The human SMAD9 (GCC) repeat links to natural selection and late-onset neurocognitive disorders.

INTRODUCTION: Whereas (GCC)-repeats are overrepresented in genic regions, and mutation hotspots, they are largely unexplored with regard to their link with natural selection. Across numerous primate species and tissues, SMAD9 (SMAD Family Member 9) reaches highest level of expression in the human brain. This gene contains a (GCC)-repeat in the interval between + 1 and + 60 of the transcription start site, which is in the high-ranking (GCC)-repeats with respect to length. METHODS: Here we sequenced this (GCC)-repeat in 396 Iranian individuals, consisting of late-onset neurocognitive disorder (NCD) (N = 181) and controls (N = 215). RESULTS: We detected two predominantly abundant alleles of 7 and 9 repeats, forming 96.2% of the allele pool. The (GCC)7/(GCC)9 ratio was in the reverse order in the NCD group versus controls (p = 0.005), resulting from excess of (GCC)7 in the NCD group (p = 0.003) and (GCC)9 in the controls (p = 0.01). Five genotypes, predominantly consisting of (GCC)7 and lacking (GCC)9 were detected in the NCD group only (p = 0.008). The patients harboring those genotypes received the diagnoses of Alzheimer's disease (AD) and vascular dementia (VD). Five genotypes consisting of (GCC)9 and lacking (GCC)7 were detected in the control group only (p = 0.002). The group-specific genotypes formed approximately 4% of the genotype pool in the human samples studied. CONCLUSION: We propose natural selection and a novel locus for late-onset AD and VD at the SMAD9 (GCC)-repeat in humans.

Ferulic Acid Attenuates Kainate-induced Neurodegeneration in a Rat Poststatus Epilepticus Model.

BACKGROUND AND AIMS: Increasing research evidence indicates that temporal lobe epilepsy (TLE) induced by kainic acid (KA) has high pathological similarities with human TLE. KA induces excitotoxicity (especially in the acute phase of the disease), which leads to neurodegeneration and epileptogenesis through oxidative stress and inflammation. Ferulic acid (FA) is one of the well-known phytochemical compounds that have shown potential antioxidant and anti-inflammatory properties and promise in treating several diseases. The current study set out to investigate the neuroprotective effects of FA in a rat model of TLE. METHODS: Thirty-six male Wistar rats were divided into four groups. Pretreatment with FA (100 mg/kg/day p.o.) started one week before the intrahippocampal injection of KA (0.8 µg/µl, 5µl). Seizures were recorded and evaluated according to Racine's scale. Oxidative stress was assessed by measuring its indicators, including malondialdehyde (MDA), nitrite, and catalase. Histopathological evaluations including Nissl staining and immunohistochemical staining of cyclooxygenase-2 (COX-2), and neural nitric oxide synthases (nNOS) were performed for the CA3 region of the hippocampus. RESULTS: Pretreatment with FA significantly attenuates the severity of the seizure and prevents neuronal loss in the CA3 region of the hippocampus in rats with KA-induced post-status epilepticus. Also, nitrite concentration and nNOS levels were markedly diminished in FA-pretreated animals compared to non-pretreated epileptic rats. CONCLUSION: Our findings indicated that neuroprotective properties of FA, therefore, could be considered a valuable therapeutic supplement in treating TLE.

A (GCC) repeat in SBF1 reveals a novel biological phenomenon in human and links to late onset neurocognitive disorder.

The human SBF1 (SET binding factor 1) gene, alternatively known as MTMR5, is predominantly expressed in the brain, and its epigenetic dysregulation is linked to late-onset neurocognitive disorders (NCDs), such as Alzheimer's disease. This gene contains a (GCC)-repeat at the interval between + 1 and + 60 of the transcription start site (SBF1-202 ENST00000380817.8). We sequenced the SBF1 (GCC)-repeat in a sample of 542 Iranian individuals, consisting of late-onset NCDs (N = 260) and controls (N = 282). While multiple alleles were detected at this locus, the 8 and 9 repeats were predominantly abundant, forming > 95% of the allele pool across the two groups. Among a number of anomalies, the allele distribution was significantly different in the NCD group versus controls (Fisher's exact p = 0.006), primarily as a result of enrichment of the 8-repeat in the former. The genotype distribution departed from the Hardy-Weinberg principle in both groups (p < 0.001), and was significantly different between the two groups (Fisher's exact p = 0.001). We detected significantly low frequency of the 8/9 genotype in both groups, higher frequency of this genotype in the NCD group, and reverse order of 8/8 versus 9/9 genotypes in the NCD group versus controls. Biased heterozygous/heterozygous ratios were also detected for the 6/8 versus 6/9 genotypes (in favor of 6/8) across the human samples studied (Fisher's exact p = 0.0001). Bioinformatics studies revealed that the number of (GCC)-repeats may change the RNA secondary structure and interaction sites at least across human exon 1. This STR was specifically expanded beyond 2-repeats in primates. In conclusion, we report indication of a novel biological phenomenon, in which there is selection against certain heterozygous genotypes at a STR locus in human. We also report different allele and genotype distribution at this STR locus in late-onset NCD versus controls. In view of the location of this STR in the 5' untranslated region, RNA/RNA or RNA/DNA heterodimer formation of the involved genotypes and alternative RNA processing and/or translation should be considered.

Lactation ameliorates neurobehavioral outcomes in the ischemic rat dams.

AIMS: Cardiac arrest and stroke as a life-threatening event that may occur in throughout the female life, especially during pregnancy or after delivery. Previous studies demonstrated that cerebral ischemia during pregnancy or the puerperium is a rare occurrence but is associated with significant mortality and high morbidity. This study was designed to assess the effects of pregnancy and lactation on behavioral deficits, neural density, and angiogenesis in rat dams undergoing global ischemia. MATERIALS AND METHODS: Thirty-two female Wistar rats were divided into four groups: virgin-Sham (Vir-Sham) group, virgin-ischemic (Vir-Isc) group, pregnancy-lactation-sham (P-L-Sham) group, and pregnancy-lactation-ischemic (P-L-Isc) group. Global brain ischemia was induced in ischemic groups by using the 2-vessel occlusion (2-VO) model at the end of lactation phase. Seven days after 2-VO, anxiety-like signals and passive avoidance memory tests were assessed in animals. KEY FINDINGS: We found that the lactation significantly improved memory and reduced anxiety-like signals in P-L-Isc group as compared with Vir-Isc group. Moreover, angiogenesis and neural density significantly increased in the P-L-Isc group as compared with the Vir-Isc group. SIGNIFICANCE: This finding for the first time indicated that lactation protects the maternal brain against ischemic insult partly through promoting angiogenesis and neurogenesis.

Novel implications of a strictly monomorphic (GCC) repeat in the human PRKACB gene.

PRKACB (Protein Kinase CAMP-Activated Catalytic Subunit Beta) is predominantly expressed in the brain, and regulation of this gene links to neuroprotective effects against tau and Aß-induced toxicity. Here we studied a (GCC)-repeat spanning the core promoter and 5' UTR of this gene in 300 human subjects, consisting of late-onset neurocognitive disorder (NCD) (N = 150) and controls (N = 150). We also implemented several models to study the impact of this repeat on the three-dimensional (3D) structure of DNA. While the PRKACB (GCC)-repeat was strictly monomorphic at 7-repeats, we detected two 7/8 genotypes only in the NCD group. In all examined models, the (GCC)7 and its periodicals had the least range of divergence variation on the 3D structure of DNA in comparison to the 8-repeat periodicals and several hypothetical repeat lengths. A similar inert effect on the 3D structure was not detected in other classes of short tandem repeats (STRs) such as GA and CA repeats. In conclusion, we report monomorphism of a long (GCC)-repeat in the PRKACB gene in human, its inert effect on DNA structure, and enriched divergence in late-onset NCD. This is the first indication of natural selection for a monomorphic (GCC)-repeat, which probably evolved to function as an "epigenetic knob", without changing the regional DNA structure.

The potential neuroprotective roles of olive leaf extract in an epilepsy rat model induced by kainic acid.

BACKGROUND AND PURPOSE: Epilepsy is recognized as a chronic neurologic disease. Increasing evidence has addressed the antioxidant and anti-inflammatory roles of olive leaf extract (OLE) in neurodegenerative diseases. So, the current study aimed to investigate the neuroprotective roles of OLE in epilepsy. EXPERIMENTAL APPROACH: Forty rats were divided into 4 groups including a control group, sham group, kainic acid (KA) group, and KA + OLE group. KA (4 µg/rat) was injected intrahippocampal, and OLE (300 mg/kg) was orally administrated for 4 weeks. Animals were sacrificed, and their hippocampi were isolated. KA- induced seizure activity was recorded. Oxidative stress index was assessed by measuring its indicators including malondialdehyde (MDA), nitrite, nitrate, and glutathione (GSH) as well as the catalase (CAT) activity. The supernatant concentration of tumor necrosis factor-α (TNF-α) and the apoptosis rate in neurons were measured. FINDINGS/RESULTS: Treatment with OLE significantly reduced the seizure score. OLE decreased oxidative stress index by reducing the concentration of MDA, nitrite, and nitrate as well as increasing the level of GSH. OLE had a significant anti-apoptotic effect on neurons. However, CAT activity and the level of TNF-α were not affected. CONCLUSION AND IMPLICATIONS: Our findings indicated neuroprotective properties of OLE, which is mainly mediated by its antioxidant and anti-apoptotic effects, therefore, could be considered as a valuable therapeutic supplement for epilepsy.

Paeonol Protection Against Intrastriatal 6-Hydroxydopamine Rat Model of Parkinson's Disease.

INTRODUCTION: Parkinson's Disease (PD) presentations comprise frequent movement disorders in the elderly with various symptoms consisting of motor and non-motor complications. Paeonol is a phenolic chemical agent that has shown antioxidant and anti-inflammatory effects in different disorders and promising effects on metabotropic glutamate receptors (mGluR)- and GABAA-mediated neurotransmission. In this research, we tried to show the neuroprotective potential of paeonol in rat PD model induced by intrastriatal 6-hydroxydopamine (6-OHDA). METHODS: Rats with intrastriatal 6-OHDA lesioning received with paeonol at a dosage of 100 mg/kg/d for one week. In the end, some biomarkers of oxidative stress, apoptosis, and astrogliosis in nigral and striatal tissues were evaluated in addition to behavioral and Tyrosine Hydroxylase (TH) immunohistochemical analysis. RESULTS: The obtained data showed that paeonol alleviates apomorphine-induced rotations and reduces the delay time to initiate and the total time in the narrow beam test. However, its beneficial behavioral effect vanished after intracerebroventricular administration of mGluR III or GABAA receptor antagonists. Moreover, paeonol significantly restored striatal malondialdehyde, tissue levels of reactive oxygen species, the activity of the protective and vital enzymes consisting of superoxide dismutase and catalase, Glial Fibrillary Acidic Protein (GFAP), DNA fragmentation, phosphor apoptosis signal-regulating kinase 1, and nigral aquaporin 4 with no significant and proper change of nitrite, interleukin-1ß, inducible nitric oxide synthase, and angiotensin II. Additionally, paeonol prevented injury and reduced tyrosine hydroxylase-containing neurons in the midbrain nigral tissue. CONCLUSION: These obtained findings evidently designate neuroprotective property of paeonol in 6-OHDA murine model of PD that is exerted via easing of oxidative stress, apoptosis, astrogliosis, and its advantageous effect is to some extent mediated via mGluR III/GABAA pathway.

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder.

BACKGROUND: Approximately 2% of the human core promoter short tandem repeats (STRs) reach lengths of ≥6 repeats, which may in part be a result of adaptive evolutionary processes and natural selection. A single-exon transcript of the human nescient helix loop helix 2 (NHLH2) gene is flanked by the longest CA-repeat detected in a human protein-coding gene core promoter (Ensembl transcript ID: ENST00000369506.1). NHLH2 is involved in several biological and pathological pathways, such as motivated exercise, obesity, and diabetes. METHODS: The allele and genotype distribution of the NHLH2 CA-repeat were investigated by sequencing in 655 Iranian subjects, consisting of late-onset neurocognitive disorder (NCD) as a clinical entity (n = 290) and matched controls (n = 365). The evolutionary trend of the CA-repeat was also studied across vertebrates. RESULTS: The allele range was between 9 and 25 repeats in the NCD cases, and 12 and 24 repeats in the controls. At the frequency of 0.56, the 21-repeat allele was the predominant allele in the controls. While the 21-repeat was also the predominant allele in the NCD patients, we detected significant decline of the frequency (p < 0.0001) and homozygosity (p < 0.006) of this allele in this group. Furthermore, 12 genotypes were detected across 16 patients (5.5% of the entire NCD sample) and not in the controls (disease-only genotypes; p < 0.0003), consisting of at least one extreme allele. The extreme alleles were at 9, 12, 13, 18, and 19 repeats (extreme short end), and 23, 24, and 25 repeats (extreme long end), and their frequencies ranged between 0.001 and 0.04. The frequency of the 21-repeat allele significantly dropped to 0.09 in the disease-only genotype compartment (p < 0.0001). Evolutionarily, while the maximum length of the NHLH2 CA-repeat was 11 repeats in non-primates, this CA-repeat was ≥14 repeats in primates and reached maximum length in human. CONCLUSION: We propose a novel locus for late-onset NCD at the NHLH2 core promoter exceptionally long CA-STR and natural selection at this locus. Furthermore, there was indication of genotypes at this locus that unambiguously linked to late-onset NCD. This is the first instance of natural selection in favor of a predominantly abundant STR allele in human and its differential distribution in late-onset NCD.

The Effect of Rosmarinic Acid on Apoptosis and nNOS Immunoreactivity Following Intrahippocampal Kainic Acid Injections in Rats.

INTRODUCTION: Kainic Acid (KA) is an ionotropic glutamate receptor agonist. KA can induce neuronal overactivity and excitotoxicity. Rosmarinic Acid (RA) is a natural polyphenolic compound with antioxidant, anti-apoptotic, anti-neurodegenerative, and anti-inflammatory properties. This study aimed to assess the effect of RA on apoptosis, nNOS-positive neurons number, as well as Mitogen-Activated Protein Kinase (MAPK) and Cyclooxygenase-2 (COX-2) immunoreactivity, following intrahippocampal Kainic acid injection in rats. METHODS: The study rats were randomly assigned to three groups of sham, KA (KA was injected into the right side of the hippocampus) and KA+RA (a dose of 10 mg/kg/day through a gavage needle for one week before KA injection). Then, histopathological changes, including apoptosis [Terminal Deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay], nNOS-positive neurons number, as well as COX-2 and MAPK immunoreactivity were evaluated in the hippocampus. RESULTS: In the RA pretreated group, nNOS-positive neurons and TUNEL-positive cells were significantly reduced compared to the KA group (P<0.05). COX-2and MAPK immunoreactivity demonstrated no significant changes compared to the KA group. They indicated a significant higher reactivity for COX-2 (P<0.01) and MAPK (P<0.005) versus the sham group. CONCLUSION: RA had neuroprotective effects, compared to KA, through reduced apoptosis and nNOS-positive neurons, but not MAPK and COX-2.

Assessment of the protective effect of KN-93 drug in systemic epilepsy disorders induced by pilocarpine in male rat.

BACKGROUND AND AIMS: Epileptic seizures occur as a consequence of a sudden imbalance between the stimuli and inhibitors within the network of cortical neurons in favor of the stimulus. One of the drugs that induce epilepsy is pilocarpine. Systemic injection of pilocarpine affects on muscarinic receptors. Increasing evidence has addressed the implication of KN-93 by blocking Ca2+ /calmodulin-dependent protein kinase II (CaMKII), suppressing oxidative stress and inflammation, and also reducing neuron decay. So, we aimed to evaluate the potential preventive effects of KN-93 in systemic epilepsy disorders induced by pilocarpine. MATERIALS AND METHODS: In this animal study, male rats were divided into five groups including treatment group (KN-93 with the dose of 5 mM/10 µL dimethyl sulfoxide (DMSO) before inducing epilepsy by 380 mg/kg pilocarpine) KN-93 group (received 5 mM KN-93), control group, epilepsy group (received 380 mg/kg pilocarpine Intraperitoneal), and sham group (received 10 µL DMSO). Oxidative stress was assessed by measuring its indicators including the concentration of malondialdehyde (MDA), nitrite, glutathione (GSH), as well as the antioxidant activity of catalase. In addition, serum levels of proinflammatory mediators including tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were determined. RESULTS: Pretreatment with KN-93 significantly reduced oxidative stress index by reducing the concentration of MDA, nitrite, and increasing the level of GSH. In addition, low concentrations of TNF-α and IL-1ß were observed in hippocampus supernatant of KN-93 pretreated rats in comparison with the pilocarpine groups. Moreover, administration of KN-93 improved neuronal density and attenuated the seizure activity and behavior. CONCLUSIONS: Overall, our findings suggest that KN-93 can effectively suppress oxidative stress and inflammation. Furthermore, KN-93 is able to attenuate seizure behaviors by preventing its effects on neuron loss, so, it is valuable for the treatment of epileptic seizures.

Huperzine A ameliorates cognitive dysfunction and neuroinflammation in kainic acid-induced epileptic rats by antioxidant activity and NLRP3/caspase-1 pathway inhibition.

Temporal lobe epilepsy (TLE) is one of the most prevalent types of epilepsy in human. Huperzine A (Hup-A) has been reported to possess antioxidative and anti-inflammatory properties; however, its role in TLE induced by kainic acid has not been determined. The current study investigated the protective effects of Hup-A (0.1 mg/kg) in kainic acid-induced model of TLE in the rat. In the current study, it was found that Hup-A significantly prevented the seizure intensity and learning and memory deterioration which was assessed by Morris water maze (MWM) and novel object recognition task (NOR). Additionally, Hup-A inhibited oxidative stress, inflammation, and acetylcholinesterase activity (AChE). In addition, catalase and superoxide dismutase (SOD) activities increased after Hup-A treatment, while malondialdehyde (MDA) and nitrite levels significantly reduced. Regarding inflammation, this drug decreased kainic acid-induced NLRP3 expression in microglial cells and caspase-1 activity in hippocampal tissue, possibly through diminishing oxidative stress. Taken together, our data showed that Hup-A could be a potential protective substance to ameliorate seizure severity and some memory deficits related to epilepsy via attenuating neuroinflammation and protection of neurons.

S-allyl cysteine protects against lipopolysaccharide-induced acute kidney injury in the C57BL/6 mouse strain: Involvement of oxidative stress and inflammation.

Sepsis is a serious and life-threatening medical condition with a higher rate of patients' morbidity and mortality and with complications such as acute kidney injury (AKI). S-allyl cysteine (SAC) is the active constituent of the medicinal plant garlic (Allium sativum) with multiple beneficial effects including anti-inflammatory and antioxidant properties. In this research, we tried to determine the protective effect of SAC pretreatment in a mouse model of AKI. To induce AKI, lipopolysaccharide (LPS) was injected once (10 mg/kg, i.p.) and SAC was administered at doses of 25, 50, or 100 mg/kg (p.o.) 1 h before LPS. Treatment of LPS-challenged C56BL/6 animals with SAC lowered serum level of creatinine and blood urea nitrogen (BUN), partially restored renal oxidative stress-related biomarkers including malondialdehyde (MDA), glutathione (GSH), and activity of superoxide dismutase (SOD) and catalase in addition to improvement of mitochondrial membrane potential (MMP). Furthermore, SAC was capable to bring renal nuclear factor-kappaB (NF-κB), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), toll-like receptor 4 (TLR4), cyclooxygenase-2 (COX2), tumor necrosis factor α (TNFα), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), Annexin V, and DNA fragmentation partially back to their control levels. Additionally, SAC pretreatment was capable to exert a protective effect, as shown histologically by lower tubular injury and pathologic changes in the kidney. In summary, SAC is capable to alleviate LPS-induced AKI through mitigation of renal oxidative stress, inflammation, and apoptosis in addition to preservation of mitochondrial integrity and its favorable effect exhibits a dose-dependent pattern.

Simvastatin and bone marrow-derived mesenchymal stem cells (BMSCs) affects serum IgE and lung cytokines levels in sensitized mice.

INTRODUCTION: The effects of bone marrow-derived mesenchymal stem cells (BMSCs) and simvastatin combination therapy on serum total and specific IgE levels and lung IL-13 and TGF-ß levels in sensitized mouse were examined. MATERIAL AND METHODS: Control (n = 5), Sensitized (S), (n = 5), S + BMSC (n = 6), S + simvastatin (n = 6) and S + BMSC + simvastatin (n = 4) groups of BALB/c mice were studied. Mice were sensitized by ovalbumin. Sensitized mice were treated with a single intravenous injection of BMSCs (1 × 106) or daily intraperitoneal injection of simvastatin (40 mg/kg) or both BMSCs and simvastatin on the last week of challenge. Serum total and ovalbumin specific IgE levels as well as IL-13 and TGF-ß levels in broncho-alveolar lavage (BAL) fluid were evaluated. RESULTS: Serum total and specific IgE levels as well as lung IL-13 and TGF-ß levels were significantly increased in S group compared to control group (P < 0.001 for all cases). Treatment with BMSCs, simvastatin and their combination significantly decreased serum total and specific IgE levels (P < 0.05 to P < 0.01). However, IL-13 and TGF-ß levels were significantly decreased by BMSCs and BMSC + simvastatin combination therapy (P < 0.05 for all cases). The effect of simvastatin and BMSCs combination therapy on serum specific IgE levels as well as lung IL-13 and TGF-ß levels were significantly higher than the effect of BMSCs and simvastatin alone (P < 0.001 for IL-13 and P < 0.01 for other cases). CONCLUSIONS: Simvastatin and BMSCs combination therapy affects serum IgE as well as lung IL-13 and TGFß levels more than BMSC therapy and simvastatin therapy alone which may be due to increased BMSCs migration into the lung tissue.

Descriptive epidemiology: prevalence, incidence, sociodemographic factors, socioeconomic domains, and quality of life of epilepsy: an update and systematic review.

INTRODUCTION: The purpose of this study was to investigate the contributions of quality of life (QOL), sociodemographic factors (age, sex, etc.), residential areas, general attitudes toward epilepsy, socioeconomic domains, prevalence and incidence in epileptic patients from Iran. MATERIAL AND METHODS: A systematic literature search was conducted, including database searches in PubMed, Medline, Embase, ScienceDirect, Scopus, ISC, Health, Web of Science, and the Cochrane Library Database of relevant articles, personal files and systematic reviews to identify studies examining risk factors in epilepsy. RESULTS: This review article shows that certain socio-demographic and socio-economic factors, geographic variation in epidemiologic patterns of epilepsy as well as clinical factors may be crucial in determining QOL in epilepsy patients and provides further evidence supporting the validity of the scale in QOL based on consideration of different target groups in different areas. CONCLUSIONS: Prevalence of epilepsy appears to be correlated with socioeconomic status in the lower socioeconomic groups. Also demographic characteristics, socio-economic factors and clinical presentation are linked to different QOL of these patients among nations. The educational program has a beneficial effect on self-management behaviors in patients with epilepsy. More work needs to be done to improve tools that help to evaluate efficiently the health-related quality of life of people with epilepsy.

Post-infarct treatment with [Pyr1]apelin-13 exerts anti-remodelling and anti-apoptotic effects in rats' hearts.

BACKGROUND: Ischaemic heart disease is the main cause of mortality in the world. After myocardial infarction (MI) cardiomyocytes apoptosis and ventricular remodelling have occurred. Apelin is a peptide that has been shown to exert cardioprotective effects. AIM: The aim of this study was to investigate the anti-apoptotic and anti-remodelling effects of [Pyr¹]apelin-13 in the rat model of post-MI. METHODS: Thirty-six male Wistar rats were randomly divided into three groups: (1) sham, (2) MI, and (3) MI treated with [Pyr¹] apelin-13 (MI+Apel). MI animals were subjected to 30-min ligation of the left anterior descending coronary artery (LAD) and 14 days of reperfusion. Twenty-four hours after LAD ligation, [Pyr¹]apelin-13 (10 nmol/kg/day, i.p.) was administered for five consecutive days. Hypertrophic parameters, left ventricular (LV) remodelling, and gene expression of Apel, apelin receptor (Apelr), Bax, caspase-3 (Casp-3), and Bcl-2 by real-time polymerase chain reaction and cardiomyocytes apoptosis by TUNEL immunostaining were assessed on day 14 post-MI. RESULTS: Post-infarct treatment with [Pyr¹]apelin-13 improved myocardial hypertrophic and LV remodelling parameters and led to a significant increase in the expression of Apel, Apelr, and Bcl-2, and a decrease in the expression of Bax and Casp-3. Furthermore, treatment with [Pyr¹]apelin-13 decreased cardiomyocyte apoptosis. CONCLUSIONS: [Pyr¹]apelin-13 has anti-hypertrophic, anti-remodelling, and anti-apoptotic effects via overexpression of Apel, Apelr, and Bcl-2 and reduces gene expression of Bax and Casp-3 in the infarcted myocardium, which can in turn lead to repair myocardium.

Effect of bone marrow derived mesenchymal stem cells on lung pathology and inflammation in ovalbumin-induced asthma in mouse.

OBJECTIVES: Bone marrow-derived mesenchymal stem cells (BMSCs) have attracted significant interest to treat asthma and its complication. In this study, the effects of BMSCs on lung pathology and inflammation in an ovalbumin-induced asthma model in mouse were examined. MATERIALS AND METHODS: BALB/c mice were divided into three groups: control group (animals were not sensitized), asthma group (animals were sensitized by ovalbumin), asthma+BMSC group (animals were sensitized by ovalbumin and treated with BMSCs). BMSCs were isolated and characterized and then labeled with Bromodeoxyuridine (BrdU). After that the cells transferred into asthmatic mice. Histopathological changes of the airways, BMSCs migration and total and differential white blood cell (WBC) count in bronchoalveolar lavage (BAL) fluid were evaluated. RESULTS: A large number of BrdU-BMSCs were found in the lungs of mice treated with BMSCs. The histopathological changes, BAL total WBC counts and the percentage of neutrophils and eosinophils were increased in asthma group compared to the control group. Treatment with BMSCs significantly decreased airway pathological indices, inflammatory cell infiltration, and also goblet cell hyperplasia. CONCLUSION: The results of this study revealed that BMSCs therapy significantly suppressed the lung pathology and inflammation in the ovalbumin induced asthma model in mouse.

Naringenin improves learning and memory in an Alzheimer's disease rat model: Insights into the underlying mechanisms.

Alzheimer's disease (AD) is one of the prevalent neurological disorders of the central nervous system hallmarked by increased beta-amyloid (Aß) deposition and ensuing learning and memory deficit. In the present study, the beneficial effect of naringenin on improvement of learning and memory was evaluated in an Alzheimer's disease rat model. The Aß-injected rats showed a lower alternation score in Y-maze task, impairment of retention and recall capability in passive avoidance test, and lower correct choices and higher errors in radial arm maze (RAM) task as compared to sham group in addition to enhanced oxidative stress and apoptosis. Naringenin, but not a combination of naringenin and fulvestrant (an estrogenic receptor antagonist) significantly improved the performance of Aß-injected rats in passive avoidance and RAM tasks. Naringenin pretreatment of Aß-injected rats also lowered hippocampal malondialdehyde (MDA) with no significant effect on nitrite and superoxide dismutase (SOD) activity in addition to lowering apoptosis. These results suggest naringenin pretreatment attenuates Aß-induced impairment of learning and memory through mitigation of lipid peroxidation and apoptosis and its beneficial effect is somewhat mediated via estrogenic pathway.

Rosmarinic acid exerts a neuroprotective effect in the kainate rat model of temporal lobe epilepsy: Underlying mechanisms.

CONTEXT: Temporal lobe epilepsy (TLE) is an intractable neurological disorder. Rosmarinic acid (RA) is a natural polyphenol with antioxidant, anti-apoptotic, and anti-inflammatory properties. OBJECTIVE: This study evaluates beneficial effect of RA in intrahippocampal kainate-induced model of TLE. MATERIALS AND METHODS: Rats were divided into sham, RA-pretreated sham, kainate, and sodium valproate (VA) or RA-pretreated kainate groups. Rats received RA or VA p.o. at doses of 10 or 300 mg/kg/d, respectively, starting 1 week before the surgery. After 6 weeks, seizure intensity, apoptosis, and oxidative stress markers were evaluated in addition to determination of Timm index as an indicator of mossy fiber sprouting (MFS) and the number of Nissl-stained neurons. RESULTS: All rats in the kainate group had seizure and 24.3% of rats in the kainate + VA group and 36.7% of rats in the kainate + RA group showed seizure. The kainate group had a significant elevation of malondialdehyde (MDA) (p < 0.05) and nitrite (p < 0.01) and reduction of glutathione (GSH) and catalase activity (p < 0.05) and pretreatment of kainate-lesioned rats with RA or VA significantly lowered MDA and nitrite content (p < 0.05) and raised activity of catalase (p < 0.05). The kainate group also had a significant reduction of neurons in CA1 and CA3 regions and an elevation of Timm index (p < 0.05-0.001) and RA or VA significantly (p < 0.05-0.01) prevented these changes. DISCUSSION AND CONCLUSION: RA could attenuate seizure, mitigates oxidative stress, augments the activity of defensive systems, and prevent hippocampal neuronal loss and MFS in the kainate model of TLE.

Aortic responsiveness to nitric oxide is affected by seasonal variation.

Cardiac attacks and sudden cardiac deaths are more common in cold seasons. Up to now the underlying pathophysiologic mechanism of the seasonal variation in cardiovascular accidents is scarcely known. There are many physiological mechanisms which exhibit seasonal variation (e.g. blood pressure). Nitric oxide (NO) is a potent vasodilator, and impaired responsiveness to its physiological effects has been reported in many pathological situations including cardiovascular accidents. The aim of the present study was to evaluate the role of NO-dependent mechanisms on seasonal variation in aortic relaxation in vitro in rats. Male Sprague-Dawley rats grown up in different seasons in natural light/dark situation were used in the study, while the temperature and humidity were kept constant throughout the study (22+/-1 degrees C). The in vitro aortic ring responsiveness to an NO donor was studied in different seasons. Intact and denuded rings were pre-contracted with phenylephrine and vaso-relaxatory response to sodium isosorbide dinitrate (10(-8) to 10(-4)M) was recorded in vitro. The vaso-relaxatory response to isosorbide dinitrate (10(-6)M) was higher in aortic rings obtained in summer compared with those in winter and fall. There was a significant difference in EC(50) of sodium isosorbide dinitrate-induced vaso-relaxation of rings obtained from rats which were grown up in summer and winter (EC(50): 2.23+/-0.069 versus 4.31+/-0.088, P<0.05). The maximum response (R(max)) to isosorbide dinitrate was, however, identical in rings obtained from these rats. In conclusion, the in vitro responsiveness of aorta to NO is affected by seasonal light/dark periods the rats are exposed. This might be one of the reasons why more sudden cardiac deaths occur also in humans during winter.