The Effect of Physical Exercise Pretreatment on Spatial Memory and Learning and Function of Mitochondria in the Brain in Type 2 Diabetic Rats.

Background: The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide, and this issue is one of the major concerns in the pending years. T2DM causes numerous complications, including cognition, learning, and memory impairments. The positive effect of physical exercise as a popular approach has been shown in many chronic diseases. Further, the improvement effects of exercise on cognition and memory impairment have been noticed. Objectives: This study examines the possible preventative effects of physical exercise on spatial memory attenuation and brain mitochondrial dysfunction caused by T2DM. Methods: Male Wistar rats received treadmill exercise (30 min per day, five days per week for two or four weeks). Then, T2DM was induced by a high-fat diet and an injection of streptozotocin (30 mg/kg). Spatial learning and memory were assessed by the Morris water maze test. Further, brain mitochondrial function, including reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP), mitochondrial swelling, outer membrane damage, cytochrome c release, and ADP/ATP ratio, were measured. Results: Impaired spatial memory in T2DM rats was observed. Furthermore, brain mitochondrial dysfunction was demonstrated proved by increased ROS generation, MMP collapse, mitochondrial swelling, outer membrane damage, cytochrome c release, and ADP/ATP ratio. Conversely, physical exercise, before diabetes onset, significantly ameliorated spatial memory impairment and brain mitochondrial dysfunction. Conclusions: This study reveals that physical exercise could prevent diabetes-induced spatial memory impairment. Moreover, it could ameliorate brain mitochondrial dysfunction as one of the possible underlying mechanisms of spatial memory impairment in T2DM.

Protective effect of a standardized Allium jesdianum extract in an Alzheimer's disease induced rat model.

Alzheimer's disease (AD) is a complex disorder with multiple underlying mechanisms. Existing treatment options mostly address symptom management and are associated with numerous side effects. Therefore, exploring alternative therapeutic agents derived from medicinal plants, which contain various bioactive compounds with diverse pharmacological effects, holds promise for AD treatment. This study aims to assess the protective effects of the hydroalcoholic extract of Allium jesdianum on cognitive dysfunction, mitochondrial and cellular parameters, as well as genetic parameters in an intracerebroventricular Streptozotocin (icv-STZ) induced rat model of AD. Male Wistar rats were injected with a single dose of STZ (3 mg/kg, icv) to establish a sporadic AD model. A. jesdianum extract (100, 200, and 400 mg/kg/day) and donepezil (5 mg/kg/day) were orally administered for 14 days following model induction. Cognitive function was evaluated using the radial arm water maze test. Mitochondrial toxicity parameters in various brain regions (whole brain, frontal cortex, hippocampus, and cerebellum) were assessed. Gene expression analysis of miR-330, miR-132, Bax, and Bcl-2 in isolated rat brain neurons was performed using RT-qPCR. A. jesdianum extract significantly attenuated cognitive dysfunction and mitigated mitochondrial toxicity induced by icv-STZ administration. Following STZ injection, there was upregulation of Bax gene expression and downregulation of miR-330, miR-132, and Bcl-2 gene expression. Treatment with A. jesdianum extract resulted in the reversal of the expression of these microRNAs and genes, indicating its potential for improving AD and reducing neuronal apoptosis. This study demonstrates the neuroprotective capabilities of A. jesdianum against STZ-induced oxidative stress and cognitive impairment in rats, highlighting its therapeutic potential in the management of AD.

Inhalation of multi-wall carbon nanotubes changes the expression of apoptosis and cancer genes in rat brain and lungs.

One of the important issues in urban areas is air pollution which causes respiratory disorders. A significant association between exposure to inhaled particulate matter (PM), mainly ultrafine particles, and increased neurological and pulmonary morbidity and mortality was observed in some research. This study aimed to demonstrate the relation between multi-wall carbon nanotubes (MWCNTs) inhalation and the carcinogenic effect of these materials in the brain and lungs. For this purpose, we investigated gene expression in rat brain and lung tissues induced by exposure to MWCNTs. Rats were exposed to MWCNTs in diameters of 10 and 100 nm (pure and impure) at a concentration of 5 mg/m3. Exposure was done through a whole-body exposure chamber for 5 h/day, 5 days/week for 14 days. After exposure, both brain and lung tissues were isolated to evaluate certain gene expressions including Bax, Bcl2, Rac1, Tp53, Mmp12, and Arc. The results showed that exposure to impure and pure MWCNTs (10 and 100 nm) at a concentration of 5 mg/m3 causes up-regulation or down-regulation of some of these genes. The results suggest that impure and pure MWCNTs (10 and 100 nm) can increase the risk of central nervous system disorders such as Alzheimer's disease and increase the risk of carcinogenesis in the lung tissues of rats exposed to MWCNTs (Tab. 2, Fig. 2, Ref. 64). Text in PDF www.elis.sk Keywords: multi-wall carbon nanotube, inhalation, gene expression, carcinogenicity, brain, lung.

Toxicity effect of sesquiterpene lactones from Jurinea gabrieliae bornm on mitochondria isolated from U87 cells.

Sesquiterpene lactones (SLs) are a typical group of secondary metabolites in asteraceae family and well-known for their biologically potential in treatment of various diseases such as cancer and inflammation. Glioblastoma (GBM) is a most common brain malignancy in adults with poor prognosis. Finding phytochemicals with potential targeting mitochondria has been suggested as an important approach for many malignancies. In this study, we purified three guaianolide-type SLs, including 8-deacyloxy-8α-(methylacryloxy)-subluteolide (A), subluteolide (B) and janerin (C) from Jurinea gabrieliae Bornm by chromatography methods. Then, mitochondrial toxicity parameters were evaluated. All three SLs selectively inhibited SDH activity in mitochondria from U87 cells but not mitochondria from normal rat brain. In addition these SLs increased ROS formation and cytochrome c release and MMP collapse only in mitochondria from U87 cells but not normal rat neurons. Our results suggest that all three SLs may act as potential agents for future development in anti-glioma therapy.

Anti-Glioma Effect of Pseudosynanceia melanostigma Venom on Isolated Mitochondria from Glioblastoma Cells

Background: Glioblastoma is the most common primary malignant tumor of the central nervous system that occurs in the spinal cord or brain. Pseudosynanceia melanostigma is a venomous stonefish in the Persian Gulf, which our knowledge about is little. This study's goal is to investigate the toxicity of stonefish crude venom on mitochondria isolated from U87 cells. Methods: In the first stage, we extracted venom stonefish and then isolated mitochondria have exposed to different concentrations of venom. Finally, mitochondrial toxicity parameters (Succinate dehydrogenase (SDH) activity, Reactive oxygen species (ROS), cytochrome c release, Mitochondrial Membrane Potential (MMP), and mitochondrial swelling) have evaluated. Results: To determine mitochondrial parameters, we used 115, 230, and 460 µg/ml concentrations. The results of our study show that the venom of stonefish selectively increases upstream parameters of apoptosis such as mitochondrial swelling, cytochrome c release, MMP collapse and ROS. Conclusion: This study suggests that Pseudosynanceia melanostigma crude venom has selectively caused toxicity by increasing active mitochondrial oxygen radicals. This venom could potentially be a candidate for the treatment of glioblastoma.

Apigenin ameliorates oxidative stress and mitochondrial damage induced by multiwall carbon nanotubes in rat kidney mitochondria.

The toxicity of carbon nanotubes (CNTs) toward the mitochondria of the kidney is not fully recognized and still needs further research. Apigenin (APG) is known as a flavonoid compound and natural antioxidant. The purpose of this study was to assess the ameliorative role of APG against multiwall CNT (MWCNT)-induced kidney toxicity in rats. The animals were administrated with APG (10 mg/kg) for 2 weeks and then were exposed to MWCNTs (5 mg/m3 ) in pure and impure forms (10 and 100 nm) for 5 h/day and 5 days/week. Then, mitochondria were isolated from the kidney tissue and mitochondrial toxicity parameters were measured. Decreases in succinate dehydrogenase activity have been reported in all groups exposed to MWCNTs. Results indicated that MWCNTs in both forms and sizes were able to increase the generation of reactive oxygen species, decline mitochondrial membrane potential, induce mitochondrial swelling, and release cytochrome c in isolated kidney mitochondria. The pretreatment of APG decreased all the abovementioned mitochondrial damage and oxidative stress parameters induced by both pure and impure MWCNTs. Our results showed that MWCNTs have the ability to enter the body, subsequently, cross cellular barriers, and reach the kidney as a sensitive organ, which can result in mitochondrial damage in kidney cells including renal tubular cells. In addition, APG can be an effective nutritional antioxidant regimen against MWCNT-induced kidney damage.

Correction to: Toxicity of multi-wall carbon nanotubes inhalation on the brain of rats.

This research was financially supported by National Institute for Medical Research Development (NIMAD).

Toxicity of Pioglitazone on Mitochondria Isolated from Brain and Heart: An Analysis for Probable Drug-Induced Neurotoxicity and Cardiotoxicity.

Pioglitazone (PG) is one of the thiazolidinedione (TZDs) drugs used in diabetic patients. TZDs are known as peroxisome proliferator-activated receptor gamma (PPARγ) agonists. Mitochondria are considered as one of the targets of these drugs. The mechanisms of the effect of PG on mitochondria are not well understood. In this study, we investigated the effect of PG on mitochondria isolated from brain and heart. Mitochondrial parameters such as succinate dehydrogenase (SDH) activity, reactive oxygen species (ROS) generation, collapse in mitochondrial membrane potential (MMP), mitochondrial swelling and cytochrome c release were evaluated. The results showed that PG at concentrations of 12.5, 25 and 50 µg/ml increased the generation of ROS, the collapse of MMP, mitochondrial swelling and the release of cytochrome c in mitochondria isolated from both brain and heart tissues. The underlying mechanisms of PG induced neuro-toxicity and cardio-toxicity may be associated with changes in mitochondrial function, ROS generation (oxidative stress), and changes in the mitochondrial membrane.

Toxicity of multi-wall carbon nanotubes inhalation on the brain of rats.

This study was designed to investigate the brain toxicity following the respiratory contact with multi-wall carbon nanotubes (MWCNTs) in male Wistar rats. Rats were exposed to 5 mg/m3 MWCNT aerosol in different sizes and purities for 5 h/day, 5 days/week for 2 weeks in a whole-body exposure chamber. After 2-week exposure, mitochondrial isolation was performed from different parts of rat brain (hippocampus, frontal cortex, and cerebellum) and parameters of mitochondrial toxicity including mitochondrial succinate dehydrogenase (SDH) activity, generation of reactive oxygen species (ROS), mitochondrial membrane potential (MMP) collapse, mitochondrial swelling, and cytochrome c release, ATP level, mitochondrial GSH, and lipid peroxidation were evaluated. Our results demonstrated that MWCNTs with different characteristics, in size and purity, significantly (P < 0.05) decreased SDH activity, GSH, and ATP level, and increased mitochondrial ROS production, lipid peroxidation, mitochondrial swelling, MMP collapse, and cytochrome c release in the brain mitochondria. In conclusion, we suggested that MWCNTs with different characteristics, in size and purity, induce damage in varying degrees on the mitochondrial respiratory chain and increase mitochondrial ROS formation in different parts of rat brain (hippocampus, frontal cortex, and cerebellum).

Contrasting Role of Concentration in Rivaroxaban Induced Toxicity and Oxidative Stress in Isolated Kidney Mitochondria.

Rivaroxaban as a small molecule is able to directly and reversibly inhibit the factor Xa. This study was designed to figure out the evaluation effect of rivaroxaban on mitochondria obtained from rat kidneys. We isolated mitochondria from rat kidneys using gradient centrifugation. Then, the toxicity parameters including succinate dehydrogenase (SDH) activity, reactive oxygen species (ROS) formation, mitochondrial swelling, mitochondrial membrane potential (MMP) collapse and cytochrome c release were measured in kidneys mitochondria following the exposure to rivaroxaban. The results showed that rivaroxaban (1.4 and 2.8 mM) raised the reactive oxygen species (ROS) generation, swelling in the mitochondria, collapse in the mitochondrial membrane potential (MMP) and cytochrome c release in the mitochondria isolated from kidneys. While, rivaroxaban at a higher concentration of 5.6 mM showed the opposite effect compared to other lower concentrations. The results indicate that rivaroxaban may have antioxidant effects at high concentrations. The results suggest that rivaroxaban (5.6 mM) has protective effects against oxidative stress and mitochondrial toxicity.

Human Placental Extract Ameliorates Structural Lung Changes Iinduced by Amiodarone in Rats.

Amiodarone is used in treatment of cardiac arrhythmias. Therapeutic use of amiodarone is limited by its side effects, including pulmonary toxicity. Human Placenta Extract (HPE) contains a variety of bio-active substances. Thus, the present study aimed to quantitatively evaluate the protective effects of HPE on the structural lung changes induced by amiodarone using stereological methods. Sprague-Dawley male rats were divided into four groups. The first, second, and third groups received no treatment, amiodarone (100 mg/kg, i.p.), and HPE (500 µL/kg, i.p.), respectively. The fourth group was treated with amiodarone + HPE. The animals' lungs were removed after 10 days. The lung volume was estimated using the Cavalieri principle on the embedded and cut tissue and corrected for shrinkage. The volume density of the parenchyma, alveolar space, and septa were estimated using point-counting method. The surface area of the alveoli, the volume-weighted means alveoli volume, and mean septum thickness were also estimated in all groups. The total volume and thickness of the alveolar septum were increased by 40 % and 28 %, respectively. However, the total volume of the alveolar space was decreased by 31 % in the amiodarone treated-rats. The mean alveolar volume was decreased by 64 % on the average in the amiodarone treated group. Yet, these changes were not detected in the amiodarone+HPE group. Moreover, RBC accumulation in the alveolar space and septa was ameliorated after HPE treatment. HPE can protect the lung tissue from the structural changes induced by amiodarone.