IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES
Year:2020 | Volume:23 | Issue:2|Papers Count:17

It is well documented that life expectancy in developed countries at birth is going to surpass the 20th century. However, regrettably, a potential decline in life expectancy has been proposed for these nations in the 21st century due to a rapid upsurge in the prevalence of fatal degenerative diseases like cardiovascular diseases (CVD), cancer and diabetes. Collectively, these three diseases accounted for 65% of all deaths in urbanized societies and were considered as a dynamic issue for shortening the genetically determined lifespan through increased mortalities, morbidities, disabilities, immense sufferings, and premature aging. These fatal degenerative diseases and premature aging are closely associated with oxidative stress produced by the free radicals in the body. In epidemiologic studies, flavonoid-rich foods (FRF) like fruits, vegetables, and beverages have been associated as protective agents against these diseases. These also have been observed for their geroprotective effects and help in preventing premature aging and deterioration of brain function, which is related to Alzheimer’ s disease and dementia. In this review, we presented a comprehensive overview of the FRF for their potential role against lifespan-shortening complications, i. e., CVD, cancer, and diabetes. We also have drawn the future perspective and dietary guidelines to reduce the fatal disease burden in urban populations.

In this paper, we discussed natural agents with protective effects against stem cell senescence. Different complications have been observed due to stem cell senescence and the most important of them is “ Aging” . Senescent cells have not normal function and their secretary inflammatory factors induce chronic inflammation in body which causes different pathologies. Stem cell senescence also has been investigated in different diseases or as drug adverse effects. We searched databases such as Embase, Pubmed and Web of Science with keywords “ stem cell” , “ progenitor cell” , “ satellite” , “ senescence” and excluded keywords “ cancer” , “ tumor” , “ malignancy” and “ carcinoma” without time limitation until May 2019. Among them we chose 52 articles that have investigated protective effects of natural agents (extracts or molecules) against cellular senescence in different kind of adult stem cells. Most of these studies were in endothelial progenitor cells, hematopoietic stem cells, mesenchymal stem cells, adipose-derived stem cells and few were about other kinds of stem cells. Most studied agents were resveratrol and ginseng which are also commercially available as supplement. Most protective molecular targets were telomerase and anti-oxidant enzymes to preserve genome integrity and reduce senescence-inducing signals. Due to the safe and long history of herbal usage in clinic, phytotherapy can be used for preventing stem cell senescence and their related complication. Resveratrol and ginseng can be the first choice for this aim due to their protective mechanisms in various kinds of stem cells and their long term clinical usage.

Objective(s): Ventricular arrhythmias including ventricular tachycardia (VT) and ventricular fibrillation (VF) are the most important causes of mortality rate. Gallic acid (GA) has beneficial effects on cardiovascular diseases. The aim of this study was to evaluate the effects of GA on electrophysiological parameters such as QRS complex, heart rate (HR), PR interval parameters, and ventricular arrhythmia following chemical induction in rat. Materials and Methods: Seventy-two male rats were divided into 9 groups (n=8). Chronic groups pretreated by GA (10, 30, and 50 mg/kg, orally) and normal saline (N/S, 1 ml/kg, orally) for 10 days. At the start of the experiments (the first day) and on the final day of the experiments (tenth day), the electrocardiogram (lead II) was recorded. At acute group, GA (50 mg/kg), and anti-arrhythmic drugs such as propranolol, amiodarone, and verapamil injected via intravenous (IV). Then, arrhythmia induced by a CaCl2 2. 5% solution (140 mg/kg, IV). Afterward, percentage of premature ventricular beats (PVB), VF, and VT were recorded at 1, and 3 min. Results: These findings showed that chronic and acute doses of GA have positive inotropic and antidysrhythmic effects by significant reduction of PVB, VT and VF on comparison with the control group. These actions are comparable to anti-arrhythmic drugs such as quinidine, propranolol, amiodarone, and verapamil. GA has not significant effect on chronotropic and dromotropic properties. Conclusion: Findings showed that GA has antiarrhythmic, and inotropic characteristics that suggested GA has effective for mild congestive heart failure, and cardiovascular disorders patients which susceptible to incidence of arrhythmias.

Objective(s): Seizure detection during online recording of electrophysiological parameters is very important in epileptic patients. In the present study, online analysis of field potential recordings was used for detecting spontaneous seizures in epileptic animals. Materials and Methods: Epilepsy was induced in rats by pilocarpine injection. During the chronic period of the pilocarpine model, local field potential (LFP) recording was run for at least 24 hr. At the same time, video monitoring of the animals was done to determine the real time of seizure occurrence. Both power and sample entropy of LFP were used for online analysis. Results: Obtained results showed that changes in LFP power are a better index for seizure detection. In addition, when we used one hundred consecutive epochs (each epoch equals 10 ms) of LFP for data analysis, the best detection was achieved. Conclusion: It may be suggested that power is a suitable parameter for online analysis of LFP in order to detect the spontaneous seizures correctly.

Objective(s): Bacterial translocation in patients with cirrhosis is an important triggering factor for infections and mortality. In the bile duct ligation (BDL) model, crucial players of bacterial translocation are still unknown. This study aims to determine the interrelation between microbiome composition in the colon, mesenteric lymph nodes, and liver, as well as the local inflammatory microenvironment in the BDL model. Materials and Methods: Liver damage was assayed by Masson trichrome staining, and hepatic enzymes. The diversity of microbiota in colon stools, mesenteric lymph nodes, and liver was determined by 16S rRNA pyrosequencing. Cytokine expression in mesenteric lymph nodes was analyzed by qRT-PCR. Results: Our results show that Proteobacteria was the predominant phylum found to translocate to mesenteric lymph nodes and liver in cirrhotic rats. Bile duct ligation induces a drastic intestinal dysbiosis, revealed by an increased relative abundance of Sarcina, Clostridium, Helicobacter, Turicibacter, and Streptococcus genera. However, beneficial bacteria, such as Lactobacillus, Prevotella and Ruminococcus were found to be notably decreased in BDL groups. Mesenteric pro-inflammatory (TNF-α , IL-1β , IL-6, TLR-4) and regulatory (TGF-β , Foxp3, and IL-10) molecules at 30 days post-BDL were significantly increased. Conversely, TGF-β and Foxp3 were significantly augmented at 8 days post-BDL. Conclusion: Dysbiosis in the colon and mesenteric lymph nodes is linked to an imbalance in the immune response; therefore, this may be an important trigger for bacterial translocation in the BDL model.

Objective(s): The molecular basis of “ metabolically healthy obese” and “ metabolically unhealthy nonobese” phenotypes is not fully understood. Our objective was to identify metabolite patterns differing in obese (metabolically healthy vs unhealthy (MHO vs MUHO)) and non-obese (metabolically healthy vs unhealthy (MHNO vs MUHNO)) individuals. Materials and Methods: This case-control study was performed on 86 subjects stratified into four groups using anthropometric and clinical measurements: MHO (21), MUHO (21), MHNO (22), and MUHNO (22). Serum metabolites were profiled using nuclear magnetic resonance (NMR). Multivariate analysis was applied to uncover discriminant metabolites, and enrichment analysis was performed to identify underlying pathways. Results: Significantly higher levels of glutamine, asparagine, alanine, L-glutathione reduced, 2-aminobutyrate, taurine, betaine, and choline, and lower level of D-sphingosine were observed in MHO group compared with MUHO. In comparison of MHNO and MUHNO groups, significantly lower levels of alanine, glycine, glutamine, histidine, L-glutathione reduced, and betaine, and higher levels of isoleucine, L-proline, cholic acid, and carnitine appeared in MUHNO individuals. Moreover, significantly affected pathways included amino acid metabolism, urea cycle and ammonia recycling in MUHO subjects and glutathione metabolism, amino acid metabolism, and ammonia recycling in MUHNO members. Conclusion: Literature review helped us to hint that altered levels of most metabolites might associate to insulin sensitivity and insulin resistance in MHO and MUHNO individuals, respectively. Besides, abnormal amino acid metabolism and ammonia recycling involved in unhealthy phenotypes (MUHO, MUHNO) might be associated with insulin resistance.

Objective(s): Scorpion venom has toxic effects on mammals, insects and crustaceans. Toxicogenic peptides are major contributors to the scorpion venom, which make it toxic. The Hemiscorpius lepturus (H. lepturus) is one of the most common scorpion bites agent, and responsible for 95% of scorpion bite deaths cases in Iran. Materials and Methods: In this project, we fractionated the H. lepturus scorpion venom and analyzed toxic fractions of the venom. The crude venom of H. lepturus was dialyzed against distilled water and then the soluble part of the venom was isolated from the non-soluble (mucoproteins) part of the venom and loaded onto the Sephadex G-50 gel filtration column, then after determining the toxicity of the obtained fractions (fractions toxicity were detected in mice by IV injection), the resulting toxic fraction was purified with three stages of ion-exchange chromatography (anion and cationic) and RPHPLC. The purity of the fractions was verified by SDS-PAGE electrophoreses. Results: The LD50 of H. lepturus venom was 177. 01 μ g/mouse. The crude venom had 7 detectable bands with molecular weights of 10-100 KDa and one band less than 10 KDa. Finally, after the different stages of chromatography, two HL2153 and HL2155 peaks were obtained from the RP-HPLC, which were depicted single bands and high purity. The electrophoretic analysis showed molecular weight 4874 Da for HL2153 and 5107 Da for HL2155 toxins. Conclusion: It is concluded that H. lepturus venom contains two HL2153 and HL2155 toxins with a relatively similar molecular weight and similar electrical charge 4874 and 5107 Da, respectively.

Objective(s): Nuclear receptor-related protein 1 (Nurr1), one of immediate-early genes, is a member of orphan nuclear receptor family. The aim of this study was to investigate the time-dependent change of Nurr1 protein expression in the mouse hippocampal CA3 region following kainic acid (KA)-induced excitotoxic neuronal damage. Materials and Methods: Male ICR mice were used as experimental animals, and 30 mg/kg KA was administered intraperitoneally. To confirm the KA-induced neuronal damage in the hippocampal CA3 region, Fluoro-Jade B histofluorescence staining was performed. In addition, the time-dependent change of Nurr1 protein expression was also examined using immunohistochemistry and western blot analysis. Results: Marked neuronal damage was observed in the hippocampal CA3 region at 24 hr after KA injection. In addition, both Nurr1 immunoreactivity and protein level were significantly increased at 6 hr and 12 hr after KA injection, and then decreased at 24 hr after KA injection. Conclusion: This result indicates that KA-induced alteration of Nurr1 protein expression may be associated with the neuronal degeneration in the hippocampal CA3 region after KA injection.

Objective(s): Hypercholesterolemia is a common metabolic disorder in developing and developed countries and is associated with the increased rates of chronic kidney disease (CKD). Statin therapy could reduce cholesterol synthesis as well as progression of CKD. Diversity between statins causes variety in pharmacokinetics and pharmacodynamics and also their pleiotropic effects. In the present investigation we aimed to evaluate the protective potentials of both atorvastatin (Ator) (as lipidsoluble statin) and rosuvastatin (Ros) (as water-soluble statin) against renal histopathological damages in the high cholesterol diet induced hypercholesterolemic rats (HCDIHR). Materials and Methods: Serum lipid profile, oxidized low density lipoprotein (OX-LDL), malondialdehyde (MDA), urea and creatinine levels, as well as renal histopathology were evaluated. Results: While Ros acted better than Ator to reduce serum low density lipoprotein cholesterol (LDL-C) (P<0. 01), atherogenic index (AI) (P<0. 01), MDA (P<0. 01), and OX-LDL (P<0. 01); no significant differences were noted in their cholesterol (P=0. 72), triglyceride (TG) (P=0. 79), and very low density lipoprotein cholesterol lowering (VLDL-C) (P=0. 79) and high density lipoprotein cholesterol elevating effects (HDL-C) (P=0. 72). Ator was more effective to reduce renal histopathologic indices compared to Ros, including accumulation of lipid droplet, glomerular foam cells, mesangial cell proliferation, renal hemorrhage, and tubulointerstitial damages in the kidneys of diet induced hypercholesterolemic rats. Conclusion: The findings underline that the lipophilic Ator may performs better than Ros in attenuating renal damages in HCDIHR.

Objective(s): Type 1 diabetes (T1D) is an autoimmune disease resulting from inflammatory destruction of islets β-cells. Nowadays, progress in cell therapy, especially mesenchymal stem cells (MSCs) proposes numerous potential remedies for T1D. We aimed to investigate the combination therapeutic effect of these cells with insulin and metformin on neuropeptide Y, melanocortin-4 receptor, and leptin receptor genes expression in TID. Materials and Methods: One hundreds male rats were randomly divided into seven groups: the control, diabetes, insulin (Ins. ), insulin+metformin (Ins. Met. ), Wharton’ s Jelly-derived MSCs (WJ-MSCs), insulin+metformin+WJ-MSCs (Ins. Met. MSCs), and insulin+WJ-MSCs (Ins. MSCs). Treatment was performed from the first day after diagnosis as diabetes. Groups of the recipient WJ-MSCs were intraportally injected with 2× 10⁶ MSCs/kg at the 7th and 28th days of study. Fasting blood sugar was monitored and tissues and genes analysis were performed. Results: The blood glucose levels were slightly decreased in all treatment groups within 20th and 45th days compared to the diabetic group. The C-peptide level enhanced in these groups compared to the diabetic group, but this increment in Ins. MSCs group on the 45th days was higher than other groups. The expression level of melanocortin-4 receptor and leptin receptor genes meaningfully up-regulated in the treatment groups, while the expression of neuropeptide Y significantly down-regulated in the treatment group on both times of study. Conclusion: Our data exhibit that infusion of MSCs and its combination therapy with insulin might ameliorate diabetes signs by changing the amount of leptin and subsequent changes in the expression of neuropeptide Y and melanocortin-4 receptor.

Objective(s): This study was designed to investigate various gastrointestinal effects of Manilkara zapota (Sapodilla), exploring its anti-diarrheal, anti-secretary, anti-spasmodic, anti-ulcer and antimotility potential. Materials and Methods: Antidiarrheal and anti-secretary activities were investigated using castor oil induced diarrhea and castor oil induced fluid accumulation. Isolated rabbit jejunum tissues (antispasmodic) were employed for in vitro experiments. Antiulcer, antimotility and molecular docking were performed using ethanol-HCl induced ulcer assay, charcoal meal transit time and Auto Doc Vina. Results: Mz. Cr exhibited protection against castor oil-induced diarrhea (P<0. 05 vs. saline group) and dose-dependently inhibited intestinal fluid secretions (P<0. 001 vs. castor oil group). Mz. Cr caused relaxation of spontaneous and K+ (80 Mm)-induced contractions with EC50 values of 0. 11mg/ ml (0. 08-0. 1, n=4) and 0. 16 mg/ml (0. 09-0. 2, n=4) respectively (*P<0. 05**P<0. 01 ***P<0. 001). It showed protective effect against gastric ulcers induced by ethanol-HCl (P<0. 001 vs. saline group). Mz. Cr reduced distance travelled by charcoal meal (P<0. 001 vs. saline group). Plant constituents: caffeoylquinic acid and methyl 4-O-galloylchlorogenate showed high binding affinities (E-value≥-6. 5 Kcal/mol) against histaminergic H2 receptors, H+/K+ ATPase pump and voltage gated L-type calcium channels, while possesses moderate affinities (E-value≥ 8 Kcal/mol) against histaminergic H1, muscarinic M1, M3 and mu-opioid, whereas lower affinities (E-value≥ 9. 5 Kcal/mol) vs. calmodulin, adrenergic α 1, phosphodiesterase enzyme and dopaminergic D2 receptors. Lupeol-3-acetate and β-amyrin-3-(3’-dimethyl) butyrate observed weak affinities. Conclusion: In present study, M. zapota is reported to exhibits anti-diarrheal, anti-secretory, antispasmodic, anti-motility, anti-ulcer effects and computational binding affinities against gastrointestinal targets.

Objective(s): Infertility in varicocele may have an adverse outcome on the future life of an infertile male. This study was designed to investigate whether varicocele affects remote organs, including the kidney, liver, and brain. We have also evaluated the protective effects of NaHS administration on the structure and function of these organs. Materials and Methods: Thirty-six rats were randomly assigned to 3 experimental groups: 1) Sham, 2) Varicocele, and 3) Varicocele + sodium hydrosulfide. Varicocele was induced via partial ligation of the left renal veins. Animals in the Varicocele + sodium hydrogen sulfide group received 30 μ mol/l NaHS in drinking water for 56 days. On the 57th day of the treatment, blood samples, as well as kidney, liver, and brain tissues, were collected to assess kidney and liver functions, measurement of oxidative stress markers, and histological changes. For evaluation of sperm parameters caudal epididymis was used. The behavioral tests were performed to evaluate the animal’ s anxiety-related behaviors. Results: Varicocele caused significant decrease in sperm parameters (motility and viability) and superoxide dismutase activity in the kidney, liver, and brain tissue. Anxiety-related parameters decreased in varicocele. Moreover, varicocele resulted in a significant increase in malondialdehyde levels in the kidney, liver and brain tissue, and liver function enzymes. Varicocele did not alter kidney function parameters. The administration of NaHS improves the above parameters. Conclusion: This study showed that notice to remote organs such as the liver and brain beside reproductive organs in varicocele is important. The administration of NaHS improved remote organ injury in varicocele via its anti-oxidant mechanism.

Objective(s): It seems that regular exercise can have inhibitory effects on the progression of breast cancer. This study, therefore, aimed to investigate the influences of interval aerobic training on mesenchymal biomarker gene expression, muscle cachexia, and tumor volume changes in mice with breast cancer. Materials and Methods: Thirty-two female Balb/c mice were allocated to four groups: Exercise Tumor Exercise, Rest Tumor Rest (Control), Rest Tumor Exercise, and Exercise Tumor Rest. Interval aerobic training was done 6 weeks before and 4 weeks after tumor induction. Weight test and inverted screen test were carried out as muscle function tests. Data were analyzed using one-way ANOVA and HSD post hoc. Results: The results showed a significant decrease in gene expressions of Twist, Vimentin, and TGF-β in Exercise Tumor Exercise group in comparison with the Control group (P<0. 05). Remarkable reduction of the rate of tumor volume was also observed in two training groups (Rest Tumor Exercise, Exercise Tumor Exercise) compared with the control group. According to function tests’ results, muscle functions were diminished due to cancer, but interval aerobic training can keep muscles in a normally-functioning state in cancer (P<0. 05). Conclusion: Considering final results, a period of interval aerobic training can be used not only as a prevention method, but also help cancer treatment and impede cachexia by tumor volume reduction, decrease mesenchymal biomarker gene expression, and increase muscle strength functions.

Objective(s): To observe and determine the effect and mechanism of psoralen on tumor necrosis factor-α (TNF-α )-induced muscle atrophy. Materials and Methods: Three sets of C2C12 cells, including blank control, TNF-α (10 or 20 ng/ml) treatment and a TNF-α (10 or 20 ng/ml) plus psoralen (80 μ M) administration were investigated. Cell viability was assessed using Cell Counting Kit-8 (CCK-8) assay. Western blot analysis was used to detect protein expression of atrophic markers. Flowcytometry was used to observe the effect of psoralen on apoptosis. A quantitative real-time PCR (qRT-PCR) assay was performed to detect the mRNA level of miR-675-5P. Results: TNF-α (1, 10, 20 and 100 ng/ml) treatment inhibited C2C12 myoblast viability (P<0. 001), while 24 hr of psoralen administration increased the viability, and lowered TNF-α cytotoxicity (P<0. 001). MURF1, MAFbx, TRIM62 and GDF15 expressions were significantly increased in TNF-α (10 ng/ml or 20 ng/ml)-treated group (P<0. 001), and psoralen could significantly decrease the expression of these proteins (P<0. 001). Apoptotic rate of C2C12 myoblasts was increased after TNF-α (10 ng/ml and 20 ng/ml) treatment, and was significantly decreased after psoralen treatment (P<0. 001). miR-675-5P was increased in TNF-α-treated C2C12 myoblasts compared to control group, and it was significantly decreased after psoralen treatment. Conclusion: Psoralen could reduce TNF-α-induced cytotoxicity, atrophy and apoptosis in C2C12 myoblasts. The therapeutic effect of psoralen may be achieved by down-regulating miR-675-5P.

Objective(s): Bacteriophages are infectious replicating entities that are under consideration as antimicrobial bioagents to control bacterial infections. As an alternative or supplement to antibiotics, bacteriophages can be used to circumvent the resistance to existing antibiotics. The aim of this study was to assess the synergistic effect of a naturally isolated phage and ampicillin against Escherichia coli O157. Materials and Methods: In the present study, a natural phage against E. coli O157 was isolated, the morphology and molecular characteristics of the phage were identified, and the combination of bacteriophage and antibiotic to combat clinically isolated drug-resistant E. coli O157 was evaluated. Results: The results showed the synergistic action between a naturally isolated phage and ampicillin in solid (disk diffusion test) and liquid culture media. Addition of the isolated phage, gT0E. co-MGY2, to the microbial lawn of bacteria in modified antibiotic disk diffusion test, altered susceptibility pattern of E. coli O157 from resistant to sensitive based on the inhibition zones. Combinations of bacteriophage and ampicillin significantly enhanced the killing of bacterial strains when compared to treatment with ampicillin or phage alone in liquid culture. Moreover, it lasted few hours for ampicillin to reverse the growth of E. coli O157, while the bacteriophage and combination treatment stopped the proliferation of bacteria from the beginning, and this can compensate the delayed onset of antibiotic action. Conclusion: The synergistic action of bacteriophages and antibiotics is an alternative that cannot only be effective against bacterial infections but also contribute to the reduction of antibiotic resistance.

Objective(s): The growing trend of research demonstrates that dynamic expression of two metastasis repressor classes (metastasis suppressor genes and anti-metastatic miRNA) has a close relationship with tumor invasion and metastasis. Using different strategies, it was revealed that cellular levels of miR-31 and Breast cancer Metastasis Suppressor1 (BRMS1) protein, which are among the most significant modulators of metastasis, have a correlation with the cell’ s capability for invading and metastasizing; cells containing higher levels of miR-31 or BRMS1 were less metastatic. This project was carried out to determine whether the combinations of miR-31 and BRMS1 genes are able to enhance the capability of repressing the claudin-low breast cancer cell (MDA-MB-231) invasion. Materials and Methods: This study used a restoration-based approach by miR-31 mimic and optimized BRMS1 gene sequences, which were cloned into a chimeric construct and transfected to the MDA-M231cells. Results: Our data revealed that the simultaneous expression of anti-metastasis miR and metastasis suppressor might inhibit migration and invasion in MDA-MB-231 cells efficiently. Conclusion: This combinatorial use of anti-metastatic miR and gene suggests a new therapeutic intervention for metastasis inhibition in MDA-MB-231.

Objective(s): The aim of this study is to investigate the renoprotective effect of erythropoietin (EPO) on hypovolemic shock and ischemia/reperfusion (IR) injury on kidneys as end-organs in an experimentally-created ruptured abdominal aortic aneurysm (rAAA) model. Materials and Methods: Thirty anesthetized Sprague-Dawley male rats were randomized to sham ((Sh n: 6) (Sh+EPO n: 6)) or shock and I/R groups ((S/IR n: 9) (S/IR+EPO n: 9)). Additional surgical procedure except aortic exploration was not performed on Sh and Sh+EPO groups. 60 min of shock, 60 min of ischemia, and 120 min of reperfusion were applied on S/IR and S/IR+EPO groups. In the S/IR and S/IR+EPO groups, hemorrhagic shock, lower torso ischemia, and reperfusion were created. At the end of the shock period, saline solutions were separately and equally administered to Sh and S/IR groups, whereas 2000 U/kg EPO was intraperitoneally administered to Sh+EPO and S/IR+EPO groups. At the end of the experimental study, some biochemical and histological parameters were studied in serum and kidney tissues. Results: Biochemical parameters were all significantly increased in the S/IR group compared with the Sh group. These parameters were not statistically significantly different between S/IR+EPO and Sh+EPO groups. In histopathologic examination, EPO prevented high-grade injury. Conclusion: Our data indicate that EPO may have a renoprotective effect and reduce the systemic inflammatory response that resulted from shock and I/R in an experimental model of rAAA.