Publications by authors named "Amir Hossein Doustimotlagh"

31 Publications

Trehalose and N-Acetyl Cysteine Alleviate Inflammatory Cytokine Production and Oxidative Stress in LPS-Stimulated Human Peripheral Blood Mononuclear Cells.

Immunol Invest 2021 Feb 25:1-17. Epub 2021 Feb 25.

Department of Clinical Biochemistry, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran.

: Evidence has shown that inflammation and oxidative stress are implicated in the development of a great number of human diseases. Trehalose possesses various biological effects including antioxidant and anti-inflammatory activities. However, there is little data on the effects of trehalose on human cells including peripheral blood mononuclear cells (PBMCs). Here, we aimed to investigate whether trehalose could attenuate oxidative stress and inflammation induced by lipopolysaccharides (LPS) in PBMCs.: The enzyme-linked immunosorbent assay (ELISA) and RT-PCR were used to assess the levels of inflammatory cytokines. To investigate the phosphorylation of c-Jun N-terminal kinase (JNK) and NF-κB, western blot analysis was utilized. Oxidant-antioxidant markers were assessed using ELISA and colorimetric procedures.: The results revealed that trehalose significantly mitigated the effect of LPS on the phosphorylation of JNK and NF-κB-P65 ( < .00). This mitigation was associated with significantly reduced levels of inflammatory cytokines IL-6, TNF-α, and IL-1β and increased levels of anti-inflammatory cytokine IL-10 ( < .05). The antioxidant N-acetyl cysteine (NAC) also showed similar effects on JNK and NF-κB-P65 phosphorylation and inflammatory cytokines ( < .00). Furthermore, trehalose alleviated oxidative stress in LPS-stimulated PBMCs as it reversed the altered levels of malondialdehyde and total thiols ( ≤ .05) and restored the activity of antioxidant enzymes glutathione peroxidase and manganese superoxide dismutase ( < .001).: The results of this study indicated that trehalose prevented inflammation and oxidative stress in the LPS-stimulated PBMCs, providing evidence for the benefits of trehalose as a potential therapeutic agent in inflammatory conditions. LPS: Lipopolysaccharide; NAC: N-Acetyl cysteine; ROS: Reactive oxygen species; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha; SOD: Superoxide dismutase; GPx: Glutathione peroxidase; MDA: Malondialdehyde; MAPK: Mitogen-activated protein kinases; JNK: c-Jun N-terminal kinase; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells.
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http://dx.doi.org/10.1080/08820139.2021.1891095DOI Listing
February 2021

Nephroprotective Effects of Boiss. Hydroalcoholic Extract, Carvacrol, and Thymol on Kidney Toxicity Induced by Cisplatin in Rats.

Evid Based Complement Alternat Med 2021 25;2021:8847212. Epub 2021 Jan 25.

Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.

Background: Cisplatin (Cis) is an anticancer drug; however, it has dose-dependent renal toxicity. The current study aims to investigate the protective effects of Boiss. hydroalcoholic extract (Z.M.B), carvacrol, and thymol on cisplatin-induced nephrotoxicity in rats.

Materials And Methods: Forty-two Wistar male rats were randomly allocated into six groups ( = 7). Group I received normal saline; group II received Cis (7 mg/kg. ip); group III received the Z.M.B extract only (500 mg/kg/d, po); group IV received Z.M.B extract (500 mg/kg/d, po) + Cis; group V received carvacrol (50 mg/kg/d, po) + Cis; and group VI received thymol (50 mg/kg/d, po) + Cis. The levels of biochemical markers, oxidative stress parameters, and histopathological staining were determined in serum and renal tissues. Also, the chemical compositions (carvacrol and thymol) of the Z.M.B extract were assayed by HPLC analysis.

Result: The results revealed that Z.M.B extract, carvacrol, and thymol markedly decreased the renal index as compared with the Cis-only group. Also, carvacrol and thymol significantly reduced the blood urea nitrogen level as compared with the Cis-only group. Furthermore, Z.M.B extract, carvacrol, and thymol significantly attenuated the Cis-induced increase in malondialdehyde and nitric oxide metabolite. Additionally, histopathological examination showed that Z.M.B extract, carvacrol, and thymol markedly ameliorated Cis-induced renal tubular necrosis.

Conclusion: The results showed renoprotective effects of Z.M.B extract, carvacrol, and thymol in Cis-induced nephrotoxicity in rats. Therefore, Z.M.B extract can be considered as a potential candidate for the protection of nephrotoxicity induced by Cis.
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http://dx.doi.org/10.1155/2021/8847212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857888PMC
January 2021

Protective Effect of Hydroalcoholic Extract of on Oxidant-Antioxidant Status in Renal Ischemia/Reperfusion Injuries in Male Rats.

J Toxicol 2021 29;2021:6646963. Epub 2021 Jan 29.

Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.

Background: Renal ischemia-reperfusion (I/R) has a pivotal role in the progression of acute renal failure. Reactive oxygen species are considered the major constituents involved in the biochemical and pathophysiological changes that were shown during kidney I/R. The purpose of this study was to examine the renoprotective effects of ethanolic extract on oxidant-antioxidant status in renal I/R-injuries in male rats. . Twenty-one male Wistar rats were arbitrarily distributed into 3 groups: sham control (SC), I/R, and I/R +  ethanolic extract (500 mg/kg). The artery and vein of the right kidney were completely blocked, and the right kidney was completely removed in all groups. Then, the left kidney artery was blocked with suture thread for 30 minutes in only I/R and I/R +  extract groups. Kidney function indices, oxidative stress markers, and hematoxylin and eosin staining were investigated in the plasma and kidney tissues.

Results: It was shown that the urine Na and K, fractional excretion of Na and K, and protein carbonyl content markedly increased in the merely I/R group as compared to SC rats, while the administration of extract markedly reduced these indices ( < 0.05). Also, glomerular filtration rate and total thiol meaningfully reduced in the I/R rats in contrast to the SC group, while the treatment with extract markedly augmented these indices ( < 0.05). However, in agreement with renal function tests, extract had no significant effects on histopathological examinations.

Conclusion: It seems that extract employs renoprotective effects on renal damage induced by I/R, possibly by improving of oxidant-antioxidant status in favor of the antioxidant system.
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http://dx.doi.org/10.1155/2021/6646963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864747PMC
January 2021

Effects of Extract on Antioxidant and Biochemical Parameters in Hemodialysis Patients: A Randomized Double-Blind Clinical Trial.

Evid Based Complement Alternat Med 2021 8;2021:1632957. Epub 2021 Jan 8.

Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.

Background: Increased oxidative stress play an important role in the risk of cardiovascular disease, mortality, and mortality patients undergoing dialysis. (watercress) contains numerous phytochemical compounds that act as an antioxidant by preventing oxidative damage to biomolecules. Therefore, this research aimed to explore the effect of the ethanolic extract of (EENO) on antioxidant and biochemical markers of hemodialysis patients.

Methods: In this double-blind, placebo-controlled trial, 46 hemodialysis patients were randomly recruited to consume either 500 mg/day EENO ( = 23) or placebo capsule ( = 23) for 4 weeks, at Shahid Beheshti Hospital, Yasuj, Iran, in 2019. Biomarkers of oxidative stress including glutathione peroxidase (GPX), superoxide dismutase (SOD), malondialdehyde (MDA), total oxidant status (TOS), total antioxidant capacity (TAC), and total sulfhydryl protein (T-SH) and biochemical parameters such as BUN, Hb, WBC, PLT, Ca, Ph, K, ALB, TChol, TG, LDL, and HDL were evaluated on days 0 and 28.

Results: The serum levels of MDA and BUN significantly decreased after taking EENO supplementation ( < 0.001); however, SOD activity increased during the same period ( < 0.001). The serum levels of TAC remained constant in the intervention group, while it significantly declined in the placebo group ( < 0.09). The extract also prevented elevation in the serum levels of LDL and TG compared to the placebo group, although it was not statistically significant.

Conclusions: The data indicated that the consumption of EENO improved some of the antioxidant parameters and minimizes the change in TG and LDL in hemodialysis patients. Therefore, due to the role of these factors in mortality and morbidity of dialysis patients, EENO can improve the condition of dialysis patients. However, more studies with longer intervention times and different doses of EENO are recommended.
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http://dx.doi.org/10.1155/2021/1632957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810522PMC
January 2021

Nano-sized FeO@SiO-molecular imprinted polymer as a sorbent for dispersive solid-phase microextraction of melatonin in the methanolic extract of Portulaca oleracea, biological, and water samples.

Talanta 2021 Jan 5;221:121620. Epub 2020 Sep 5.

Department of Chemistry, Yasouj University, Yasouj, 75918-74831, Iran. Electronic address:

In this study, a magnetic molecularly imprinted polymer (MMIP (FeO@SiO-MIP)) was used for the dispersive magnetic solid-phase microextraction (d-MSP-μ-E) to design an easy and effective method for melatonin (MLT) extraction in the methanolic extract of Portulaca oleracea, human urine and plasma, and water samples. HPLC with UV detection was utilized, and pH, the type and volume of eluent, MMIP mass, and contact time were considered as effective factors in the study of MLT separation and pre-concentration. These factors were optimized by Plackett-Burman and multi-objective response surface methodology (RSM). The values were 10 mg, 14 min, 4.2, methanol, 0.180 mL, 2.5 min, for the MMIP mass, time of sorption, sample pH, eluent type, eluent volume, and time of elution, respectively. At the optimum conditions, the limit of detection (LOD) was 0.046 ng mL, and the limit of quantification (LOQ) was 0.156 ng mL. The sorption capacity of the proposed MMIP sorbent was 109.1 mg g at the optimum conditions. Besides, linear dynamic range (LDR) was 0.2-4200 ng mL, and the precision of the method (RSD %) for triplicate measurements was <6.1%. The MMIP showed saturation magnetization of 19.75 emu g, resulting in fast separation of the sorbent. The sorption test revealed the high sorption capacity of the MMIP for MLT and its homogeneous binding sites. In all spiked levels (50, 100, 200, and 500 ng mL), 93.07-104.1% was the range obtained for the recovery of MLT. The relative selectivity factor (β) values of MLT/tryptophan, MLT/serotonin, MLT/ferulic acid, MLT/mefenamic acid, MLT/quercetin, MLT/luteolin, and MLT/chlorogenic acid were 1.60, 1.68, 2.02, 2.38, 2.32, 2.40, and 2.50, respectively. The results of desorption-regeneration cycles (seven times) by employing the MMIP showed the high stability of the resultant material. In conclusion, the MMIP combined with the magnetic separation showed a specific sorption behavior for MLT and suggested a simple, flexible, selective, and powerful analytical tool.
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http://dx.doi.org/10.1016/j.talanta.2020.121620DOI Listing
January 2021

Circulating mRNA and plasma levels of osteoprotegerin and receptor activator of NF-κB ligand in nonalcoholic fatty liver disease.

Biotechnol Appl Biochem 2020 Oct 3. Epub 2020 Oct 3.

Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.

Pathogenesis of the beginning and progression of nonalcoholic fatty liver disease (NAFLD) has not been clarified exactly. The osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) axis seems to play an imperative function in the onset and progression of this disease. The goal of the present study was to investigate the peripheral blood mononuclear cell (PBMC) expression and plasma levels of RANKL and OPG cytokines in NAFLD patients and compare them with healthy group. Plasma levels of OPG and RANKL were determined with ELISA kits in 57 men with NAFLD and 25 healthy men as controls. Biochemical and anthropometric parameters tests were also evaluated in the study groups. RANKL and OPG mRNA contents were evaluated by quantitative RT-PCR. OPG contents were markedly decreased in NAFLD patients as compared with healthy patients [1.43 (1.05-5.45)] versus [2.94 (1.76-4.73)] ng/mL; P = 0.007). The levels of RANKL were significantly reduced in NAFLD patients [74.00 (56.26-203.52) ng/mL] than in healthy patients [119.37 (83.71-150.13) ng/mL]; (P = 0.03). Also, OPG and RANKL gene expression were significantly decreased in NAFLD patients in comparison with the control group (P < 0.05). Moreover, receiver operating characteristic curve indicated that OPG may have a good capability to discriminate between NAFLD patients and normal individuals. A positive correlation was observed between OPG and RANKL in plasma sample (r = 0.495) (P = 0.000). Decreased plasma levels and gene expression of RANKL and OPG cytokines in NAFLD patients indicate that there is a relationship between these cytokines and the pathology of NAFLD disease. Confirmation of this association as well as the mechanism and role of these cytokines in NAFLD require further studies.
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http://dx.doi.org/10.1002/bab.2047DOI Listing
October 2020

Assessment of function, histopathological changes, and oxidative stress in liver tissue due to ionizing and non-ionizing radiations.

Caspian J Intern Med 2020 May;11(3):315-323

Cancer Research Center, Health Research Institute, Babol University of Medical Sciences, Babol Iran.

Background: Compared to past decades, humans are exposed to rapidly increasing levels of radiofrequency electromagnetic radiations (RF-EMF). Despite numerous studies, the biological effects of human exposure to different levels of RF-EMF are not fully understood yet. This study aimed to evaluate the bioeffects of exposure to "900/1800 MHz" and "2.4 GHz" RF-EMFs, and x-rays alone as well as their potential interactions, i.e. inducing simple additive, adaptive, or synergistic effects.

Methods: 120 Wistar rats were randomly divided into ten groups of 12 each. The rats were exposed to RF-EMF, 10 cGy, and 8 Gy x-rays, a combination of these exposures, or only sham-exposed. The levels of liver enzymes were determined in serum samples by an auto-analyzer. Moreover, the histopathological changes, and the levels of malondialdehyde (MDA), nitric oxide, ferric reducing antioxidant power, total thiols, and protein carbonyl (PCO) were measured.

Results: Among the markers of liver function, gamma-glutamyltransferase was not associated with irradiation but, aspartate transaminase, alanine transaminase, and alkaline phosphatase showed some levels of association. MDA and PCO levels after 8 Gy irradiation increased, but pre-exposure to RF-EMF could modulate their changes. At the cellular level, the frequency of lobular inflammation was associated with the type of intervention.

Conclusion: The exposure to both ionizing and non-ionizing radiations could alter some liver function tests. A short term pre-exposure to RF-EMF before exposure to an 8 Gy challenging dose of x-rays caused the alterations in oxidative stress markers and liver function tests, which indicate that oxidative stress is possibly involved in the adaptive response.
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http://dx.doi.org/10.22088/cjim.11.3.315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442457PMC
May 2020

Novel osteoprotective nanocochleate formulation: A dual combination therapy-codelivery system against glucocorticoid induced osteoporosis.

Nanomedicine 2020 10 22;29:102273. Epub 2020 Jul 22.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Phosphatidylserine nanocochleates (Nanocochs) are novel delivery systems that may play a prominent osteoprotective role with their cargo, vitamin D3 (Vit-D3), against osteoporosis. Therefore, this study was conducted to characterize a Nanococh containing vitamin D3 (Nanococh-D3) and investigate its potential role in improving GIO in a rat model. Roll-shaped Nanococh-D3 particles were obtained in a size range of 320 nm with a sustained release performance. Oral Nanococh-D3 significantly increased the bioavailability of Vit-D3, enhanced bone mechanical strength, and improved osteogenic biomarkers including B-ALP, osteocalcin, Ca, and OPG in GIO rats. This formulation markedly suppressed gene expression of RANK and RANKL in treated rats. Histomorphometric analysis showed significant repairs in bone tissues and TRAP staining indicated a significant decrease in osteoclasts using Nanococh-D3 in osteoporotic rats. Nanococh alone similar to Nanococh-D3 acted better than AL as a standard anti-osteoporotic drug in the improvement of bone strength. In conclusion, our results established the potential role of Nanococh-D3 against osteoporosis in rats.
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http://dx.doi.org/10.1016/j.nano.2020.102273DOI Listing
October 2020

Association between circulating visfatin and pre-eclampsia: a systematic review and meta-analysis.

J Matern Fetal Neonatal Med 2020 Jul 7:1-13. Epub 2020 Jul 7.

Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Objective: Pre-eclampsia (PE) is a serious pregnancy status characterized by high blood pressure. Although visfatin is usually associated with PE. Observational studies evaluating the relationship between circulating visfatin and pre-eclampsia have reported inconsistent results. We conducted this systematic review and meta-analysis to summarize published data on the association between visfatin and pre-eclampsia.

Methods: Electronic databases PubMed, ISI web of science, EMBASE, Scopus and the Cochrane library were comprehensively searched for selection of eligible studies until January 5, 2020. A random-effects model and the generic inverse variance method were used for quantitative data synthesis. The assessment of study quality was performed using the e Newcastle-Ottawa scale and the Agency for Healthcare Research and Quality. Sensitivity analyses and prespecified subgroup were conducted to evaluate potential heterogeneity. Random-effects meta-regression was conducted to assess the impact of potential confounders on the estimated effect sizes. The protocol for this study was registered in PROSPERO (No. CRD42018105861) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Results: Thirteen studies comprising a total of 536 subjects were included in this meta-analysis. We observed that the pre-eclampsia risk is associated with a statistically significant elevation of visfatin level [SMD (1.33 µg/l) (95% CI 0.37, 2.2)  = .007]. No significant publication bias was observed in the meta-analysis. Subgroup and sensitivity analyses indicated that the pooled effects size were affected by systolic blood pressure [SMD (1.82 µg/l) 95% CI (0.94, 2.7),  < .05], gestational age [SMD (2.01 µg/l) 95% CI (0.57, 3.4),  = .006], body mass index [SMD (1.6 µg/l) 95% CI (0.37, 3),  < .05] and pregnancy trimesters[SMD (2.3 µg/l) 95% CI (0.95, 3.7),  = .001]. Random-effects meta-regression showed a significant association of visfatin level with potential confounders including systolic blood pressure, gestational age and birth weight at delivery of pre-eclampsia patients.

Conclusions: Collectively, our data revealed that the increase of visfatin level can be associated with the risk of pre-eclampsia. However, further studies on pre-eclampsia populations are warranted for corroboration of our findings.
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http://dx.doi.org/10.1080/14767058.2020.1789581DOI Listing
July 2020

Phosphatidylserine nanoliposomes inhibit glucocorticoid-induced osteoporosis: A potential combination therapy with alendronate.

Life Sci 2020 Sep 2;257:118033. Epub 2020 Jul 2.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

The present study aimed to investigate the effects of phosphatidylserine liposomes (PSLs) and phosphatidylserine liposomes containing alendronate (AL-PSLs) on the improvement of methylprednisolone (MP) induced osteoporosis in a rat model. AL-PSLs formulation was prepared, characterized, and evaluated in different pH media to simulate gastrointestinal condition. Osteoporosis was induced by 3 weeks oral administration of MP (10 mg/kg) and then treatment by PSLs, AL-PSLs, and alendronate (AL). Bone metabolic and biomechanical markers were measured in treated rat groups. Also, Tartrate-resistant acid phosphatase (TRAP) staining and histomorphometry were evaluated on bone tissues of treated rats. AL-PSLs were obtained in a size range of 155 nm and negatively surface charge with an entrapment efficiency of 42%. The AL leakage from AL-PSLs did not exhibit a significant difference in acidic or basic media in comparison with the neutral condition. The concentrations of calcium, osteocalcin, bone alkaline phosphatase, and osteoprotegerin (OPG) of serum were significantly increased in PSLs and AL-PSLs treated groups compared to the MP group. Also, PSLs and AL-PSLs significantly improved the thickness and volume of the cortical and trabecular bone mass in treated groups. In addition, TRAP staining indicated a significant decrease of osteoclast number in osteoporotic rats treated with AL-PSLs and PSLs. In this study, AL-PSLs and even PSLs alone made a potential bone mechanical strength in glucocorticoid-induced bone loss more than AL in rats. In conclusion, our findings suggest that PSLs consumption with or without an anti-osteoporotic drug might be an applicable choice in control of osteoporosis.
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http://dx.doi.org/10.1016/j.lfs.2020.118033DOI Listing
September 2020

Protective effect of Nasturtium officinale R. Br and quercetin against cyclophosphamide-induced hepatotoxicity in rats.

Mol Biol Rep 2020 Jul 12;47(7):5001-5012. Epub 2020 Jun 12.

Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.

Cyclophosphamide (CPA) is used in the management of autoimmune conditions and malignant illnesses. However, its therapeutic use is limited because of its severe side effects, especially hepatotoxicity attributed to oxidative stress. Nasturtium officinale R. Br (watercress or WC) has pharmacological properties, such as anti-inflammation, and antioxidant activities. Therefore, the present study was design to assess effects of WC or its active ingredient, quercetin (QE), against CPA-induced hepatotoxicity. For this study, 49 male Wistar rats (200-250 g) were randomly selected and categorized into seven equal groups. The animals were pre- and post-treated with both hydroalcoholic extract of WC (500 mg/kg) and quercetin (75 mg/kg) for 10 consecutive days, and intraperitoneal administration of CPA (200 mg/kg) was performed on only day 10, one hour before the last dose of WC or quercetin. On day 11, all the animals were sacrificed, and their blood and liver were gathered for evaluation of the liver enzyme, hepatic oxidative stress markers, antioxidant enzymes activity, and hematoxylin and eosin staining. CPA significantly increased malondialdehyde (MDA), protein carbonyl (PCO) and nitric oxide (NO) levels and liver biomarkers. Otherwise, hepatic catalase (CAT), reduced glutathione (GSH), total thiol content (tSH), and ferric reducing antioxidant power (FRAP) were considerably lower than the control group. Results showed that WC has the ability to reduce the changes (MDA, PCO, FRAP, CAT, ALT and AST) and QE (MDA, PCO, AST) induced by CPA (p < 0.05). Histopathological finding confirmed the indicated results. These findings propose that WC and QE have protective effect against the CPA-induced hepatotoxicity by decreasing oxidative stress.
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http://dx.doi.org/10.1007/s11033-020-05556-7DOI Listing
July 2020

Evaluation of the protective potential of hydroalcoholic extract of on acetaminophen-induced nephrotoxicity in rats.

Heliyon 2020 May 14;6(5):e03898. Epub 2020 May 14.

Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.

Background: Acetaminophen (APAP) is an antinociceptive and antipyretic drug that can be useful in therapeutic doses, although it can cause serious damage to the kidney if used overdose. The current study aimed to evaluate the protective effect of (TD) extract on APAP-induced kidney damage in rats.

Methods: Thirty female Wistar rats were randomly divided into 5 groups: control, APAP (3 g/kg), TD (500 mg/kg), APAP + TD (500 mg/kg), and APAP + N- acetylcysteine (140 mg/kg). The APAP groups received APAP on the 6th day and the rats were sacrificed on the 7th day. Plasma levels of creatinine (Cr) and urea were measured. Ferric reducing antioxidant power (FRAP), nitric oxide (NO) metabolite, total thiol (T-SH), tumor necrosis factor-α (TNF-α) and antioxidant enzymes activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were measured in kidney tissue. The gene expression of TNF-α was also measured by real-time PCR. The histological examination of kidney tissue was also performed.

Results: Results showed that urea, Cr and FRAP markers markedly elevated in the APAP rats compared with the control group. There was a significant decrease in T-SH levels in the APAP animals in comparison with the control group. CAT activity also augmented in the APAP group compared to the control group. Urea and Cr levels were significantly decreased in the APAP + TD group in comparison with the APAP group. The administration of TD extract significantly increased the SOD enzyme activity. Histological findings were improved in the group treated with TD extract.

Conclusion: In general, the results indicate that TD extract can protect against APAP-induced nephrotoxicity by improving biochemical, histological and antioxidant effects. However, more studies are required to determine the mechanism of this extract.
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http://dx.doi.org/10.1016/j.heliyon.2020.e03898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266780PMC
May 2020

Hepatoprotective and antioxidant activity of hydroalcoholic extract of on acetaminophen-induced liver toxicity in male rats.

Heliyon 2019 Dec 24;5(12):e03029. Epub 2019 Dec 24.

Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.

Background: Acetaminophen (APAP) at high doses causes adverse side effects such as hepatotoxicity. The aim of the current study was to investigate the hepatoprotective and antioxidant effects of hydroalcoholic extract of (SP) on hepatotoxicity induced by APAP in male rats.

Methods: Adult male Wistar rats were allocated into four groups: control (C), APAP (2 g/kg), APAP + SP (500 mg/kg), and APAP + Silymarin (SM, 100 mg/kg) as positive control group. On the seventh day, the rats were sacrificed after taking blood samples. Then levels of biochemical parameters, oxidative stress markers and activity of antioxidant enzymes were measured.

Results: In the APAP group, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes activity was significantly increased and the level of protein carbonyl (PCO) was insignificantly increased as compared to control group. In addition, the activity of glutathione peroxidase (GPX) and total thiol in the APAP group was significantly decreased compared to the normal rats. extract administration significantly reduced the activity of AST and ALT enzymes and the level of PCO compared to the APAP group, while significantly elevated the activity of GPX enzyme.

Conclusion: Hydroalcoholic extract of SP diminishes hepatotoxicity induced by APAP by reducing the amount of liver function indicators (AST and ALT). Furthermore, the hydroalcoholic extract of SP is capable of reducing oxidative stress through inhibiting protein oxidation as well as boosting the activity of GPX enzyme. In this respect, the hepatoprotective impact induced by the SP extract may possibly be attributable to its reactive oxygen species scavenging and antioxidant properties.
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http://dx.doi.org/10.1016/j.heliyon.2019.e03029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201135PMC
December 2019

The effects of rosmarinic acid on oxidative stress parameters and inflammatory cytokines in lipopolysaccharide-induced peripheral blood mononuclear cells.

Mol Biol Rep 2020 May 29;47(5):3557-3566. Epub 2020 Apr 29.

Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.

Rosmarinic acid (RA) is a potential herbal medicine and has received considerable attention due to its strong antioxidant properties. The aim of this study is to investigate the impact of RA on inflammation and oxidative stress induced by lipopolysaccharide (LPS) in peripheral blood mononuclear cells (PBMCs). PBMCs were pre-treated with various contents of RA (20, 40, 80 µM) for 24 h, then, stimulated with LPS (10 ng/ml) for more 6 h. ELISA and Real-time PCR were done to detect the levels of IL-6, TNF-α, COX-2, IL-1β and IL-10. Western blot was done to investigate the phosphorylated amounts of P65-NF-κB and JNK. Inflammatory cytokines and oxidant-antioxidant parameters were determined by colorimetric and ELISA methods. The results indicated that LPS augmented the protein levels of IL-6, TNF-α, and IL-1β cytokines as well as the mRNA levels of IL-6, TNF-α, IL-1β, COX-2, and IL-10 cytokines in in PBMCs. However, pretreatment with RA could reduce the impact of LPS on inflammatory markers. In addition, RA inhibited P65-NF-κB and JNK phosphorylation. LPS also caused a decrease in antioxidant enzymes, total thiol, and total antioxidant capacity as well as an increment in malondialdehyde and nitric oxide metabolite contents that RA abrogated them. Collectively, our finding demonstrated that RA ameliorates LPS-induced inflammation in PBMCs. RA reduces oxidative stress by preventing lipid peroxidation and nitric oxide production as well as restarting the activity of the GPx and SOD enzymes. Furthermore, our findings indicated that RA was able to protect PBMCs from inflammation via inhibiting the NF-κB and JNK MAPK pathways. This evidence shows a promising therapeutic role for RA in inflammatory status.
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http://dx.doi.org/10.1007/s11033-020-05447-xDOI Listing
May 2020

Antioxidant and protective effect of Stachys pilifera Benth against nephrotoxicity induced by cisplatin in rats.

J Food Biochem 2020 05 10;44(5):e13190. Epub 2020 Mar 10.

Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.

The aim of current study was to assess the antioxidant and renoprotective effects of Stachys pilifera Benth (S.P.B.) hydroalcoholic extract on nephrotoxicity induced with cisplatin (CP). Adult rats with bodyweight of 180-220 g were divided into five groups (n = 7) treated as follows: group 1, control; group 2, CP; group 3, pretreatment with S.P.B. before CP; group 4, posttreatment with S.P.B. after CP; and, group 5, S.P.B. extract. A single dose of CP (7 mg/kg) was intraperitoneally injected on the fifth day and hydroalcoholic extract of S.P.B. (500 mg kg  day ) was orally administered. The levels of oxidative stress markers, biochemical tests, and histopathological staining were assayed in serum and renal tissue. Also, the chemical composition of S.P.B. extract was determined by GC-MS analysis. The main compositions of S.P.B. extract identified by GC-MS analysis, were hexadeca-2,6,10,14-tetraen-1-ol, 3,7,11,16-tetramethyl (24.77%), thymol (14.1%), and linolenic acid (13.4%). In groups treated and pretreated with S.P.B., blood urea nitrogen, creatinine, malondialdehyde, and nitric oxide metabolite in serum as well as malondialdehyde and protein carbonyl content of kidney tissues were significantly decreased in comparison to CP group; in contrast, total thiol group showed a significant increase in treated group as compared to CP group. Furthermore, histological investigation indicated that treatment with S.P.B. improved renal damages induced by CP. The current study showed that S.P.B. hydroalcoholic extract improved the biochemical parameters and kidney function as well as restored antioxidant activity in CP-induced nephrotoxicity. However, it needs more investigations to define the mechanism of S.P.B. action. PRACTICAL APPLICATIONS: In different regions of Iran, Stachys is demonstrated by 34 species, out of which 13 are endemic, one of these endemic species is Stachys pilifera Benth (S.P.B.). The oil of S.P.B. is mainly consisted of cis-chrysanthenyl acetate, cis-chrysanthenol, spathulenol, β-caryophyllene, linalool, and terpinen-4-ol. Moreover, phytochemical studies have shown the presence of compounds such as diterpenes, phenylethanoid glycosides, saponins, terpenoides, and flavonoids in Stachys species. The aerial parts of S.P.B. are consumed as herbal tea to treat several disorders, for example, infections, asthma, and rheumatoid arthritis in Iranian folk medicine. The aim of current study was to evaluate the antioxidant and protective effects of S.P.B. hydroalcoholic extract on nephrotoxicity induced with cisplatin (CP). The current study showed that S.P.B. hydroalcoholic extract improved the biochemical parameters and kidney function as well as restored antioxidant activity in CP-induced nephrotoxicity. However, it needs more researches to define the mechanism of S.P.B. action.
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http://dx.doi.org/10.1111/jfbc.13190DOI Listing
May 2020

Effect of garlic intake on inflammatory mediators: a systematic review and meta-analysis of randomised controlled trials.

Postgrad Med J 2021 Mar 12;97(1145):156-163. Epub 2020 Feb 12.

Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran

Background: Garlic is a species in the onion genus, . Data have shown that garlic has anti-inflammatory activity; however, the findings are inconclusive and inconsistent. We aimed to evaluate the impact of garlic intake on inflammatory mediators through systematic review and meta-analysis of existing data.

Methods: Electronic databases were completely investigated using databases of ISI Web of Science, Medline, Scopus, Cochrane Library and EMBASE until October 2019. A random effects model and the generic reverse variance procedure were used for quantitative data production. Sensitivity analyses and prespecified subgroup were done to evaluate potential heterogeneity. Random effect meta-regression was conducted to investigate the effects of possible confounders on the assessed effect size.

Results: Ten trials with one observational study, including 530 participants, met the eligibility criteria. The findings showed reduction in the tumour necrosis factor alpha (TNF-α) (-0.31 pg/mL, 95% CI -1.07 to 0.46) and C reactive protein (CRP) levels (-0.20 mg/L, 95% CI -1.4 to 1.05) following supplementation with garlic, although it had no marked impact on the interleukin 6 (IL-6) level (0.37 pg/mL, 95% CI -0.58 to 1.33). In the subgroup analysis, we found that garlic supplementation significantly decreased TNF-α, highly sensitive CRP and IL-6 levels in subgroups of >8, >6 and ≥4 weeks of intervention duration, respectively, and dose of garlic consumption between 2 and 2.4 g/day.

Conclusion: These findings suggested that current evidence may support garlic as an adjunct to pharmacological management of metabolic diseases.

Prospero Registration Number: CRD42018108816.
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http://dx.doi.org/10.1136/postgradmedj-2019-137267DOI Listing
March 2021

Circulating Levels of Pro-inflammatory Cytokines in Patients with Nonalcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis.

Iran J Immunol 2019 Dec;16(4):327-333

Department of Genetic, Marvdasht branch, Islamic Azad University, Marvdasht, Iran.

Background: Pro-inflammatory cytokines are associated with systemic inflammatory responses.

Objective: To investigate the levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) compared to healthy individuals.

Methods: This case-control study was conducted on 30 patients with NAFL, 30 patients with NASH, and 30 healthy volunteers. The plasma level of IL-1β, IL-6, and TNF-α were determined by ELISA, and biochemical parameters were measured using colorimetric methods.

Results: IL-1β and IL-6 levels were significantly higher in patients with NASH compared with NAFL and control group. However, TNF-α levels had no significant variations in NAFL and NASH patients compared to the control group (p=0.903 and p=0.960, respectively).

Conclusion: Results showed that the levels of ALT activity and pro-inflammatory cytokines were higher in patients with NASH compared to control and NAFL subjects; Therefore, steatosis and inflammation develop as a result of excessive pro-inflammatory factors in NASH.
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http://dx.doi.org/10.22034/IJI.2019.80284DOI Listing
December 2019

Metformin attenuates oxidative stress and liver damage after bile duct ligation in rats.

Res Pharm Sci 2019 Apr 8;14(2):122-129. Epub 2019 Mar 8.

Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, I.R. Iran.

The aim of the current study was to investigate the antioxidative effect of metformin (MTF) on bile duct ligation (BDL)-induced hepatic disorder and histological damage in rats. The rats were divided into 4 groups including sham control (SC), BDL alone (BDL surgery), MTF1 (BDL surgery and administration of 250 mg/kg of MFM) and MTF2 (BDL surgery and administration of 500 mg/kg of MTF). After BDL, the animals treated with MTF by gavage for 10 days. Hematoxylin and eosin staining, biochemical analysis and oxidative stress markers were assayed to determine histological alterations, liver functions, and oxidant/antioxidant status. Hepatotoxicity was verified by remarkable increase in plasma levels of aminotransferases and alkaline phosphatase activity and liver histology 10 days after the BDL surgery. Our finding showed that treatment with MTF markedly reduced plasma alkaline phosphatase and alleviated liver injury indices ( ≤ 0.05). Furthermore, BDL caused a considerable increase in the protein carbonyl and malondialdehyde content ( ≤ 0.05). However, MTF reduces oxidative stress by constraining the protein oxidation and lipid peroxidation, and increases antioxidant reserve by increasing the ferric reducing ability of plasma and reducing glutathione levels. MTF exerts antioxidative effects in the liver fibrosis and may represent a hepato-protective effect when given to rats with BDL-induced hepatic injury.
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http://dx.doi.org/10.4103/1735-5362.253359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791170PMC
April 2019

Inactivation of the superoxide dismutase by malondialdehyde in the nonalcoholic fatty liver disease: a combined molecular docking approach to clinical studies.

Arch Physiol Biochem 2019 Sep 2:1-8. Epub 2019 Sep 2.

Medicinal Plants Research Center, Yasuj University of Medical Sciences , Yasuj , Iran.

The objective of the present study was to investigate the plasma levels of oxidative stress markers and the activity of antioxidant enzymes in NAFLD and healthy subjects. Furthermore, the interaction behaviors of malondialdehyde (MDA) with Cu/Zn superoxide dismutase (SOD1) enzyme were elucidated by molecular docking. The study involved 60 patients with NAFLD and 25 healthy volunteers. The plasma levels of oxidative stress parameters and antioxidant enzymes activity were determined. NAFLD patients had significantly higher alanine aminotransferase, MDA and nitric oxide metabolites values, as well as significantly lower total thiol and SOD activity than the control group. Based on the molecular docking, MDA could deactivate the enzymatic activity of SOD1. Impaired antioxidant defense systems may be involved in the progression of NAFLD. This study provides direct evidence at a molecular level to explain that MDA may exert its oxidant activity by specific action within the specific molecular pathway. Highlights Impairing antioxidant defense systems may be a main factor in the progression of nonalcoholic fatty liver disease (NAFLD). Increasing MDA and NO metabolites, as well as decreasing TSH values and SOD activity in NAFLD patients as compared to control subjects Increasing MDA level in NAFLD patients may be inactivate SOD activity by reaction with the key residues Cu ion inside active site of the enzyme catalytic site.
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http://dx.doi.org/10.1080/13813455.2019.1659827DOI Listing
September 2019

The influence of TRAIL, adiponectin and sclerostin alterations on bone loss in BDL-induced cirrhotic rats and the effect of opioid system blockade.

Life Sci 2019 Sep 29;233:116706. Epub 2019 Jul 29.

Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Occupational Sleep Research Center (OSRC), Tehran University of Medical Sciences, Bahrloo Hospital, Tehran, Iran. Electronic address:

Aims: Osteoporosis is a common extra-hepatic complication in patients with chronic liver disease. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL), sex hormones, adiponectin, and sclerostin are involved in the regulation of bone turnover but little is known about their role in the promotion of hepatic osteodystrophy. Endogenous opioids are reported to increase during cholestasis and may influence bone resorption. The purpose of this study was to investigate the circulating levels of these factors and their expression in the femur of bile duct ligated (BDL) rats, to evaluate the biomechanical bone strength, and the effect of naltrexone (NTX).

Materials And Methods: BDL and sham-operated (SO) rats received 10 mg/kg NTX as an opioid-receptors antagonist or saline once daily for 28 days intraperitoneally. Three-point bending test was performed on the right femurs and, plasma bone alkaline phosphatase (BALP), sex hormones, TRAIL, adiponectin, sclerostin, as well as the mRNA expression levels of the latter three proteins, were measured in the femur tissues.

Key Findings: Plasma TRAIL, estrogen, adiponectin, sclerostin and, BALP levels increased in BDL animals when compared to the related controls, whereas testosterone level decreased and NTX reversed these effects significantly. Femur strength decreased in cirrhotic animals and interestingly, blocking opioid-receptors by NTX improved it significantly (p ≤ 0.05).

Significance: High levels of TRAIL, adiponectin and, sclerostin after bile duct ligation, suggest that these factors may have some roles in bone loss after cirrhosis. Administration of NTX improved all the mentioned factors except for bone strength. Effect of NTX on bone loss in BDL rats needs more study to clarify.
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http://dx.doi.org/10.1016/j.lfs.2019.116706DOI Listing
September 2019

Hepatoprotective and antioxidant activity of watercress extract on acetaminophen-induced hepatotoxicity in rats.

Heliyon 2019 Jul 9;5(7):e02072. Epub 2019 Jul 9.

Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.

Introduction: Acetaminophen (APAP) as an analgesic and antipyretic drug can result to liver damages while using more than 4 g/day. Therefore, APAP toxicity causes the liver to dysfunction. This study aims to investigate the hepatoprotective and antioxidant activity of hydroalcoholic extract of watercress (WC) in APAP-induced hepatotoxicity in rats.

Materials And Methods: Randomly, twenty-four Wistar rats were divided into four groups of six each. Groups named as control, APAP, APAP + WC and APAP + S for group 1, 2, 3, and 4, respectively. Group 1 received distilled water 1 ml/kg for 7 days. In group 2, 3, and 4, rats pretreated by receiving distilled water (1 ml/kg), WC extract (500 mg/kg), silymarin extract (mg/kg) for 7 days, respectively. Of note, to induce acute hepatotoxicity in groups 2, 3, and 4, rats posttreated by orally intoxicated with single dose of APAP (2 g/kg) on the sixth day. The animals were sacrificed on the seventh day. Alanine amino transferase (ALT), aspartate amino transferase (AST), ferric reducing ability of plasma (FRAP), protein carbonyl (PCO), total thiol (T-SH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) activities were measured in plasma. It should be noted that the chemical composition of WC extract was identified by GC-MS analysis.

Results: The results have shown that there was a significant increase in AST, ALT, FRAP and PCO content in APAP group in comparison to control. Also, there was a significant reduction in T-SH levels and GPx activity in APAP group compared to control. However, administration of WC extract and silymarin not only causes a significant decrease in AST activity, but they markedly increased T-SH content and GPx activity compared to APAP group. GC-MS analysis showed the major compositions were found to be benzenepropanenitrile (48.30 %), Phytol (10.10 %), α-cadinene (9.50%) and linolenic acid (8.0).

Conclusions: It is concluded that the WC extract reduces APAP-induced toxicity through its hepatoprotective and antioxidant activity in rats.
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http://dx.doi.org/10.1016/j.heliyon.2019.e02072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624241PMC
July 2019

The hydroalcoholic extract of watercress attenuates protein oxidation, oxidative stress, and liver damage after bile duct ligation in rats.

J Cell Biochem 2019 09 23;120(9):14875-14884. Epub 2019 Apr 23.

Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.

Cholestatic liver disease is recognized by extreme collagen formation and deposition, which is mediated by free radicals. The aim of the current study was to investigate the probable hepatoprotective effects of hydroalcoholic extract of watercress (WC) against oxidative stress and liver injury in bile duct ligation (BDL)- induced cholestatic rats. A total of 32 male Wistar rats were divided into four groups; sham control (SC), BDL, SC + hydroalcoholic extract of WC and BDL + hydroalcoholic extract of WC. WC-treated rats received daily WC 500 mg/kg/day for 10 days. Biochemical tests, hepatic oxidative stress markers, and antioxidant enzymes activity were estimated. Further, liver hydroxyproline content was assayed and histological analysis was made. The BDL model markedly elevated the protein carbonyl (PCO) and hydroxyproline contents and decreased the glutathione peroxidase (GPx) activity. Hydroalcoholic extract of WC significantly decreased the surge in liver PCO and hydroxyproline levels and increased the reduced GPx enzyme activity contents in the hepatic tissue. As determined by hematoxylin and eosin staining, BDL considerably induced hepatocyte necrosis. Moreover, these changes were significantly attenuated by the hydroalcoholic extract of WC treatment. Our data indicate that the hydroalcoholic extract of WC extract attenuated liver damage in BDL rats by decreasing the hydroxyproline content and histopathological indexes. Also, it reduced oxidative stress by preventing the hepatic protein oxidation and enhancing the activity of the GPx enzyme via antioxidative effect and free-radical scavenging. Our findings suggest that hydroalcoholic extract of WC could be a beneficial new curative agent for cholestatic liver damage.
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http://dx.doi.org/10.1002/jcb.28749DOI Listing
September 2019

Exploring the binding mechanism of saccharin and sodium saccharin to promoter of human p53 gene by theoretical and experimental methods.

J Biomol Struct Dyn 2020 02 11;38(2):548-564. Epub 2019 Mar 11.

Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.

In the past few decades, extensive discussions have been on the impact of artificial sweeteners on the risk of cancer. The present study aimed to evaluate the interaction of saccharin (SA) and sodium saccharin (SSA) with the promoter of the human p53 gene. The binding ability was assessed using the spectroscopic technique, molecular docking and molecular dynamics (MD) simulation methods. Free energy of binding has been calculated using Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Fluorescence spectra of mentioned gene with concentration profiles of SA and SSA were obtained in a physiological condition. A gradual increase without any significant spectral shift in the fluorescence intensity of around 350 nm was evident, indicating the presence of an interaction between both compounds and gene. The docking results showed that both compounds were susceptible to bind to 5'-DG56DG57-3' nucleotide sequence of gene. Furthermore, the MD simulation demonstrated that the binding positions for SA and SSA were 5'-A1T3T4-3' and 5'-G44T45-3' sequences of gene, respectively. The binding of these sweeteners to gene made significant conformational changes to the DNA structure. Hydrogen and hydrophobic interactions are the major forces in complexes stability. Through the groove binding mode, the non-interactive DNA-binding nature of SSA and SA has been demonstrated by the results of spectrofluorometric and molecular modeling. This study could provide valuable insight into the binding mechanism of SA and its salt with p53 gene promoter as macromolecule at the molecular level in atomistic details. This work can contribute to the possibility of the potential hazard of carcinogenicity of this sweetener and to design and apply new and safer artificial sweeteners. AbbreviationsSASaccharinSSASodium SaccharinPp53gpromoter of human p53 geneMDMolecular dynamicsRMSDRoot-mean-square deviationRMSFRoot-mean-square fluctuationRgRadius of GyrationSASASolvent-Accessible Surface AreaADIAcceptable daily intakeMM/PBSAMolecular Mechanics/Poisson-Boltzmann Surface AreaCommunicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2019.1582438DOI Listing
February 2020

Redox imbalance and IL-17 responses in memory CD4 T cells from patients with psoriasis.

Scand J Immunol 2019 Jan 19;89(1):e12730. Epub 2018 Dec 19.

Immunology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

All stages of the inflammatory process involved in T cell-mediated chronic skin disorders like psoriasis are affected by redox imbalance. On the other hand, Th17 cells have a critical role in the pathogenesis of psoriasis. In this study, we evaluated redox status in memory CD4 + T cells and plasma of patients with psoriasis and its correlation with IL-17 response. To this end, memory T cells were isolated from 10 patients with psoriasis and 10 controls. Intracellular Glutathione (GSH), reactive oxygen species (ROS) and superoxide as well as IL-17 were measured using flow cytometry. Plasma total anti-oxidant capacity (TAC) was quantified by ferric reducing ability of plasma (FRAP) assay. The expression of catalase (CAT), superoxide dismutase 1(SOD1), superoxide dismutase 2 (SOD2), nuclear factor, erythroid 2 like 2 (NFE2L2) and cytochrome b-245 beta chain (CYBB) genes were analysed using real-time PCR. Our results showed an increased intracellular ROS production in memory CD4 + T cells of patients compared to controls, (P = 0.04). Furthermore, a significant decrease in expression of catalase gene was found in patients, (P = 0.02). However, no significant differences were observed for intracellular GSH, IL-17 and TAC levels between patients and controls. Also, no correlation was seen between the intracellular IL-17 level and intracellular ROS, GSH and catalase gene expression levels. Collectively, we found an increased ROS production in stimulated memory T cells of patients that could be due to reduced expression of catalase gene. However, it seems that these redox abnormalities have no relationship with IL-17 response in memory T cells.
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http://dx.doi.org/10.1111/sji.12730DOI Listing
January 2019

Activation of the Glutathione Peroxidase by Metformin in the Bile-duct Ligation induced Liver Injury: In vivo Combined with Molecular Docking Studies.

Curr Pharm Des 2018 ;24(27):3256-3263

Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.

Background: Inhibition of hepatic fibrosis is an attainable objective in managing the chronic liver disease. The present study aimed to investigate possible defensive effects of metformin on the activities of antioxidant enzymes, hydroxyproline content, and biochemical factors in bile duct ligation (BDL)-induced cholestatic rats. The interactive behavior of metformin with glutathione peroxidase (GPx) enzyme was also explained by molecular docking and conformation characterization.

Methods: The present study was conducted on 28-adult male Wistar rats classified into four 7-animal groups: sham-control, mere BDL, and BDL+ metformin that received daily metformin as gavage in two doses of 250 and 500 mg/kg bw for 10 days. Biochemical analysis, hydroxyproline content, and antioxidant enzymes activity were also determined.

Results: The hydroxyproline content significantly increased, but the GPx enzyme activity significantly decreased in the hepatic tissue following BDL, indicating that an oxidative stress-related model in rats was successfully constituted. Administration of metformin at two doses attenuated hydroxyproline content in the cholestatic liver and ameliorated the depletion of GPx enzyme activities compared to the non-treated BDL group (P-value ≤ 0.05). Molecular docking study provides the evidence for metformin ability to regulate enzymatic activity of GPx.

Conclusion: The research data indicated that due to novel hepatoprotective effects of metformin in an animal model with BDL-induced liver injury, it was a potential beneficial therapeutic agent for treating the cholestatic liver disease. The main mechanism might contribute to antioxidant actions, particularly via GPx enzyme.
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http://dx.doi.org/10.2174/1381612824666181003114108DOI Listing
November 2019

Genetic variants in long noncoding RNA H19 and MEG3 confer risk of type 2 diabetes in an Iranian population.

Gene 2018 Oct 4;675:265-271. Epub 2018 Jul 4.

Department of Laboratory Sciences, Faculty of Paramedicine, Yasuj University of Medical Sciences, Yasuj, Iran. Electronic address:

Purpose: Long-noncoding RNAs (lncRNAs) have been reported to regulate glucose homeostasis and insulin synthesis and secretion. However, the association of genetic variants of lncRNAs and type 2 diabetes (T2D) has not been evaluated. Therefore, in the present study we investigated the association between H19 rs217727 and H19 rs3741219 variants and MEG3 rs7158663 polymorphism with T2D susceptibility.

Materials And Methods: The study population consists of 969 subjects including 496 T2D patients and 473 non-diabetic age and sex-matched controls. The H19 and MEG3 variants genotyping were performed by PCR-RFLP method.

Results: Our results revealed that the T allele of rs217727 was more frequent in T2D group compared with controls (P = 0.007, OR = 1.1, 95% CI:1.02-1.18). Moreover, the rs217727-TT genotype was significantly associated with T2D after adjustment for age, BMI and lipid levels (P = 0.041, OR = 1.53, 95% CI: 1.01-2.32). However, no significant difference was detected for allele or genotype frequencies of H19 rs3741219 between T2D and controls (P = 0.71). Furthermore, the findings showed that the AA genotype of MEG3 rs7158663 was associated with significantly increased risks of T2D compared with the GG genotype (P = 0.026, OR = 1.79, 95% CI: 1.07-2.99). The results remained significance after analysis by logistic regression (P = 0.033, Adjusted OR = 1.72, 95% CI: 1.04-2.84). Finally, bioinformatics analysis showed that these SNPs could alter local RNA folding structure and also the miRNA-lncRNA interactions.

Conclusions: Our findings provided the evidence of significant association between H19 rs217727-TT and MEG3 rs7158663-AA genotypes with T2D susceptibility.
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http://dx.doi.org/10.1016/j.gene.2018.07.002DOI Listing
October 2018

A study on OPG/RANK/RANKL axis in osteoporotic bile duct-ligated rats and the involvement of nitrergic and opioidergic systems.

Res Pharm Sci 2018 Jun;13(3):239-249

Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, I.R. Iran.

Chronic liver disease (CLD) affects millions of people and its impact on bone loss has become a subject of interest. Nitric oxide and endogenous opioids are suggested to increase during cholestasis/cirrhosis and may impact bone resorption by different mechanisms. The receptor activator of nuclear factor-κB (RANK)/RANK-ligand (RANKL)/osteoprotegerin (OPG) signaling pathway regulates bone resorption, but its role in metabolic bone disease subsequent to CLD is unknown. We aimed to investigate the involvement of nitrergic and opioidergic systems in bone loss relative to the RANK/RANKL/OPG pathway, in bile duct-ligated (BDL) rats. Eighty BDL/sham-operated (SO) rats received injections of 3 mg/kg/day Nω-Nitro-L-arginine methyl ester ± naltrexone (10 mg/kg/day) or saline for 28 days. Plasma bone turnover markers, OPG, RANK, and RANKL along with mRNA expression levels of the latter three were assessed. Plasma bone turnover markers and OPG level increased, but RANKL decreased in the BDL group compared with their SO controls (both: ≤ 0.05). Administration of naltrexone reduced bone turnover markers and OPG level while increased RANKL content in comparison to BDL rats ( ≤ 0.05). As compared to untreated BDL rats, nitric oxide inhibition showed no effect on bone turnover marker i.e. OPG, RANK, and RANKL levels. BDL significantly increased RANK mRNA, but had no significant effect on RANKL and OPG mRNA expression. The lack of association between plasma levels and quantitative gene expression of RANKL and OPG suggests an indirect function of these markers in BDL rats. Considering that opioid receptor blockage by naltrexone in BDL animals caused a significant decrease in OPG and an increase in RANKL plasma contents, it could be postulated that the opioidergic system may have a regulatory effect on these bone markers.
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http://dx.doi.org/10.4103/1735-5362.228954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5921404PMC
June 2018

Erythrocytes Membrane Alterations Reflecting Liver Damage in CCl₄-Induced Cirrhotic Rats: The Ameliorative Effect of Naltrexone.

Acta Med Iran 2016 Oct;54(10):631-639

Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Cirrhosis is the consequence of chronic liver disease. Deleterious effects of oxidative stress on hepatocytes may be reflected in the erythrocyte membrane. Naltrexone (NTX) has been shown to attenuate hepatocellular injury in fibrotic animal models. The aim of this study was to investigate the progressive effect of CCl4 on the liver and whether the improvement of liver cirrhosis can be monitored through alterations in the erythrocyte membrane. In this study, 84 male Wistar rats were divided into 4 groups and received reagents (i.p.) as follows: 1- CCl₄, 2- NTX + CCl₄, 3- Mineral Oil (M), and 4- NTX + M. After 2, 6 and 8 weeks, the blood and liver tissue samples were collected. Plasma enzyme activities, the content of erythrocyte GSH and some membrane compositions, including protein carbonyl, protein sulfhydryl, and malondialdehyde were assessed. After 6 and 8 weeks, plasma enzyme activities and the content of protein carbonyl were higher in CCl4 group significantly, as compared to other groups (P<0.001). NTX significantly diminished protein carbonyl and plasma enzyme activities (P<0.001). GSH did not change until the 6th week. However, CCl4+NTX increased it significantly as compared to CCl₄ group (P<0.05). Protein sulfhydryl showed changes in NTX+CCl₄ group which indicated a significant increase in protein sulfhydryl content in a 6th week compared to CCl4 group (P<0.05). MDA did not show any significant alteration. CCl₄-induced cirrhosis is accompanied by increased content of oxidative stress markers, especially protein carbonyl of RBC membrane and plasma enzyme activities. This study shows that the progression of liver cirrhosis and the ameliorative effect of NTX can be followed through alterations of these markers.
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October 2016

Nitrergic and opioidergic systems affect radiographic density ‎and histomorphometric indices in bile-duct-ligated cirrhotic rats.

Histol Histopathol 2017 Jul 26;32(7):743-749. Epub 2016 Oct 26.

Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Metabolic bone disease is a major issue in chronic liver disease. Increased production of nitric oxide (NO) and elevation of endogenous opioids have been suggested to occur during cholestasis/cirrhosis. We aimed to investigate the involvement of nitrergic and opioidergic systems in bone loss after bile-duct-ligation (BDL) in rats using optical density (OD) evaluation and histomorphometric analysis. BDL- and sham-operated (SO) rats received injections of 3 mg/kg Nω-Nitro-L-arginine methyl-ester-hydrochloride (L-NAME) as an NO-synthase inhibitor, 10 mg/kg naltrexone (NTX) as an opioid-receptors antagonist or saline once daily for 28 days. Lateral cephalometric radiographs were taken on days 0 and 28 and histomorphometric and biochemical indices were measured. Plasma levels of total bilirubin and alkaline-phosphate were markedly increased in BDL compared with SO rats (p≤0.05). Among the studied variables, osteoclast number/mm trabecular surface showed significant increase in BDL animals compared to controls, which was significantly reduced following NO-synthase inhibition (p≤0.05). Similarly, cortical area slightly decreased in BDL animals in comparison to controls, whereas both L-NAME and NTX significantly increased this variable. Following BDL, optical density increased in the skulls of cirrhotic animals and showed a significant decrease after blocking opioid-receptors (p≤0.05). Inhibition of NO-synthase and/or opioid receptors caused significant changes in OD and histomorphometric parameters in BDL rats, both in favor of reducing bone loss. If confirmed by further studies, it seems that manipulation of these systems might be able to improve bone problems in subjects with cholestasis/cirrhosis.
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http://dx.doi.org/10.14670/HH-11-836DOI Listing
July 2017

The modulatory effect of nitric oxide in pro- and anti-convulsive effects of vasopressin in PTZ-induced seizures threshold in mice.

Epilepsy Res 2016 10 28;126:134-40. Epub 2016 Jul 28.

Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Vasopressin neuropeptides play an important role in the several cognitive, social, and neuroendocrine functions. Also, several studies report the involvement of nitrergic system in the vasopressin functions in central nervous system. This study investigates the effect of Arginine-Vasopressin (AVP) in pentylenetetrazol (PTZ)-induced seizures threshold and the probable role of nitric oxide (NO). AVP is administered intraperitoneally (0.01-20μg/kg, i.p.) 30min before induction of seizures. Administration of AVP (0.1μg/kg) significantly lowered the PTZ-induced seizures threshold. But, administration of AVP (10 and 20μg/kg) increased the seizures threshold, significantly. Pretreatment of SR 49059 (V1a receptor antagonist, 2mg/kg, i.p.) just reversed the pro-convulsant effect of AVP. Meanwhile, SSR 149415 (V1b receptor antagonist, 10mg/kg, i.p.) pretreatment reversed both pro-and anti-convulsant effects of AVP. The nitric oxide precursor, L-arginine (60mg/kg, i.p.) increased pro-convulsant effect of AVP, but did not change anticonvulsant activity. The nitric oxide synthase (NOS) inhibitor L-NAME (10mg/kg, i.p.) reversed both pro- and anti-convulsant effect of AVP. Selective inducible NOS inhibitor, aminoguanidine (100mg/kg, i.p.) just reversed the anti-convulsant effects of AVP. The results of the present study showed nitric oxide system may contribute to the biphasic effects of AVP on PTZ-induced seizures. V1a receptor may modulate only the proconvulsive effect. While, V1b receptors can mediate both the pro- and anti-convulsive effect of AVP.
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http://dx.doi.org/10.1016/j.eplepsyres.2016.07.006DOI Listing
October 2016