Iranian Journal of Basic Medical Sciences
Volume:22 Issue: 5, May 2019

Metabolic syndrome is described as a group of risk factors in which at least three unhealthy medical conditions, including obesity, high blood sugar, hypertension or dyslipidemia occur simultaneously in a patient. These conditions raise the risk for diabetes mellitus and cardiovascular diseases. Many recent studies have focused on herbal remedies and their pharmacological effects on metabolic syndrome. Crataegus pinnatifida or Chinese hawthorn has been widely used in the treatment of hyperlipidemia and cardiovascular diseases. Its leaves, fruits and seeds have various active substances such as, flavonoids, triterpenic acids and sesquiterpenes, which through different mechanisms can be beneficial in metabolic syndrome. Flavonoids found in the leaves of hawthorn can significantly reduce atherosclerotic lesion areas, the fruit extracts contain two triterpenic acids (oleanolic acid and ursolic acid), that have the ability to inhibit the acyl-coA-cholesterol acyltransferase (ACAT) enzyme and as a result reduce very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) cholesterol levels. Another example regards a sesquiterpene found in the seeds of C. pinnatifida, which exhibits the ability to inhibit platelet aggregation, thus showing antithrombotic activity. Various studies have shown that C. pinnatifida can have beneficial effects on controlling and treating high blood sugar, dyslipidemia, obesity and atherosclerosis. The aim of this review is to highlight the interesting effects of C. pinnatifida on metabolic syndrome.

The patients with renal diseases, especially end-stage renal disease (ESRD), are at high risk of developing cardiovascular disturbances. Some hormones such as brain natriuretic peptide appear to be important serum biomarkers in predicting cardiac death in ESRD patients. Renal diseases cause inflammation, anemia, uremic toxins, fluid overload, and electrolyte disturbance. Kidney transplantation is considered the choice treatment for patients with ESRD. Ischemia-reperfusion (IR), which occurs during renal transplantation is one of the factors that affect the outcome of renal transplantation. Renal graft rejection is the result of IR injury and there is no effective treatment to prevent IR injury. Reperfusion after ischemia may cause injury through generation of reactive oxygen and nitrogen species, inflammatory responses by increased levels of tumor necrosis factor-α (TNF-α) and interleukins (IL), and apoptotic processes, and leads to acute kidney injury (AKI). Thus, antioxidant, anti-apoptotic and anti-inflammatory hormones, which inhibit these pathways, can protect against IR injury and improve transplanted renal function in patients with ESRD.

The possible action of nonsteroidal anti-inflammatory drugs (NSAIDs) in the reduction of reactive oxygen species (ROS) and also as anti-apoptotic agents may suggest them as putative agents for the treatment of neurodegenerative diseases. This study was designed to explore some pathways alterations induced by NSAIDs following 6-hydroxydopamine (6-OHDA)-induced cell death in PC12 cells as an in vitro model of Parkinson's disease (PD) and to compare the effects of celecoxib, indomethacin and ibuprofen. The cell viability, ROS content, glutathione (GSH) level, and apoptosis were measured using resazurin, dichlorofluorescein diacetate (DCFH-DA), 5,5′-dithiobis-2-nitrobenzoic acid (DTNB), propidium iodide (PI) and flowcytometry, real-time PCR and western blot. Based on the results, pretreatment with celecoxib, indomethacin and ibuprofen for 24 hr significantly induced concentration and time-dependent protection against 6-OHDA-induced PC12 cell death. Cell viability (P<0.001), GSH level (P<0.01) and cytoplasmic content of nuclear factor kappa B (NFκB) (P<0.01) were increased, also ROS content (P<0.001) and apoptosis biomarkers such as the cleaved caspase-3 (P<0.001), Bax (P<0.01), phospho- stress-activated protein kinases / c-Jun N-terminal kinases (P-SPAK/JNK) (P<0.01) and cleaved poly ADP ribose polymerase (PARP) (P<0.001) protein levels were all decreased after pretreatment of cells with NSAIDs in 6-OHDA-induced PC12 cells. It is suggested that NFκB and SAPK/JNK pathways have an important role in 6-OHDA-induced cell injury. Overall, it seems that pretreatment with NSAIDs protect dopaminergic cells and may have the potential to slow the progression of PD.

The protective effect of regular running on sleep deprivation (SD)-induced cognitive impairment has been revealed. In this study, we focused on the effects of regular exercise, sleep deprivation and both of them together on the microRNA-1b (miR-1b) expression and their relation to the behavioral parameters and brain-derived neurotrophic factor (BDNF) expression. We used ovariectomized (OVX) female rats. The exercise program was mild-moderate treadmill training for 4 weeks. 72 hr SD was achieved using the multiple platform method and the spatial learning and memory parameters have been evaluated by the Morris water maze (MWM) test. The levels of studied genes were quantified by real-time PCR. SD down-regulated pri-miR-1b, miR-1b (P˂0.05), and BDNF mRNA (P˂0.01) in the hippocampus. Furthermore, female rats under exercise conditions showed significant up-regulation of the miR-1b and BDNF mRNA (P˂0.001). In addition, miR-1b positively correlated with cognitive function (P˂0.05) and BDNF mRNA (P˂0.01). Our data demonstrated that regular treadmill exercise could reverse the down-regulation of hippocampal miR-1b, which has a probable role in the SD-induced cognitive impairment.

Lung cancer is one of the most common malignant tumors, which seriously threatens the health and life of the people. Recently, a novel long non-coding RNA (lncRNA) termed lncFOXO1 was found and investigated in breast cancer. However, the effect of lncFOXO1 on lung cancer is still ambiguous. The current study aimed to uncover the functions of lncFOXO1 in lung cancer cell proliferation, metastasis and apoptosis. LncFOXO1 expression levels in lung cancer tissues or cells were detected using qRT-PCR. Then, overexpression and knockdown vectors of lncFOXO1 were transfected into A549 cells to investigate the effect of lncFOXO1 on cell proliferation, invasion, migration and apoptosis. These experiments were assessed using MTT, colony formation, transwell, flow cytometry and western blot assays, respectively. In vivo experiment was performed to examine the tumor weight using Xenograft tumor model assay. The important pathway of PI3K/AKT was finally examined using western blot. The decreased expression level of lncFOXO1 was observed in lung cancer tissues and cells (A549, H460, HCC827 and H1299). Knockdown of lncFOXO1 significantly promoted A549 cells viability, colony formation and invasion. However, lncFOXO1 overexpression obviously reversed the results. Moreover, lncFOXO1 overexpression induced A549 cells apoptosis by regulating Bax, cleaved-caspase-3 and Bcl-2. In vivo experiment revealed that lncFOXO1 overexpression inhibited tumor weight. Furthermore, lncFOXO1 knockdown promoted colony formation and mediated Myc and Cyclin D1 expressions by regulating PI3K/AKT signaling pathway. LncFOXO1 inhibited lung cancer cell proliferation, metastasis, and induced apoptosis through down-regulating PI3K/AKT pathway.

Recognized as a distinguished environmental and global toxicant, Bisphenol A (BPA) affects the liver, which is a vital body organ, by the induction of oxidative stress. The present study was designed to investigate the protective effect of quercetin against BPA in hepatotoxicity in Wistar rats and also, the activity of mitochondrial enzymes were evaluated. To this end, 32 male Wistar rats were divided into four groups (six rats per group), including control, BPA (250 mg/kg), BPA + quercetin (75 mg/kg), and quercetin (75 mg/kg). The BPA-induced alterations were restored in concentrations of alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) due to the quercetin treatment (75 mg/kg) (all P<0.001). While the levels of mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and malondialdehyde (MDA) decreased by the quercetin treatment in the liver mitochondria (P<0.001), Catalase (CAT) and glutathione (GSH) increased (P<0.001). According to the results, the potential hepatotoxicity of BPA can be prevented by quercetin, which protects the body against oxidative stress and BPA-induced biochemical toxicity. Moreover, the reproductive toxicity of BPA after environmental or occupational exposures can be potentially prohibited by quercetin.

Prenatal stresses increase incidence of neurodevelopmental disorders and influence cognitive abilities. Glucocorticoids are released in stress condition as endpoint activation of hypothalamus-pituitary-adrenal (HPA) axis. Evidence indicates a cross-talk between gut microbiota and brain function. This study assesses the effect of probiotic supplementation on behavioral functionand HPA axis action in stressed rats. The young rats born from dams exposed to noise stress (ST) during third trimester of pregnancy were used. Two groups of stressed animals were received a two-week probiotic supplementation before (pre-ST) and after (post-ST) birth. The time and distance to find hidden platform in Morris water maze were evaluated as spatial memory. Also entry to open arms in elevated plus-maze was considered as anxiety-like behaviors. The serum level of corticosterone was measured as the HPA axis function. While the stressed rats decreased entries to open arms to one third compared to the controls (CON) the probiotic treatment increased the entries by two times. The ST rats required more time and distance to find the platform than did the CON animals. The pre- and post-ST rats significantly restored the impaired behavior almost near the CON ones. While the serum corticosterone concentration increased by 50% in the ST rats it was reduced to almost normal level in the pre- and post-ST rats. Our findings confirmed a link between the gut microbiome and probiotics with the behavioral functions and HPA axis. The probiotic treatment favorably affected the stress-dependent behavioral disorders and the interaction between HPA and gut-brain-microbiota axes.

Gallic acid (GA), a potent anti-oxidant, plays an important role in reducing diabetic induced cardiac disorders. Therefore, the present investigation was purposed to determine the beneficial effect of GA in cardiac arrhythmias during reperfusion in diabetes induced by alloxan. Male Sprague-Dawley rats (200–250 g) were randomly divided into three groups (eight in each group): control (C), diabetic (D), and diabetic treated with GA (D+G) groups. GA was administered by gavage (25 mg/kg, daily) for eight weeks. Diabetes was induced by a single intraperitoneal injection of alloxan (120 mg/kg). Ischemia-reperfusion (IR) injury was performed by ischemia and then reperfusion (30 and 120 min, respectively). The score and magnitude of arrhythmias, creatine kinase (CK-MB), and lactate dehydrogenase (LDH) of the heart, electrocardiographic, and hemodynamic parameters were measured. One-way ANOVA followed by LSD tests were used for the differences between groups. The percentage of incidence was also evaluated by Fisher’s exact test. The duration (P<0.05), onset (P<0.01), score and incidence of arrhythmia, QT interval (P<0.001), LDH, and CK-MB (P<0.05) were significantly elevated and the contractility of the heart (±dp/dt, P<0.01), LVSP, QRS complex voltage (P<0.05), and heart rate (P<0.01) were significantly reduced in the diabetic animals compared with the control rats. However, administration with GA significantly improved these alterations in the diabetic group compared with the diabetic animals. This study indicated the beneficial effects of GA on cardiac electrophysiology and arrhythmias during reperfusion in diabetes.

Bisphenol A (BPA) that is a monomer of plastic products may possibly interfere with epigenetics and be involved in onset and progression of several diseases. This study was aimed to detect the epigenetic effects of in utero BPA exposure in mice offspring. All experiments were performed according to the national guidelines for laboratory animals and after ethical approval. Thirty adult BALB/c female mice were divided into 3 equal groups, G1 (controls), G2 (ethanol 0.10 ml/100ml of PBS so that final concentration would be 0.01%) vehicle control and G3 (BPA 10 mg/kg). Chemicals were given twice a week throughout the pregnancy. Once delivered at term, female offspring were observed for body weight, behavior and movements. Blood glucose, serum insulin, cholesterol and high-density lipoprotein cholesterol (HDLc) were measured at 5 and 15 months postnatal. Animals were sacrificed at 15 months and pancreas, kidney, adipose tissue and uterine tissue were taken and stained with either Hematoxylin and eosin (H & E) or immunostaining and examined under light microscope. Offspring of group G3 revealed abnormal changes of body weight, behavior and movements. Blood glucose, serum insulin, cholesterol and HDLc were high in group G3 offspring compared to controls. H & E staining showed changes in the parenchyma of pancreas, kidneys and uterus, which were confirmed by staining with anti- islet-1, kidney-specific (Ksp) cadherin, and anti- MLH antibody. In utero exposure of BPA exerts diabetogenic and atherogenic effects with less parenchymal tissue in endocrine pancreas, kidney and uterus.

KRAS proto-oncogene mutation can be considered a diagnostic factor for treating various malignancies. Helicobacter pylori infection, a risk factor for stomach cancer, may cause DNA damage and genetic changes. The aim of the current study was to assess the association of gastric cancer and KRAS mutation, demographic factors, and H. pylori infection. DNA was extracted from a total of 140 FFPE gastric cancer tissue samples. detection of KRAS mutation (codons 12 and 13) in tumors was performed by PCR amplification, followed by gel electrophoresis and DNA sequencing. PCR diagnosed any H. pylori infection. KRAS mutation was detected in 6 of the 140 (4.2%) gastric cancer tissue samples. 18 samples (12.8%), all of which were male (P<0.05), tested positive for H. pylori infection. KRAS mutations were present in 22.2% (4/18) of the samples with H. pylori infection (P<0.05). The mean age of patients was 62.25±12.61 years (range: 30–93 years). A male predominance (2.5 to 1) was reported in the gastric cancers, and at diagnosis, women were significantly younger than men (P=0.004). No association was observed between age or gender and KRAS mutation. Neither was one found between age and H. pylori infection. Tumors from H. pylori+ subjects were significantly more likely to have KRAS mutation than tumors from H. pylori- subjects (OR=17.1). The data suggest that H. pylori infection when compared with the absence of H. pylori infection, is associated with a higher prevalence of KRAS mutation in gastric cancer.

Growing evidences have indicated microRNAs as modulators of tumor development and aggression. On the other hand, a phenomenon known as epithelial-mesenchymal transition (EMT) that indicates a transient phase from epithelial-like features to mesenchymal phenotype is a key player in tumor progression.  In this study, we aimed to assess the potential impacts of miR-30a-5p as an inhibitor of melanoma progression and metastasis. MiR-30a-5p was transfected into B16-F10 melanoma cells. Then, the B16-F10 cells were injected subcutaneously or intravenously (IV) in to C57BL/6 mice. Then, the mice were euthanized and tumor size, tumor weight, snail1 protein expression and nodules in the lungs were evaluated. The migration of cancerous cells was significantly suppressed in vitro following the ectopic presentation of miR-30a-5p into B16-F10 melanoma cells. Furthermore, the metastatic behavior of the neoplastic cells was further suppressed in a xenograft mouse model of melanoma as observed with limited lung infiltration. We also found that transfected miR-30a-5p into melanoma cells could decrease snail1 and N-cadherin expression. MiR-30a-5p may represent an effective therapeutic target for the management of melanoma and other snail-overexpressing neoplasms.

microRNA-29 (miR-29) family miRNAs have been mentioned as tumor suppressive genes in several human cancers. The purpose of this study was to investigate the function of miR-29a in nasopharyngeal carcinoma (NPC) cells. Human NPC cell line 5-8F was transfected with mimic, inhibitor or scrambled controls specific for miR-29a. Subsequently, cell viability, migration, apoptosis and expression changes of VEGF were assessed by trypan blue staining, MTT assay, transwell assay, flow cytometry, Western blot and RT-qPCR. TargetScan online database was used to predict the targets of miR-29a, and luciferase reporter assay was carried out for testing the targeting relationship between VEGF and miR-29a. Western blot analysis was performed to determine the expression changes of core proteins in PI3K/AKT and JAK/STAT pathways. Overexpression of miR-29a suppressed 5-8F cells viability and relative migration, but increased apoptotic cell rate. Consistently, Bcl-2 was downregulated, Bax was upregulated, and caspase-3 and -9 were cleaved by miR-29a overexpression. VEGF was a target gene of miR-29a. Besides, VEGF silence exerted similar effects like miR-29a, as the viability and migration were repressed and apoptosis was induced. Finally, we found that PI3K/AKT and JAK/STAT pathways were deactivated by miR-29a or VEGF silence. These findings highlighted the tumor suppressive effects of miR-29a on NPC cells, as its overexpression inhibited 5-8F cells viability, migration, and induced apoptosis. miR-29a exerted tumor suppressive functions might be via targeting VEGF and deactivating PI3K/AKT and JAK/STAT pathways.

This study was carried out to boost the pharmacologic influence of carvedilol (CAR) (as a poorly water-soluble drug) by developing CAR-eudragit® RS100 (Eud) nanofibers and nanobeads benefiting an electrospraying approach. CAR-Eud nanoformulations with varying ratios (1:5 and 1:10) at total solution concentrations of 10 %, 15 % and 20 % w/v were formulated. The solution concentration remarkably impressed the size and morphology of the samples; in which, the nanobeads (mean diameter of 135.83 nm) were formed at low solution concentrations and high concentrations led to nanofibers (mean diameter of 193.45 nm) formation. DSC thermographs and PXRD patterns along with FTIR spectrum precisely showed CAR amorphization and no probable chemical interactions between CAR and Eud in the electrosprayed nanosystems. The in vitro release considerations demonstrated that the nanoformulations with the drug: polymer ratios of 1:10 and 1:5 depict rapid dissolution rate compared to the physical mixtures (PMs) and the pure drug. The in vivo studies in Wistar male rats suggested that the electrosprayed nanoformulation (1:10; 20 %) reduced the isoproterenol (ISO) induced elevation of heart rate, necrosis and accumulation of neutrophils in the heart tissue more efficient than the pure drug and PM. Our finding illustrated that the electrospraying as a profitable one-step procedure could be productively benefited to improve the physicochemical features and pharmacologic influences of CAR.

Valproic and arundic acids are astrocytes-modulating agents with potential effects in the treatment of Alzheimer’s disease (AD). S100B is an astrocytic cytokine with a possible role in the pathogenesis of AD. In this study, we aimed to assess the glioprotective effects of valproic and arundic acids against amyloid-β-peptide (Aβ)-induced glial death and contribution of S100B to the glioprotective effects of these agents in an astrocytic culture.    We used Aβ25–35 at a concentration of 200 μM in 1321N1 astrocyte cells. We treated the cells with valproic acid (0.5 and 1 mM) and/or arundic acid 50 µM for 24 hr. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) test was used to measure cell viability. The intracellular and extracellular S100B levels were measured using an ELISA kit. The data were analyzed using one-way analysis of variance followed by the Tukey’s test.    Aβ (200 µM) decreased the cell viability compared to the control group (P<0.001). Valproic acid (0.5 and 1 mM) and arundic acid (50 µM) ameliorated the gliotoxic effects of Aβ (P<0.05). The Aβ-treated group had higher S100B levels (both intracellular and extracellular) compared to the negative control groups (P<0.001). Arundic and valproic acids (0.5 and 1 mM) decreased both the intracellular and extracellular S100B levels compared to the Aβ-treated group (P<0.001). By considering homeostatic and neuroprotective functions of astrocyte, the astroprotective effects and the attenuation of S100B level may be responsible, at least in part, for the beneficial effects of valproic and arundic acids in AD.

Cisplatin (Cis) is an anticancer compound, which is used for the treatment of various cancers. Sumatriptan (Suma) is a selective agonist of 5-hydroxytryptamine 1B/1D (5HT1B/1D) receptor, which is prescribed for the management of migraine. It is well-established that Suma has anti-inflammatory and antioxidant properties. We have explored the protective effects of Suma in the mitigation of Cis-induced nephrotoxicity. The mice received a single IP injection of Cis (20 mg/kg) on the first day of the experiment. Suma treatment (0.1 and 0.3 mg/kg/day, IP) was started on day 1 and continued for 3 consecutive days. Creatinine (Cr), blood urea nitrogen (BUN) and malondialdehyde (MDA) levels were elevated and glutathione peroxidase (GPx) as well as superoxide dismutase (SOD) activities were decreased in Cis-treated mice. Suma (more potently 0.3 mg/kg) reduced Cr, BUN and MDA levels and increased SOD and GPx levels. Suma also reduced the acute renal injury (tubular degeneration, tubular cells vacuolation, tubular necrosis and cast), which corresponded to kidney damage in Cis-treated mice. These findings demonstrate that Suma mitigates Cis-induced renal injury by inhibition of oxidative stress and enhancing the antioxidant enzymes activities.

Honey’s ability to kill microorganisms and even eradication of chronic infections with drug-resistant pathogens has been documented by numerous studies. The present study is focused on the action of honey in its sub-inhibitory levels to impact on the pathogens coordinated behaviors rather than killing them. The impact of local honey on the quorum sensing related virulence of multidrug resistant Pseudomonas aeruginosa burn isolates was investigated by detection its effect on the virulence, biofilm formation and expression of quorum sensing related and exotoxin A genes. Experiments to characterise and quantify the impact of honey on the P. aeruginosa quorum sensing networks showed that the expression of exotoxin A ( ETA), las and rhl glucons reduced by low concentrations of honey including the associated virulence factors. Our results indicated that honey fights infections either by its bactericidal components which vigorously kill cells or by weakening bacterial coordination and virulence through interruption of quorum sensing system.

Charcot-Marie Tooth disease (CMT) is one of the main inherited causes of motor and sensory neuropathies with variable expressivity and age-of onset. Although more than 70 genes have been identified for CMT, more studies are needed to discover other genes involved in CMT. Introduction of whole exome sequencing (WES) to capture all the exons may help to find these genes. Here, we tried to find the genetic cause of the neuropathy in two Iranian brothers using WES. Blood sample was collected from probands and their family members to extract the genomic DNA. The extracted DNA from one of the affected case was subjected for WES. The variant calls were filtered  to reveal the pathogenic variant. Presence of the candidate mutation was confirmed using Sanger sequencing. The pathogenic potential of the variant was examined using in silico software. Using ClustalW multiple alignment, the presence of variant in conserved domain of protein was investigated. The parent and another affected boy were also checked for presence of the variant using PCR-sequencing. The obtained data presented a novel TTC del mutation in CDS 738 of dystrophin related protein 2 (DRP2) gene, which was validated by sequencing. The variant was located in a conserved domain of DRP2 protein and predicted as pathogenic. Two affected boys were hemizygous for the mutation and received the mutation from mother. Here, we provided the evidence for the contribution of DRP2 in CMT. Also, the symptoms shed light on molecular aspect of this genetically heterogeneous disease.