and presence of GA showed that the GA protein causes the structural instability in the BAD protein, and the effect of GA can be explained by the creation of hydrogen bonds with proteins. CONCLUSION: GA is a polyphenol compound in plants that can suppress cell growth and induce apoptosis in PC3 cells in prostate cancer in the range of IC50 concentrations. The apoptotic properties of GA induce pre-apoptotic factors.

Effects of Zizyphus jujube extract on memory and learning impairment induced by bilateral electric lesions of the nucleus Basalis of Meynert in rat.

Alzheimer's disease (AD) is a common neurodegenerative condition that affects the elderly population. Its primary symptom is memory loss. The memory dysfunction in AD has been associated with cortical cholinergic deficiency and loss of cholinergic neurons of the nucleus basalis of Meynert (NBM). Zizyphus jujube (ZJ) activates choline acetyltransferase and may have beneficial effects in AD patients. This study investigates the effect of ZJ extract in intact rats and in rat model of AD. 49 male Wistar rats were divided into seven equal groups (1-control, without surgery, received water), 2-AD (bilateral NBM lesion, received water), 3 and 4-AD + ZJ (NBM bilateral lesion, received ZJ extract 500 and 1,000 mg/kg b.w. per day for 15 days), 5-sham (surgery: electrode introduced into NBM without lesion, received water), 6 and 7-without surgery and lesion, received ZJ extract-the same as groups 3 and 4). The learning and memory performance were assessed using passive avoidance paradigm, and the memory cognition for spatial learning and memory was evaluated by Morris water maze. In shuttle box test ZJ extract (500 and 1,000 mg) significantly increased step-through latency in AD + ZJ groups compared with AD group. In Morris water maze test (in probe day), both AD + ZJ groups receiving extract (500 and 1,000 mg) demonstrated significant preference for the quadrant in which the platform was located on the preceding day as compared with AD group. Our results suggested that ZJ has repairing effects on memory and behavioral disorders produced by NBM lesion in rats and may have beneficial effects in treatment of AD patients.

The effect of Ramadan fasting on serum leptin, neuropeptide Y and insulin in pregnant women.

BACKGROUND: Many pregnant Muslim women choose to fast during Ramadan every year worldwide. This study aimed to examine the effect of Ramadan fasting on serum leptin, neuropeptide Y and insulin in pregnant women and find whether fasting during pregnancy could have a negative effect on the health of mothers and fetuses. METHODS: This cross-sectional study was conducted on 39 healthy volunteer fasting pregnant women. Serum leptin, neuropeptide Y, insulin levels, body mass index and weight were measured five times on 0, 7th, 14th and 28th days of Ramadan and on the 14th day post-Ramadan. The data were analyzed by SPSS software (version 11.5) using repeated measures ANOVA to find whether any changes occurred in the variables of interest during the study, and Pearson correlation coefficient was used to examine the relations among the variables. RESULTS: A significant change in fasting blood sugar, neuropeptide Y and leptin was observed during the study (p< 0.05). Fasting blood sugar decreased significantly during Ramadan and increased after Ramadan, with the lowest value at the end of Ramadan. Neuropeptide Y increased both during Ramadan and two weeks after Ramadan. Also, leptin decreased significantly two weeks after Ramadan compared to the end of Ramadan. No significant change was observed in insulin level during the study (p>0.05). CONCLUSION: The result of this study revealed the important role of leptin and neuropeptide Y in the long term regulation of energy balance in pregnant women with chronic diurnal fasting, and it further revealed that Ramadan fasting did not significantly change the serum insulin level.

Antihyperlipidemic effects of Sesamum indicum L. in rabbits fed a high-fat diet.

The present study aimed to investigate the anti-hyperlipidemic effects of sesame in a high-fat fed rabbit model. Animals were randomly divided into four groups of eight animals each for 60 days as follows: normal diet, hypercholesterolemic diet (1% cholesterol), hypercholesterolemic diet (1% cholesterol) + sesame seed (10%), and hypercholesterolemic diet (1% cholesterol) + sesame oil (5%). Serum concentrations of total cholesterol, LDL-C, HDL-C, triglycerides, apoA and apoB, SGOT, SGPT, glucose and insulin were measured at the end of supplementation period in all studied groups. Hypercholesterolemic feeding resulted in a significant elevation of TC, TG, LDL-C, HDL-C, SGOT and SGPT as compared to the normocholesterolemic diet group (P < 0.05). Supplementation with sesame seed did not cause any significant alteration in lipid profile parameters, apolipoproteins, hepatic transaminases, glucose and insulin as compared to the hypercholesterolemic diet group (P > 0.05). In contrast, rabbits supplemented with sesame oil were found to have lower circulating concentrations of TC, LDL-C, HDL-C, SGOT and SGPT (P < 0.05), whilst concentrations of TG, apoA, apoB, insulin and glucose remained unaltered compared to the hypercholesterolemic diet group (P > 0.05). Supplementation with sesame oil, but not sesame seed, can ameliorate serum levels of lipids and hepatic enzymes in rabbits under a high-fat diet.

Co-administration of trientine and flaxseed oil on oxidative stress, serum lipids and heart structure in diabetic rats.

The administration of flaxseed oil or flaxseed oil plus trientine in diabetic rats reduced triglyceride, very low density lipoprotein, and total cholesterol. Furthermore, the combined treatment significantly increased superoxide dismutase activity and attenuated serum Cu2+. The results suggest that the administration of flaxseed oil plus trientine is useful in controlling serum lipid abnormalities, oxidative stress, restoring heart structure, and reducing serum Cu2+ in diabetic rats.

Protective effect of artichoke (Cynara scolymus) leaf extract against lead toxicity in rat.

CONTEXT: Artichoke, Cynara scolymus L. (Asteraceae), has many natural antioxidants and multiple pharmacological actions. Recent studies have shown that it has antitoxic activity. OBJECTIVE: Lead (Pb) is a dangerous environmental toxicant that induces a broad range of dysfunctions in human. This study evaluated the protective effect of the hydroethanolic extract of artichoke against altered biochemical parameters in rats fed with lead-containing diet. MATERIALS AND METHODS: Thirty-two rats were randomly divided into four groups. The first (control) group received standard diet. The second, third and fourth groups received 500 mg lead/kg diet, 500 mg lead/kg diet plus 300 mg/kg b.w. artichoke extract daily, and 500 mg lead/kg diet plus 1 mg vitamin C/100 g b.w. daily for 6 weeks, respectively. Serum lead, lipoprotein profile, ALT (alanine transaminase), AST (aspartate transaminase), ALP (alkaline phosphatase), malondialdehyde (MDA) and liver histopathology assessments were conducted. RESULTS: Serum lead, triglyceride (TG), VLDL, ALT, AST, ALP and MDA levels decreased significantly (p < 0.05) in the artichoke-treated group (35.85, 38.26, 38.38, 21.90, 12.81, 26.86 and 46.91%, respectively) compared to lead-intoxicated rats without treatment. No significant change was observed in serum lead, ALP and ALT between artichoke and vitamin C-treated groups (p > 0.05). Furthermore, the liver histopathology in rats treated with artichoke showed a mild degree of lymphocyte infiltration that was relatively comparable to the control and vitamin C-treated groups. DISCUSSION AND CONCLUSION: These results clearly show that the artichoke extract in lead-poisoned rats has suitable chelating properties for the reduction of blood lead levels.

Ferulic acid prevents cyclosporine-induced nephrotoxicity in rats through exerting anti-oxidant and anti-inflammatory effects via activation of Nrf2/HO-1 signaling and suppression of NF-κB/TNF-α axis.

Cyclosporine is one of the main immunosuppressive agents used in the treatment of autoimmune diseases or transplantation. Despite the favorable effects, cyclosporine-mediated nephrotoxicity critically restricts the clinical use of the agent. Given this, herein, we aimed to evaluate whether ferulic acid could prevent cyclosporine-mediated nephrotoxicity in rats. A total of 32 Wistar rats were chosen to be treated with cyclosporine, ferulic acid, and the combination of both agents for 21 days. To evaluate the nephron-protective mechanism of ferulic acid, the serum levels of biochemical parameters, as well as the tissue levels of several oxidative and anti-oxidative mediators, were examined. The expression and the tissue levels of nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α, heme oxygenase (HO-1), and nuclear factor erythroid 2-related factor 2 (Nrf2) were evaluated using the qRT-PCR and ELISA, respectively. Our results showed while cyclosporine elevated the serum levels of renal-related markers in the rats, in the presence of ferulic acid, there was a significant reduction in the levels of urea, uric acid, creatinine, and sGOT. Moreover, we found that ferulic acid remarkably prevented cyclosporine-mediated nephrotoxicity by restoring the anti-oxidant system through activating the Nrf2/HO-1 axis. By halting the NF-κB-mediated upregulation of TNF-α, it also seems that ferulic acid prevented lymphocytes infiltration into kidney tissue and consequently suppressed inflammatory responses. Overall, the results of the present study suggest that due to the anti-oxidant and anti-inflammatory properties of ferulic acid, this agent could be used alongside cyclosporine to reduce its adverse effects on kidney tissue.

Hepatoprotective effects of silymarin against diclofenac-induced liver toxicity in male rats based on biochemical parameters and histological study.

Diclofenac (DIC) is a phenyl acetic acid derivative which is well known for its analgesic and anti-inflammatory. In our study, the rats were divided into four groups. Group 1, control group; Group 2 received DIC-only; Groups 3 and 4 received DIC plus silymarin. The results showed that levels of CAT, SOD, GPx and GSH significantly reduced and levels of ALT, AST, ALP, total bilirubin, nitrite content, MDA, serum TNF-α and TNF-α gene expression were significantly elevated in second group compared to control group. In other hand, treatment with silymarin resulted in a significant elevation in CAT, SOD, GPx, GSH and a significant reduction in MDA, ALT, AST, ALP, total bilirubin, nitrite content, serum TNF-α, and gene expression of TNF-α in comparison with second group. Histopathological injuries were also improved by silymarin administration. The results confirm that silymarin has a protective effect on DIC-induced liver toxicity and oxidative stress in male rats.

Quercetin Synergistically Enhances the Anticancer Efficacy of Docetaxel through Induction of Apoptosis and Modulation of PI3K/AKT, MAPK/ERK, and JAK/STAT3 Signaling Pathways in MDA-MB-231 Breast Cancer Cell Line.

Docetaxel is widely used in the treatment of metastatic breast cancer. However, its effectiveness is limited due to chemoresistance and its undesirable side effects. The combination of chemotherapeutic agents and natural compounds is an effective strategy to overcome drug resistance and the ensuing inevitable toxicities. Quercetin is a natural flavonoid with strong antioxidant and anticancer activities. This study aimed to evaluate the cytotoxic and modulatory effects of combined docetaxel and quercetin on the MDA-MB-231 human breast cancer cell line. The cell viability was assessed by MTT assay. The induction of apoptosis was examined using flow cytometry. The role of p53 in the apoptotic process was evaluated via qRT-PCR. The levels of BAX, BCL2, ERK1/2, AKT, and STAT3 proteins were measured by Western blot analysis. The results showed that the single-agent treatment with docetaxel or quercetin leads to a decrease in the viability of the MDA-MB-231 cells at 48 h. Furthermore, the combination of docetaxel (7 nM) and quercetin (95 µM) displayed the greatest synergistic effects with a combination index value of 0.76 accompanied by the up regulation of p53 and a significant increase in BAX level, as well as decrease in the levels of BCL2, pERK1/2, AKT, and STAT3 proteins (P < 0.05). The concomitant use of docetaxel and quercetin leads to the cell growth inhibition associated with the induction of apoptosis and inhibition of cell survival. Therefore, this study provides a promising therapeutic approach to enhance the efficacy of docetaxel in a less-toxic manner.

Antioxidant, anti-inflammatory and protective potential of gallic acid against paraquat-induced liver toxicity in male rats.

OBJECTIVE: As a herbicide, paraquat is a toxic agent that has devastating effects on human health. Gallic acid, on the other hand, is a natural compound that its anti-oxidant values have been reported in previous studies. Given these, this study was designed to evaluate whether gallic acid could reduce the toxic effects of paraquat in the liver of rats. MATERIALS AND METHODS: Six groups of rats were considered in this study. Group 1 (control group), group 2 (25 mg/kg of paraquat), group 3 (paraquat-plus-silymarin), and groups 4, 5, and 6 (paraquat together with gallic acid at the doses of 25, 50, and 100 mg/kg, respectively). After treatment, biochemical, oxidative, and histopathological parameters were evaluated in the rats. RESULTS: We found that as compared to the control group, while paraquat reduced the hepatic levels of anti-oxidative compounds such as vitamin C (p<0.001), superoxide dismutase (SOD) (p<0.001), and catalase (CAT) (p<0.001), the toxic agent increased the serum levels of protein carbonyl (PC) (p<0.001), malondialdehyde (MDA) (p<0.05), and IL-1ß (p<0.001). Paraquat also increased (p<0.05) both serum lipid profile and liver-associated markers in the rats. Nevertheless, gallic acid not only enhanced (p<0.05) the activity of vitamin C, SOD, and CAT but also remarkably reduced (p<0.05) the serum lipid profile, as well as the oxidative and inflammatory markers in the paraquat-treated rats. Gallic acid had also ameliorating effects on the damaged morphology of hepatocytes upon paraquat treatment. CONCLUSION: The results of this study suggested that gallic acid possesses reinforcing effects on the antioxidant defense system and could be administered to reduce the toxicity of paraquat.

Gallic acid exerts anti-inflammatory, anti-oxidative stress, and nephroprotective effects against paraquat-induced renal injury in male rats.

Paraquat (PRQ) is a toxic chemical compound that is very noxious to animals and humans. Gallic acid is a phenolic compound that has antioxidant properties. In this study, we evaluated the ameliorative effect of gallic acid against PRQ-induced renal injury and oxidative stress. In this research, the rats were segregated into six groups. Group 1 is the control group; group 2 received paraquat only; group 3 received gallic acid only; and groups 4, 5, and 6 received paraquat plus gallic acid at doses of 25, 50, and 100 mg/kg bw respectively. Findings of this work displayed that the renal contents of the vitamin C, superoxide dismutase (SOD), and catalase (CAT) significantly reduced and the levels of the serum protein carbonyl, creatinine, serum glutamate pyruvate transaminase (sGPT), urea, serum glutamate oxaloacetate transaminase (sGOT), uric acid, MDA, serum IL-1ß, and the kidney IL-1ß gene expression were remarkably increased in the group receiving PRQ only compared with that in the control group. On the other hand, treatment with gallic acid after exposure to PRQ led to a significant elevation in renal vitamin C, SOD, and CAT levels plus a remarkable decrease in the serum protein carbonyl, creatinine, sGPT, urea, sGOT, uric acid, MDA, IL-1ß, and renal gene expression of IL-1ß in comparison with the PRQ-only-treated rats. Histological changes were also ameliorated by gallic acid administration. The data approve that gallic acid diminished the deleterious effects of PRQ exposure. In this regard, our results indicated that the administration of gallic acid could alleviate the noxious effects of PRQ on the antioxidant defense system and renal tissue.

QSAR Modeling, Molecular Docking and Molecular Dynamics Simulations Studies of Lysine-Specific Demethylase 1 (LSD1) Inhibitors as Anticancer Agents.

BACKGROUND: Histone Lysine Demetylases1 (LSD1) is a promising medication to treat cancer, which plays a crucial role in epigenetic modulation of gene expression. Inhibition of LSD1with small molecules has emerged as a vital mechanism to treat cancer. OBJECTIVE: In the present research, molecular modeling investigations, such as CoMFA, CoMFA-RF, CoMSIA and HQSAR, molecular docking and Molecular Dynamics (MD) simulations were carried out on some tranylcypromine derivatives as LSD1 inhibitors. METHODS: The QSAR models were carried out on a series of Tranylcypromine derivatives as data set via the SYBYL-X2.1.1 program. Molecular docking and MD simulations were carried out by the MOE software and the SYBYL program, respectively. The internal and external predictability performances related to the generated models for these LSD1 inhibitors were justified by evaluating cross-validated correlation coefficient (q2), noncross- validated correlation coefficient (r2ncv) and predicted correlation coefficient (r2pred) of the training and test set molecules, respectively. RESULTS: The CoMFA (q2, 0.670; r2ncv, 0.930; r2pred, 0.968), CoMFA-RF (q2, 0.694; r2ncr, 0.926; r2pred, 0.927), CoMSIA (q2, 0.834; r2ncv, 0.956; r2pred, 0.958) and HQSAR models (q2, 0.854; r2ncv, 0.900; r2pred, 0.728) for training as well as the test set of LSD1 inhibition resulted in significant findings. CONCLUSION: These QSAR models were found to be perfect and strong with better predictability. Contour maps of all models were generated and it was proven by molecular docking studies and molecular dynamics simulation that the hydrophobic, electrostatic and hydrogen bonding fields are crucial in these models for improving the binding affinity and determining the structure-activity relationship. These theoretical results are possibly beneficial to design new strong LSD1 inhibitors with enhanced activity to treat cancer.

Apoptotic Effects of Bilirubin on Skin Cancer Cell Lines SK-MEL-3 (Melanoma) and A431 (Non-Melanoma).

BACKGROUND: Bilirubin has long been exclusively considered as a potentially dangerous sign of liver diseases, but it is currently regarded as a reliable signaling molecule as well. OBJECTIVE: This study investigated the effects of unconjugated bilirubin on survival, proliferation, apoptotic and cell arrest capacities of melanoma SKMEL-3 and non-melanoma A431 skin cancer cells in comparison with normal Human Dermal Fibroblast (HDF) cells. METHODS: The MTT assay test was used to identify survival and the IC50 at various concentrations of bilirubin on SKMEL-3, A431, and HDF cells for 24h and 48h. The comet assay technique was used to investigate genotoxicity effects, and flow cytometry was run to investigate apoptotic and cell arresting effects of bilirubin on the cells. The gene expression of cyclin D1, cyclin E1, survivin, Bcl-2, and p53 was investigated by qRT-PCR. The molecular docking of bilirubin on CDKs (Cyclin-Dependent Kinases 2, 4, and 6) and pro-apoptotic factors Bad, Bak, Bax, Bid, Bik, and Bim was performed by Autodock software version 2. RESULTS: The IC50 of bilirubin on HDF, A431, and SKMEL-3 cells was 125, 115, and 95 µM at 24h and 115, 100, and 75 µM at 48h, respectively. Although cell arrest in the G1 phase occurred in all cells, bilirubin induced genotoxicity and apoptosis in SKMEL-3 and A431 cancer cells more pronouncedly than those in normal HDF cells. CONCLUSION: Bilirubin led to cell arrest in the G1 phase in SKMEL-3, A431, and HDF cells. Additionally, bilirubin induced apoptotic pathways in SKMEL-3 and A431 cancer cells.