Molecular mechanisms underlying the effect of tooth shortening on memory dysfunction in Wistar male rat.

OBJECTIVE: We investigated the effects of molar tooth shortening on the mRNA expression of the AßPP/BACE1, BDNF/TrkB, and Bax/Bcl-2 signaling pathways in the Wistar male rat hippocampal regions. DESIGN: Four groups (n = 5 per group) of male Wistar rats (control, SRM (shortened right molar), SLM (shortened left molar), and SBM (shortened bilateral molar)) were used. RNA was isolated from the hippocampus and transformed into cDNA. Real-time quantitative PCR was used to evaluate the mRNA expression levels of AßPP, BACE1, Bax, Bcl-2, BDNF, and TrkB. RESULTS: Differential mRNA expression was observed in rat groups. SBM significantly upregulated the AßPP, BACE1, and Bax mRNA expressions, whereas the expression levels of Bcl-2, BDNF, and TrkB were decreased. SRM and SLM approximately had the same effect on the expression enhancement of AßPP, BACE1, and Bax; however, SRM was more effective than SLM in increasing the expression of these genes. CONCLUSIONS: Symmetrical molar teeth shortening affected the mRNA expression of AßPP and BACE1, which is related to learning and memory dysfunction.

In diabetic male Wistar rats, quercetin-conjugated superparamagnetic iron oxide nanoparticles have an effect on the SIRT1/p66Shc-mediated pathway related to cognitive impairment.

BACKGROUND: Quercetin (QC) possesses a variety of health-promoting effects in pure and in conjugation with nanoparticles. Since the mRNA-SIRT1/p66Shc pathway and microRNAs (miRNAs) are implicated in the oxidative process, we aimed to compare the effects of QC and QC-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) on this pathway. METHODS: Through the use of the chemical coprecipitation technique (CPT), SPIONs were synthesized, coated with dextran, and conjugated with quercetin. Adult male Wistar rats were given intraperitoneal injections of streptozotocin to look for signs of type 1 diabetes (T1D). The animals were randomized into five groups: the control group got deionized water (DI), free QC solution (25 mg/kg), SPIONs (25 mg/kg), and QCSPIONs (25 mg/kg), and all groups received repeat doses administered orally over 35 days. Real-time quantitative PCR was used to assess the levels of miR-34a, let-7a-p5, SIRT1, p66Shc, CASP3, and PARP1 expression in the hippocampus of diabetic rats. RESULTS: In silico investigations identified p66Shc, CASP3, and PARP1 as targets of let-7a-5p and miR-34a as possible regulators of SIRT1 genes. The outcomes demonstrated that diabetes elevated miR-34a, p66Shc, CASP3, and PARP1 and downregulated let-7a-5p and SIRT1 expression. In contrast to the diabetic group, QCSPIONs boosted let-7a-5p expression levels and consequently lowered p66Shc, CASP3, and PARP1 expression levels. QCSPIONs also reduced miR-34a expression, which led to an upsurge in SIRT1 expression. CONCLUSION: Our results suggest that QCSPIONs can regulate the SIRT1/p66Shc-mediated signaling pathway and can be considered a promising candidate for ameliorating the complications of diabetes.

Molar tooth shortening induces learning and memory impairment in Wistar rat.

OBJECTIVE: This study aimed to investigate the relationship between different patterns of molar crown loss and the association between symmetrical and asymmetrical shortening molar teeth with memory impairment. MATERIALS AND METHODS: Male Wistar rats were divided into four groups (n = 10) including control, SLM (shortened left molar), SRM (shortened right molar), and SBM (shortened bilateral molar) groups. Morris water maze (MWM) and passive avoidance test (PAT) were performed to assess spatial and fear memory, respectively. Besides, histological assessment of hippocampus and gingival tissues was done. RESULTS: In the MWM test, SBM and SLM groups had higher escape latency over training trials and spent less time in the target quadrant in the probe trial (p < 0.01). In the PAT, step-through latency was significantly reduced in three groups, and time spent in the dark compartment increased in SBM (p < 0.01) and SLM (p < 0.05) groups. In addition, each teeth shortening group indicated a reduction in density (p < 0.01) and thickness layer (p < 0.05) of pyramidal cells. Gingival was normal after shortening of the molar crown. CONCLUSIONS: Different patterns of molar teeth shortening induced learning and memory impairment; however, symmetrical molar teeth shortening has more effects on memory impairment.

Quercetin attenuates neurotoxicity induced by iron oxide nanoparticles.

Iron oxide nanoparticles (IONPs) have been proposed as targeted carriers to deliver therapeutic molecules in the central nervous system (CNS). However, IONPs may damage neural tissue via free iron accumulation, protein aggregation, and oxidative stress. Neuroprotective effects of quercetin (QC) have been proven due to its antioxidant and anti-inflammatory properties. However, poor solubility and low bioavailability of QC have also led researchers to make various QC-involved nanoparticles to overcome these limitations. We wondered how high doses or prolonged treatment with quercetin conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) could improve cognitive dysfunction and promote neurogenesis without any toxicity. It can be explained that the QC inhibits protein aggregation and acts against iron overload via iron-chelating activity, iron homeostasis genes regulation, radical scavenging, and attenuation of Fenton/Haber-Weiss reaction. In this review, first, we present brain iron homeostasis, molecular mechanisms of iron overload that induced neurotoxicity, and the role of iron in dementia-associated diseases. Then by providing evidence of IONPs neurotoxicity, we discuss how QC neutralizes IONPs neurotoxicity, and finally, we make a brief comparison between QC and conventional iron chelators. In this review, we highlight that QC as supplementation and especially in conjugated form reduces iron oxide nanoparticles neurotoxicity in clinical application.

Quercetin­conjugated superparamagnetic iron oxide nanoparticles modulate glucose metabolism-related genes and miR-29 family in the hippocampus of diabetic rats.

Quercetin (QC) is a dietary bioflavonoid that can be conjugated with nanoparticles to facilitate its brain bioavailability. We previously showed that quercetin-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) reduced the level of blood glucose in diabetic rats. Glucose transporters (GLUTs), insulin-like growth factor-1 (IGF-1), and microRNA-29 (miR-29) play a critical role in brain glucose homeostasis. In the current study, we examined the effects of QCSPION on the expression of glucose metabolism-related genes, and the miR-29 family as a candidate regulator of glucose handling in the hippocampus of diabetic rats. Our in silico analyses introduce the miR-29 family as potential regulators of glucose transporters and IGF-1 genes. The expression level of the miR-29 family, IGF-1, GLUT1, GLUT2, GLUT3, and GLUT4 were measured by qPCR. Our results indicate that diabetes significantly results in upregulation of the miR-29 family and downregulation of the GLUT1, 2, 3, 4, and IGF-1 genes. Interestingly, QCSPIONs reduced miR-29 family expression and subsequently enhanced GLUT1, 2, 3, 4, and IGF-1expression. In conclusion, our findings suggest that QCSPION could regulate the expression of the miR-29 family, which in turn increases the expression of glucose transporters and IGF-1, thereby reducing diabetic complications.

Protective effect of quercetin on alteration of antioxidant genes expression and histological changes in the dental pulp of the streptozotocin-diabetic rats.

OBJECTIVE: We aimed to assess the effect of quercetin as one of the most common polyphenols with anti-inflammatory and antioxidant properties on expression levels of catalase (CAT), superoxide dismutase 1 (SOD1), and glutathione peroxidase 1 (GPX1), involved in the detoxification of reactive oxygen species (ROS), and histology of dental pulp in streptozotocin-diabetic rats. DESIGN: Type 1 diabetes mellitus (T1DM) was induced by intraperitoneal injection of streptozotocin in adult male Wistar rats. Animals (n = 24) were equally distributed into control, diabetes, and diabetes treated with quercetin groups. Rats were gavaged daily with quercetin (25 mg/kg) for forty days. To measure the mRNA levels of antioxidant genes, quantitate real-time PCR was applied. The oxidative stress parameters such as total antioxidant capacity (TAC) and histopathological assessments were performed. RESULTS: A significant increase in the relative quantification mRNA levels of SOD1, CAT, GPX1 was detected in diabetic rat dental pulp. Besides, persistent hyperglycemia led to the enhancement of TAC level and degeneration of connective tissue of the dental pulp. Interestingly, quercetin normalized the expression mRNA levels of CAT, SOD1, GPX1 to near the normal level. Moreover, quercetin treatment normalized TAC levels. CONCLUSIONS: Because of the crucial role of antioxidants in diabetic complications, the findings of the current study presented a molecular basis for the protective effect of quercetin on dental pulp in diabetic conditions.

Quercetin-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) increases Nrf2 expression via miR-27a mediation to prevent memory dysfunction in diabetic rats.

Oxidative stress is one of the earliest defects involved in the development of diabetes-induced cognitive impairment. Nrf2 is the master regulator of the cellular antioxidant system can be regulated by some microRNAs. The study aimed to evaluate the effects of quercetin (QC) and quercetin-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) on Nrf2-controlled antioxidant genes through the redox-sensitive miR-27a. Expression levels of miR-27a, Nrf2, SOD1, GPX1, and CAT were measured by quantitative real-time PCR. Moreover, the oxidative stress parameters including total antioxidant capacity (TAC) and histological alterations were investigated. The expression level of miR-27a was significantly up-regulated in diabetic rats. While expression levels of Nrf2, SOD1, GPX1, and CAT were significantly down-regulated under diabetic condition. Interestingly, QCSPIONs decreased expression level of miR-27a and subsequently enhanced the expression levels of Nrf2, SOD1, and CAT to the control level. No significant difference was observed in the expression level of GPX1. Besides, QC in pure and especially conjugated form was able to normalize TAC and regenerate pathological lesions in STZ-diabetic rats. Our result demonstrates that QCSPIONs as an effective combined therapy can decrease miR-27a expression, which in turn increases the Nrf2 expression and responsive antioxidant genes, resulting in improvement of memory dysfunction in diabetic rats.

Effects of quercetin-conjugated with superparamagnetic iron oxide nanoparticles on learning and memory improvement through targeting microRNAs/NF-κB pathway.

Quercetin-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) have an ameliorative effect on diabetes-induced memory impairment. The current study aimed to compare the effect of quercetin (QC) and QCSPIONs on inflammation-related microRNAs and NF-κB signaling pathways in the hippocampus of diabetic rats. The expression levels of miR-146a, miR-9, NF-κB, and NF-κB-related downstream genes, including TNF-α, BACE1, AßPP, Bax, and Bcl-2 were measured using quantitative real-time PCR. To determine the NF-κB activity, immunohistochemical expression of NF-κB/p65 phosphorylation was employed. Computer simulated docking analysis also performed to find the QC target proteins involved in the NF-κB pathway. Results indicate that diabetes significantly upregulated the expression levels of miR-146a, miR-9, TNF-α, NF-κB, and subsequently AßPP, BACE1, and Bax. Expression analysis shows that QCSPIONs are more effective than pure QC in reducing the expression of miR-9. Interestingly, QCSPIONs reduce the pathological activity of NF-κB and subsequently normalize BACE1, AßPP, and the ratio of Bax/Bcl-2 expression better than pure QC. Comparative docking analyses also show the stronger binding affinity of QC to IKK and BACE1 proteins compared to specific inhibitors of each protein. In conclusion, our study suggests the potent efficacy of QCSPIONs as a promising drug delivery system in memory improvement through targeting the NF-κB pathway.

Crosstalk between obesity, diabetes, and alzheimer's disease: Introducing quercetin as an effective triple herbal medicine.

Obesity and diabetes are the most common metabolic disorders, which are strongly related to Alzheimer's disease (AD) in aging. Diabetes and obesity can lead to the accumulation of amyloid plaques, neurofibrillary tangles (NFTs), and other symptoms of AD through several pathways, including insulin resistance, hyperglycemia, hyperinsulinemia, chronic inflammation, oxidative stress, adipokines dysregulation, and vascular impairment. Currently, the use of polyphenols has been expanded in animal models and in-vitro studies because of their comparatively negligible adverse effects. Among them, quercetin (QT) is one of the most abundant polyphenolic flavonoids, which is present in fruits and vegetables and displays many biological, health-promoting effects in a wide range of diseases. The low bioavailability and poor solubility of QT have also led researchers to make various QT-involved nanoparticles (NPs) to overcome these limitations. In this paper, we review significant molecular mechanisms induced by diabetes and obesity that increase AD pathogenesis. Then, we summarize in vitro, in vivo, and clinical evidence regarding the anti-Alzheimer, anti-diabetic and anti-obesity effects of QT. Finally, QT in pure and combination form using NPs has been suggested as a promising therapeutic agent for future studies.

Effect of quercetin-conjugated superparamagnetic iron oxide nanoparticles on diabetes-induced learning and memory impairment in rats.

BACKGROUND: Diabetes mellitus plays a causative role in cognitive decline. Newly, neuroprotective effects of flavonoids have been widely investigated in neurodegenerative diseases. Quercetin (QC) is a phyto-derived bioactive flavone with numerous beneficial activities. However, its limited permeability to cross the blood-brain barrier, low oral bioavailability, poor aqueous solubility, and rapid gastrointestinal digestion lead to the administration of high dose of QC in clinical application. MATERIALS AND METHODS: In order to overcome these limitations, we conjugated QC with superparamagnetic iron oxide nanoparticles (QCSPIONs) and supplemented streptozotocin-induced diabetic rats with it to improve diabetes-related memory impairment. In this regard, 40 rats were distributed into five groups with eight animals: control, diabetes, and diabetes treated with SPIONs, QC, and QCSPIONs. All treatments (at the dose of 25 mg/kg) were dissolved in deionized water and gavaged for 35 consecutive days. RESULTS: At the end of the study, QCSPIONs possessed significantly better efficacy than free QC on the improvement of memory performance. In the Morris water maze test, QCSPIONs compared to free QC reduced much better the escape latency over training trials (P<0.01) and increased the time spent in the target quadrant in probe trial (P<0.001). In the passive avoidance test, it increased step-through latency (P<0.05) and reduced the time spent in the dark compartment (P<0.01). In addition, both free QC and QCSPIONs were able to prevent the changes in body weight and decrease blood glucose levels in diabetic rats (P<0.05). CONCLUSION: Overall, according to these results, we conclude that QC in the conjugated state with lower dose offers significantly higher potency in ameliorating diabetes-related memory impairment. Thus, this study offers an effective combined therapy for improving learning and memory.

Association of CAT C-262T and SOD1 A251G single nucleotide polymorphisms susceptible to gastric cancer.

Oxidative stress is known to be one of the major factors involved in the development and progression of cancer. Oxidative stress can occur due to an imbalance between concentrations of reactive oxygen species and antioxidant capacities. Catalase (CAT; OMIM 115500) and superoxide dismutase 1 (SOD1; OMIM 147450) play important roles in the primary defense against oxidative stress. In the present study, we investigated possible associations between polymorphisms of CAT C-262T (rs1001179) and SOD1 A251G (rs2070424) with susceptibility to gastric cancer. This case-control study included 160 gastric cancer patients and 241 age and gender frequency-matched healthy controls. Genotyping was done using PCR-RFLP based method. There were no significant differences in T allele frequencies in patients as compared to the controls in the CAT C-262T polymorphism (OR=0.80, 95% CI: 0.52- 1.23, P=0.304). Subjects with AG (OR=0.47, 95% CI: 0.24-0.91, P=0.026) or AG+GG (OR=0.45, 95% CI: 0.23-0.88, P=0.021) genotypes of the rs2070424 polymorphism were at lower risks of developing gastric cancer in comparison with the AA genotype. Our findings showed that there was no significant association between CAT C-262T polymorphism and gastric cancer susceptibility. However, we found that the G allele of the SOD1 A251G polymorphism has protective effects against the risk of gastric cancer.