Protective impact of Betanin against noise and scrotal hyperthermia on testicular toxicity in Wistar rat: Role of apoptosis, oxidative stress and inflammation.

The heat exposure and white noise can induce damage on reproductive organs. The main objective of this study is to observe, if betanin administration could ameliorate oxidative stress, apoptosis and inflammation in testis of rodents following noise and scrotal hyperthermia exposure. Wistar rats were divided into 6 groups; control, betanin, noise, hyperthermia and two treatment groups. Scrotal hyperthermia model was performed by heat exposure of rat testicular (43 °C) for 15 min and 3 times per weeks for 14 days. Noise induction model was done following exposure of rats with 100-dB noise level for 14 days and 8 h daily similar to real exposure condition in human. Betanin was administrated at the sub-effective dose (15 mg/kg) by gavage route for 4 weeks (5 times a week) to male rats. The animals were euthanized and testis were dissected and stored at -80 °C. Then, the oxidative stress biomarkers (MDA and GSH), apoptosis (cytochrome c & Annexin V), and inflammatory cytokines (TNF-α & IL-6) were measured by the real time polymerase chain reaction (RT-PCR) of testis collected samples. The data output demonstrates the impact of noise and hyperthermia in testicular toxicity induction by mitigating oxidative damage, apoptosis and inflammatory mediators. Following treatment with 15 mg/kg per day of betanin, lipid peroxidation and GSH content have been modulated, and TNF-α and IL-6 gene expression has been declined. Our results revealed that in Wistar rats, betanin displays protective effects against noise and scrotal hyperthermia-induced acute testicular toxicity through the inhibition of oxidative stress, apoptosis, and inflammation.

The role of gender differences in the outcome of juvenile social isolation: Emphasis on changes in behavioral, biochemical and expression of nitric oxide synthase genes alteration.

Social isolation can cause serious problem in performance of individuals in community. As gender differences may cause variation results in the severity of depressive behavior and response of patients to therapy, the impact of gender and the interaction of the level of endocrine secretion in depression were investigated in this study. Wistar rats of both sexes were subjected to post-weaning social isolation (PWSI) conditions and, together with the control group, experienced several behavioral tests including open-field Test (OFT), elevated plus maze (EPM), force swimming test (FST), splash test and novel object recognition test (NOR). Hippocampal tissue was isolated to measure biochemical factors such as nitric oxide level, FRAP amount, MDA level. In addition, real-time-PCR test was used to quantify the genes expression level of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS). On the other hand, sexual hormone levels in blood were measured. Both cognitive and behavioral f unctions were declined as the result of PWSI induction in male and diestrus female rats. The consequent surge of estradiol during estrous phase seems to suppress the accumulation of reactive oxygen species (ROS), and modulate iNOS and nNOS expression. In conclusion, while the pattern of PWSI in surge cellular antioxidants, raising cellular ROS level is gender-specific, this alleviation was in relation with the drop of estradiol and unrelated with testosterone level.

Mitotherapy inhibits against tenofovir induced nephrotoxicity on rat renal proximal tubular cells.

Tenofovir, as nucleotide reverse transcriptase inhibitors (NRTIs), is used to prevent and cure HIV/AIDS. Ample evidence confirmed that the nephrotoxicity of tenofovir has been linked to mitochondrial dysfunction. It seems that transplantation with healthy mitochondria instead of damaged mitochondria may be a beneficial approach to therapy. Therefore, it decided to investigate the impact of mitotherapy on tenofovir against renal proximal tubular cells (RPTCs) toxicity by measurement of oxidative stress and cytotoxicity biomarkers and restoring of mitochondrial function on isolated mitochondria. EC50 of tenofovir was achieved at 40 µM following 2 h incubation in Earle's solution (pH = 7.4; 37 °C). Freshly isolated mitochondria (80 µg/ml) were added to damage RPTCs affected by tenofovir in treated groups. One Way ANOVA analysis showed that healthy mitochondrial transplantation decreased oxidative stress biomarkers following tenofovir toxicity in RPTCs. Our data revealed that mitotherapy makes cell survival possible in RPTCs affected by tenofovir. In addition, it supposed that a novel and ideal strategy for the treatment of chemicals-induced nephrotoxicity.

Valine conjugated polymeric nanocarriers for targeted co-delivery of rivastigmine and quercetin in rat model of Alzheimer disease.

Multifunctional nanocarriers are increasingly promising for disease treatment aimed at finding effective therapy and overcoming barriers in drug delivery. Herein, valine conjugated chitosan (VLCS) was used for surface modification of nanocarriers (NCs) based on Poly (ε-caprolactone)-Poly (ethylene glycol)-Poly (ε-caprolactone) (PCL-PEG-PCL) triblock copolymers (NCs@VLCS). The nanocarriers were co-loaded with rivastigmine (RV) and quercetin (QT) to yield the final RV/QT-NCs@VLCS as a multifunctional nanocarrier for Alzheimer's disease (AD) treatment. The large amino acid transporter 1 (LAT-1) was selected for the direction of the NCs to the brain. The biocompatibility of the nanocarrier was studied in HEK-293 and SH-SY5Y cells and rats. The Morris water maze test demonstrated a faster regain of memory loss with RV/QT-NCs@VLCS compared to the other groups. Furthermore, RV/QT-NCs@VLCS and RV/QT-NCs improved GSH depletion induced by scopolamine (SCO), with RV/QT-NCs@VLCS having a superior effect. The real-time PCR analysis revealed that co-delivery of RV and QT by NCs@VLCS showed significantly higher efficacy than sole delivery of RV. RV/QT-NCs@VLCS treatment also modulated the expression of BDNF, ACHE, and TNF-α. The findings revealed that NCs@VLCS co-loaded with RV and QT, significantly increased efficacy relative to the single use of RV and could be considered a potent multifunctional drug delivery system for Alzheimer's treatment.

Edaravone Improves Streptozotocin-Induced Memory Impairment via Alleviation of Behavioral Dysfunction, Oxidative Stress, Inflammation, and Histopathological Parameters.

Alzheimer's disease (AD), as the main cause of dementia, has a progressive and neurodegenerative pattern with number of cases increasing over the next decades. Therefore, discovering an effective treatment with the ability to invert memory impairment and pathophysiological events of AD seems to be required. The present study performed to investigate the probable effects of Edaravone (EDV) in AD-like disorder induced by intracerebroventricular streptozotocin (ICV-STZ) administration in mice. This study also compares the two different methods of ICV-STZ in the memory impairment induction. NMRI male mice were administrated with 3 mg/kg of STZ for two times during 48 hours span, and after 24 hours, animals were treated with EDV (5 and 10 mg/kg), Donepezil, and Memantine for 14 days. After behavioral tests regarding memory and cognitive function, animals were sacrificed, and the hippocampi were utilized for further analyses. Our results demonstrated that administration of STZ induced memory impairment in the Morris water maze (MWM) test and decreased the discriminative factor in novel object recognition (NOR). The biochemical output shows a significant decrease in ferric reducing antioxidant power (FRAP) and glutathione (GSH) levels followed by increase in malondialdehyde (MDA) and protein carbonylation (PCO) levels. The output showed no difference between the patterns of AD-like disorder induction. Following our treatment groups, administration of EDV (5 and 10 mg/kg), Donepezil, and Memantine significantly improved memory performance and discriminatory behavior. Aforementioned treatments managed to improve FRAP and GSH content of hippocampus, while significantly attenuating MDA, PCO, and nitric oxide overproduction. In addition, no significant difference has been observed between the effect of 5 and 10 mg/kg EDV application. It was supposed that EDV managed to ameliorate memory dysfunction, discriminatory behavior, oxidative stress, and cellular antioxidant power in a dose-independent pattern in mice.

A worldwide systematic review, meta-analysis and meta-regression of nitrate and nitrite in vegetables and fruits.

This study aimed to conduct on the concentration of nitrate/nitrite (mg kg-1) in vegetables and fruits with a special emphasize on the effect of climate condition. The highest concentration (mean and 95%CI) of nitrate/nitrite was determined in Rocket (4825.15; 3044.14-6606.16), Mizuna (3500; 2702.48-4297.52), and Bok choy (3407.40; 2841.39-3973.42) in vegetable group and in wolfberry (2395.83; 1611.89-3179.77), Jack fruit (237.8; 202.88-272.71) and Cantaloupe (220.32; -224.53 to 665.19) in fruits group. Brazil (2816.77), Estonia (2133.76), Republic of China, Taiwan (2118.28) were the nations with the highest average concentration of nitrate/nitrite in all samples taken from these nations across the globe. Furthermore, Chinese fruits contain the highest concentrations of nitrates/nitrites of other countries (500.57; 416.74-584.41). Nitrate is present in greater quantities in fruits (44.02; 42.12-45.93) and vegetables (438.31; 422.51-454.11) than nitrite; however, the quantity of nitrite has a relatively similar content in both. Our findings revealed that increase in humidity (> 60%), annual rainfall (> 1500 mm), average temperature (> 10 °C) and application of fertilizers lead to significant increase in accumulation of nitrate/nitrite composition of vegetables and fruits (p < 0.05). According to the results of rating countries using the Food Security Index (GFSI), countries with high scores-like Poland and Portugal, which have GFSI scores of 75.5 and 78.7 and average contamination levels of 8.26 and 11.08, respectively-have a trend of average nitrate/nitrite levels of fruit and vegetable products that is significantly decreasing (p = 0.00). Although GFSI levels and other environmental variables can influence nitrate/nitrite levels, fertilizer usage (kg ha-1) is one of the most significant controllable and impactful factors in contaminants residue, which should be manage. The result of our study, will serve as a basis to estimate the dietary exposure to nitrates and nitrites from fruits and vegetables among populations around the world based on climatology and monitor the related health outcomes.

Melamine in Iranian foodstuffs: A systematic review, meta-analysis, and health risk assessment of infant formula.

The presence of melamine in food is one of the most significant threats to consumer health and food safety now confronting the communities. The goal of this systematic review and meta-analysis was to determine the melamine content of different food products available on the Iranian market. The pooled melamine concentration (95% confidence interval) on 484 samples of animal-based foodstuffs was as follows: 0.22 (0.08, 0.36 mg kg-1) for milk, 0.39 (0.25, 0.53 mg kg-1) for coffee mate, 1.45 (1.36, 1.54 mg kg-1) for dairy cream, 0.90 (0.50, 1.29 mg kg-1) for yoghurt, 1.25 (1.20, 1.29 mg kg-1) for cheese, 0.81 (-0.16, 1.78 mg kg-1) for hen eggs, 1.28 (1.25, 1.31 mg kg-1) for poultry meat, 0.58 (0.35, 0.80 mg kg-1) for chocolates, and 0.98 (0.18, 1.78 mg kg-1) for infant formula. Based on the results of health risk assessment study on toddlers under 2 years old who ingested infant formula (as a melamine-sensitive group), all groups of toddlers are at an acceptable level of non-carcinogenic risk (THQ ≤ 1). Toddlers were classified according to their ILCR (carcinogenic risk) levels due to infant formula consumption as follows: under 6 months (0.0000056), 6-12 months (0.0000077), 12-18 months (0.0000102), and 18-24 months (0.0000117). The melamine carcinogenicity in infant formula for children had an ILCR value of 0.000001-0.0001 in the investigation, which was considerable risk. According to the findings, Iranian food products (notably infant formula) should be analyzed for melamine contamination on a regular basis.

Enhancing the Neuroprotection Potential of Edaravone in Transient Global Ischemia Treatment with Glutathione- (GSH-) Conjugated Poly(methacrylic acid) Nanogel as a Promising Carrier for Targeted Brain Drug Delivery.

Ischemic stroke is the most common among various stroke types and the second leading cause of death, worldwide. Edaravone (EDV) is one of the cardinal antioxidants that is capable of scavenging reactive oxygen species, especially hydroxyl molecules, and has been already used for ischemic stroke treatment. However, poor water solubility, low stability, and bioavailability in aqueous media are major EDV drawbacks. Thus, to overcome the aforementioned drawbacks, nanogel was exploited as a drug carrier of EDV. Furthermore, decorating the nanogel surface with glutathione as targeting ligands would potentiate the therapeutic efficacy. Nanovehicle characterization was assessed with various analytical techniques. Size (199 nm, hydrodynamic diameter) and zeta potential (-25 mV) of optimum formulation were assessed. The outcome demonstrated a diameter of around 100 nm, sphere shape, and homogenous morphology. Encapsulation efficiency and drug loading were determined to be 99.9% and 37.5%, respectively. In vitro drug release profile depicted a sustained release process. EDV and glutathione presence in one vehicle simultaneously made the possibility of antioxidant effects on the brain in specific doses, which resulted in elevated spatial memory and learning along with cognitive function in Wistar rats. In addition, significantly lower MDA and PCO and higher levels of neural GSH and antioxidant levels were observed, while histopathological improvement was approved. The developed nanogel can be a suited vehicle for drug delivery of EDV to the brain and improve ischemia-induced oxidative stress cell damage.

Synergistic effects of combined therapy with cerebrolysin and enriched environment on anxiety-like behavior and spatial cognitive deficits in posttraumatic stress disorder-like mouse model.

Posttraumatic stress disorder (PTSD) is a serious neuropsychiatric disorder that occurs after exposure to stressful, fearful, or troubling events. Cerebrolysin (CBL), consists of low molecular weights neurotrophic factors and amino acids obtained from purified porcine brain proteins. This study aimed to evaluate the possible therapeutic effects of enriched environment (EE) and CBL alone or combined for reducing anxiety and cognitive deficits in PTSD-like mouse models. For this purpose, inescapable electric foot shocks were delivered to Balb/c mice for two consecutive days. Then mice were treated with CBL (2.5 mL/kg) and/or were kept in EE (2 h per day) or received their combination for 14 consecutive days. The hole-board test and Lashley III paradigm were used to assess anxiety and spatial learning and memory, respectively. Changes in the serum corticosterone level and expression of synaptic elements, including; growth-associated protein 43, post-synaptic density 95, and synaptophysin were assessed in the hippocampus. This model caused anxiety and spatial memory impairment associated with increased serum corticosterone levels and decreased synaptic elements. Nevertheless, CBL and/or combination treatment could reverse behavioral and molecular alterations. Our findings indicated that CBL, separately or in combination with EE, is effective in reducing anxiety and spatial memory impairment in PTSD-like mice.

Metformin attenuates depressive-like behaviour of methamphetamine withdrawal in mice: A mechanistic approach.

OBJECTIVES: Methamphetamine (METH) as a potent psychostimulant drug with a high potency of dependence rate that results in neurotoxicity has become a major drug of abuse in many parts of the world. Unfortunately, there is limited evidence regarding treatment of METH withdrawal syndrome. Therefore, we aimed to investigate whether metformin mitigate the methamphetamine (METH) withdrawal syndrome in male mice. Based on the literature, depression and anxiety are the major METH withdrawal symptoms. METHODS: Here, METH (2 mg/kg) was administered to mice twice a day for 14 constitutive days to induce animal model of METH-induced withdrawal syndrome. To do this, mice in control group and those with METH withdrawal syndrome were divided into treatment (receiving metformin in 3 doses of 50, 100 and 200 mg/kg for 10 days) and non-treatment sub-groups. Following the behavioural test, the animals were sacrificed; their hippocampus was dissected to measure oxidative stress parameters and expression of cellular energy homeostasis and immune-inflammatory genes. RESULTS: Our data revealed that metformin provoked antidepressant effects in behavioural tests through AMPK overexpression as an important mitochondrial energetic sensor and inhibition of Tlr4 overexpression in the immune system gene expression. In addition, metformin was able to improve oxidative stress biomarkers and neuronal damage in the hippocampus and restore cellular energy homeostasis and immune system gene expression. CONCLUSIONS: The data suggested that metformin can influence the hippocampus through targeting mitochondria and their performance, and consequently, neuroinflammation responses and brain metabolic changes. It is supposed to be a new therapeutic option in clinical trials of depression and anxiety following METH withdrawal treatment.

Correlation between coenzyme Q10 content and the nutrient sensors in AKI induced by Hemiscorpius lepturus envenomation.

Introduction: Acute kidney injury (AKI) may have a negative effect on mitochondrial hemostasis and bioenergetics as well as coenzyme Q10 (CoQ10) content. PGC-1α, AMPK, sirtuin 1 (Sirt1), and Sirt3, as the key metabolic regulators under nutritional stress, stimulate energy production via mitochondrial biogenesis during AKI. However, no report is available on the relationship between CoQ10 level and nutrient sensors in the pathophysiology of AKI caused by Hemiscorpius lepturus scorpion envenomation. Methods: Three doses of venoms (1, 5, and 10 mg/kg) were administered by subcutaneous (SC) injection to male albino mice. The animals were sacrificed 1 day or 7 days after administration of venom and their kidneys were collected to analyze gene expression involved in AKI, nutrient sensors, and apoptosis signaling activation by real-time polymerase chain reaction (PCR) and the measurement of CoQ10 level using the High-performance liquid chromatography (HPLC) method. Results: The data indicated a significant decrease in CoQ10 level after the administration of venom in 5 and 10 mg/kg. In addition, 1 day after the treatment, a significant over-expression of Sirt1 (5 and 10 mg/kg) was observed compared with normal mice. Overexpression of Sirt3 occurred 1 day and 7 days after treatment only at the dose of 5.0 mg/kg of venom. Furthermore, over-expression of AMPK as an important mitochondrial energetic sensor happened 1 day and 7 days after the injection of venom (5 mg/kg) (P < 0.01). The significant increase in the gene expression of caspase-9 and 3 after the injection of venom (5 and 10 mg/kg) confirmed the role of cell death signaling. Conclusion: The venom-induced energy-sensing pathways have a key role in gene expression of PGC-1α, AMPK, Sirt3, and CoQ10 content after venom-induced AKI.

Thymus daenensis extract prevents scopolamine­induced memory impairment through declining oxidative stress in rats.

Memory and cognitive impairment induced by oxidative stress are among the main hallmarks of Alzheimer's disease's (AD) pathology. The present study aimed to investigate the potential neuroprotective effects of Thymus daenensis (T. daenensis) extract against scopolamine­induced memory impairment and oxidative stress in rats. T. daenensis, widely distributed in Iran and Europe, is known to be a rich source of natural antioxidants and has been traditionally used for various medical purposes. The present study investigated the post­treatment effects of T. daenensis on learning and memory functions, antioxidant cellular defense, and oxidative stress using the scopolamine rat model of AD. The experiments were performed by intraperitoneal injection of scopolamine for 10 consecutive days in Wistar male rats (180-220 g). Additionally, the animals received T. daenensis extract (50­200 mg/kg) by gavage for 14 consecutive days after induction of memory impairment. The animals were divided into 8 groups, namely: control, 200 mg/kg of T. daenensis extract (D200), donepezil (DON), scopolamine (ALZ), ALZ animals treated with different doses of the extract (ALZ+D50 or 100 or 200 mg/kg) and ALZ animals treated with (ALZ+DON). The animals were then subjected to the Morris water maze (MWM) paradigm as a standard criterion for memory function assessment, and after extracting the brain tissues, the related biochemical oxidative stress parameters were determined in the brain. Our results indicated that T. daenensis extract significantly improved animals' performance in the MWM while significantly reducing oxidative stress and antioxidant imbalance. Furthermore, the extract did not show hepatotoxic effects on treated animals. In addition, the extract treatment significantly decreased both cellular malondialdehyde (MDA) and protein carbonyl (PCO) content while conversely increasing the total reduced glutathione (GSH) content and also the levels of total and endogenous antioxidants in the ferric reducing antioxidant power (FRAP) assay. It seems that the administration of T. daenensis significantly improved both cellular biochemical aspects and memory performance in animal models. Conclusively, it could be beneficial for scopolamine­induced neurotoxicity.

The impacts of vorinostat on NADPH oxidase and mitochondrial biogenesis gene expression in the heart of mice model of depression.

The comorbidity of depression and high risk of cardiovascular diseases (CVD) have been reported as major health problems. Our previous study confirmed that fluoxetine (FLX) therapy had a significant influence on brain function but not on the heart in depression. In the present study, suberoyanilide hydroxamic acid (SAHA) was proposed as another therapeutic candidate for treatment of depression comorbid CVD in maternal separation model, following behavioral analyses and gene expression level in the heart. Our data demonstrated that SAHA significantly attenuates the NOX-4 gene expression level in treated mice with SAHA and FLX without significant change in NOX-2 expression level. SAHA decreased the gene expression level of peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) and nuclear respiratory factors (Nrf2) in heart tissues of maternally separated mice. It supposed that non-effectiveness of FLX on mitochondrial biogenesis and NOX gene expression level in the heart of depressed patient can be related to recurrence of depression. It revealed that SAHA not only reversed the depressive-like behavior similar to our previous data but also recovered the heart mitochondrial function via effect on NOX-2, NOX-4, and mitochondrial biogenesis genes' (PGC-1α, Nrf-2, and peroxisome proliferator-activated receptor-α (PPAR-α)) expression levels. We suggest performing more studies to confirm SAHA as a therapeutic candidate in depression comorbid CVD.

Protective effects of Vinca herbaceous extract against scopolamine-induced behavioral disturbances and brain oxidative stress in rats.

Ethnopharmacological relevance: Alzheimer's disease (AD) as the most common type of dementia, is affecting the life of many senior individuals around the world. Vinca herbacea Waldst. & Kit. (V. herbacea) as a middle east originated plant demonstrated antioxidant and antitumor effects. This plant traditionally used to treat diabetes and hypertension, but its mechanism remains unclear. Aim of the study: In the present study, post-treatment effects of V. herbacea on learning and memory functions, antioxidant cellular defense and oxidative stress were investigated using the scopolamine rat model of AD. Materials and methods: Wistar male rats (170-190 g) were administered Scopolamine, an anti-muscarinic drug, (2 mg/kg) for 10 days followed by V. herbacea extract (200, 300 and 400 mg/kg) and/or donepezil (DON; 1 mg/kg, which were administered before behavioral studies for 10 consecutive days. All the rats were then subjected to Morris water maze (MWM) task. Biochemical parameters of oxidative stress were quantified using the whole brain. Results: Our data showed significant decrease performance in target quadrant in water maze task following administration of scopolamine (SCOP). Also, V. herbacea and DON, did not induce any neurotoxicity and hepatotoxic effects at the highest utilized doses in healthy rats. Treatment with V. herbacea extract (200&400 mg/kg) and DON improved memory performance significantly in comparison with AD rats. In addition, V. herbacea extract in AD rats exhibited a decrease in malondialdehyde (MDA) and protein carbonyl (PCO) levels and an increase in total antioxidant capacity (FRAP) and glutathione (GSH) amounts in brain and liver. Conclusion: It seems that cholinergic deficits and oxidative stress are consistently associated with Alzheimer's disease (AD). The richness of V. herbacea in case of indole alkaloids and flavonoids confirms the potentials of this herb in management of oxidative stress, resorting synaptic acetylcholine level and improving cellular antioxidant resources.

Mitigated Oxidative Stress and Cognitive Impairments in Transient Global Ischemia using Niosomal Selegiline-NBP delivery.

Stroke is the most common reason for adult disabilities and the second ground for death worldwide. Our previous study revealed that selegiline serves as an alternative candidate in transient hypoxia-ischemia. However, aggressive and restless behavior was observed in stroke-induced rats receiving 4 mg/kg selegiline. In comparison, 1 mg/kg selegiline could induce negligible therapeutic effects on mitochondrial dysfunction and histopathological changes. Therefore, we designed oral noisome-based selegiline attached to 4-(4-nitrobenzyl) pyridine to improve transient global ischemia by attenuating cognitive impairments, oxidative stress, and histopathological injury. The investigation was performed in transient hypoxia-ischemia-induced rats by oral administration of nanoformulation containing selegiline (0.25-1 mg/kg) for 4 weeks (3 times a week). Novel object recognition (NOR) was considered to evaluate their cognitive dysfunction. Oxidative stress parameters and brain histopathological assessments were determined following the scarification of rats. Outstandingly, our data demonstrated slower selegiline release from niosomes relative to free drug, which was also in a controlled manner. Our data confirmed significant improvement in cognitive behavior in the NOR test, an increase in glutathione level and total antioxidant power, a decline in MDA and protein carbonyl level, as well as a decreased number of dead cells in histopathological assessment after being exposed to (0.5-1 mg/kg) selegiline-NBP nanoformulation. These data manifested that the selegiline-NBP nanoformulation (0.5-1 mg/kg) could significantly reduce oxidative damage, cognitive dysfunction, and histopathological damage compared to transient hypoxia-ischemia rats, which is 20 times lower than the therapeutic dose in humans. Therefore, the proposed nanoformulation would be capable as an alternative candidate without side effects in stroke.

Self-assembled magnetic polymeric micelles for delivery of quercetin: Toxicity evaluation on isolated rat liver mitochondria.

Multifunctional nanocarriers as a promising platform could provide numerous opportunities in the field of drug delivery. Drug carriers loaded with both magnetic nanoparticles (MNPs) and therapeutic agents would allow the combination of chemotherapy with the possibility of monitoring or controlling the distribution of the nano vehicles in the body which may improve the effectiveness of the therapy. Furthermore, by applying these strategies, triggering drug release and/or synergistic hyperthermia treatment are also reachable. This study aimed to explore the potential of the quercetin (QUR) loaded magnetic nano-micelles for improving drug bioavailability while reducing the drug adverse effects. The bio-safety of developed QUR loaded magnetic nano-micelles (QMNMs) were conducted via mitochondrial toxicity using isolated rat liver mitochondria including glutathione (GSH), malondialdehyde (MDA), and the ferric reducing ability of plasma (FRAP). QMNMs with a mean particle size of 85 nm (PDI value of 0.269) and great physical stability were produced. Also, TEM images indicated that the prepared QMNMs were semi-spherical in shape. These findings also showed that the constructed QMNMs, as a pH-sensitive drug delivery system, exhibited a stable and high rate of QUR release under mildly acidic conditions pH (5.3) compared to neutral pH (7.4). The most striking result to emerge from the data is that an investigation of various mitochondrial functional parameters revealed that both QMNMs and QUR have no specific mitochondrial toxicity. Altogether, these results offer overwhelming evidence for the bio-safety of QMNMs and might be used as an effective drug delivery system for targeting and stimuli-responsive QUR delivery.

Neuroprotective Effect of Apigenin on Depressive-Like Behavior: Mechanistic Approach.

Apigenin, as a natural flavonoid present in several plants is characterized with potential anticancer, antioxidant, and anti-inflammatory properties. Recent studies proposed that apigenin affects depression disorder through unknown mechanistic pathways. The effects of apigenin's anti-depressive properties on streptozocin-mediated depression have been investigated through the evaluation of behavioral tests, oxidative stress, cellular energy homeostasis and inflammatory responses. The results demonstrated anti-depressive properties of apigenin in behavioral test including forced swimming and splash tests and oxidative stress biomarkers such as reduced glutathione, lipid peroxidation, total antioxidant power and coenzyme Q10 levels. Apigenin, also, demonstrated its regulatory potency in cellular energy homeostasis and immune system gene expression through inhibiting Nlrp3 and Tlr4 overexpression. Furthermore, failure in energy production as the key factor in various psychiatric disorders was reversed by apigenin modulating effect on AMPK gene expression. Overall, 20 mg/kg of apigenin was recognized as the dose suitable for minimizing the undesirable adverse effects in the STZ-mediated depression model proposed in this study. Our data suggested that apigenin could be able to adjust behavioral dysfunction, biochemical biomarkers and recovered cellular antioxidant level in depressed animals. The surprising results were achieved by raise in COQ10 level, which could regulate the overexpression of the AMPK gene in stressful conditions. The regulatory effect of apigenin in inflammatory signaling pathways such as Nlrp3, and Tlr4 gene expression was studied at the surface part of the hippocampus.

The effects of minocycline in improving of methamphetamine withdrawal syndrome in male mice.

Methamphetamine (METH) is a potent psychostimulant drug with an increasing rate of abuse over recent years. Depressive-like behaviors are one of the major symptoms patients in the METH withdrawal period experience. There is limited evidence regarding the METH withdrawal treatment, and conventional managements are not completely effective. Furthermore, extensive promising literature supports minocycline, a well-known antibiotic with anti-oxidant, anti-inflammatory properties, to treat depressive-like behaviors. Therefore, we hypothesized that administration of minocycline might mitigate the methamphetamine (METH) induced depression in male mice. Administration of METH (2 mg/kg) to mice two times a day for 14 constitutive days was done to induce the METH-induced withdrawal syndrome model. Animals were divided into 10 groups (n = 10 in each group), and three doses of minocycline (2.5, 5 and 10 mg/kg) were daily administered to male albino mice for 10 days. Following the behavioral test, the animals were scarified, their hippocampus were dissected to measure oxidative stress parameters. Our data revealed that chronic administration of minocycline provoked antidepressant effects in behavioral tests, such as forced swim test (FST), tail suspension test (TST) and splash test. Additionally, minocycline was able to improve oxidative stresses and neuronal damage in the hippocampus and restore the body's antioxidant system by increasing glutathione (GSH) and the cellular energy (ATP) and reducing the malondialdehyde (MDA) level. According to our promising results of minocycline on targeting mitochondria and its performance, we suggest minocycline as a new therapeutic option in clinical trials of depression treatment.

Magnetic nanostructured lipid carrier for dual triggered curcumin delivery: Preparation, characterization and toxicity evaluation on isolated rat liver mitochondria.

In this research, magnetic nanostructured lipid carriers (Mag-NLCs) were synthesized for curcumin (CUR) delivery. NLCs are drug-delivery systems prepared by mixing solid and liquid (oil) lipids. For preparation of NLCs, cetylpalmitate was selected as solid lipid and fish oil as liquid lipid. CUR-Mag-NLCs were prepared using high-pressure homogenization technique and were characterized by methods including X-ray diffraction (XRD), transmission electron microscopy (TEM), vibrating sample magnetometer (VSM), and dynamic light scattering (DLS). The CUR-Mag-NLCs were developed as a particle with a size of 140 ± 3.6 nm, a polydispersity index of 0.196, and a zeta potential of -22.6 mV. VSM analysis showed that the CUR-Mag-NLCs have excellent magnetic properties. Release rate of the drug was higher at 42 °C than 37 °C, indicating that release of the synthesized nanoparticles is temperature-dependent. Evaluation of mitochondrial toxicity was done using the isolated rats liver mitochondria including glutathione (GSH), malondialdehyde (MDA), and the ferric- reducing ability of plasma (FRAP) assays to study biosafety of the CUR-Mag-NLCs. Results of In vitro study on the isolated mitochondria revealed that both CUR-Mag-NLCs and curcumin have no specific mitochondrial toxicity.

Investigation of therapeutic effect of curcumin α and ß glucoside anomers against Alzheimer's disease by the nose to brain drug delivery.

Alzheimer's disease (AD) is one of the greatest geriatric medicinal challenges of our century and is the main disease leading to dementia. Despite extensive scientific research advances, available disease-modifying treatment strategies remained limited; thus, increasing demand for new drugs. In recent years, medicinal plants attracted attention due to their potential role in dementia. In the present study, α and ß anomers of curcumin glucosides (CGs) were synthesized and evaluated for Alzheimer's treatment. CGs were synthesized by fusion reaction as a novel and easy method with more advantages (high yield, short reaction time, and low chemicals), and the products were characterized using HNMR. Wistar male rats were used to administer different treatments. They divided into control, sham, Alzheimer, and test groups (Alzheimer + α anomer and Alzheimer + ß anomer). Animals received normal saline, Scopolamine (1 mg/kg), high dose anomers, scopolamine, and two doses (12.5 and 25 mg/kg) of anomers, respectively, for 10 days. Then the Morris Water Maze (MWM) test was performed on all animals. Finally, the animals' brains were extracted and homogenized for glutathione, acetylcholine esterase activity, protein carbonyl, and lipid peroxide level detection. The escape latency and the distance towards the hidden platform in Morris water maze in the Alzheimer group were significantly higher than both the control and test groups. Besides, there were no significant differences between sham and control groups in all tests. Both anomers led to a significant increase in glutathione, and acetylcholine levels while they caused a decrease in lipid peroxidation and protein carbonyl levels in brain tissue. It seems that intranasal administration of both anomers positively influenced maze learning in scopolamine receiving subjects. Although both anomers resulted in similar biochemistry tests, a higher dose of ß anomer indicated better results than α anomer not only in behavioral tests but also in biochemical tests.