Metformin accelerates myelin recovery and ameliorates behavioral deficits in the animal model of multiple sclerosis via adjustment of AMPK/Nrf2/mTOR signaling and maintenance of endogenous oligodendrogenesis during brain self-repairing period

BACKGROUND: Multiple sclerosis (MS) is a devastating autoimmune disorder characterized by oligodendrocytes (OLGs) loss and demyelination. In this study, we have examined the effects of metformin (MET) on the oligodendrogenesis, redox signaling, apoptosis, and glial responses during a self-repairing period (1-week) in the animal model of MS. METHODS: For induction of demyelination, C57BL/6 J mice were fed a 0.2% cuprizone (CPZ) for 5 weeks. Thereafter, CPZ was removed for 1-week and molecular and behavioral changes were monitored in the presence or absence of MET (50 mg/kg body weight/day). RESULTS: MET remarkably increased the localization of precursor OLGs (NG2+/O4+ cells) and subsequently the renewal of mature OLGs (MOG+ cells) in the corpus callosum via AMPK/mammalian target of rapamycin (mTOR) pathway. Moreover, we observed a significant elevation in the antioxidant responses, especially in mature OLGs (MOG+/nuclear factor erythroid 2-related factor 2 (Nrf2+) cells) after MET intervention. MET also reduced brain apoptosis markers and lessened motor dysfunction in the open-field test. While MET was unable to decrease active astrogliosis (GFAP mRNA), it reduced microgliosis by down-regulation of Mac-3 mRNA a marker of pro-inflammatory microglia/macrophages. Molecular modeling studies, likewise, confirmed that MET exerts its effects via direct interaction with AMPK. CONCLUSIONS: Altogether, our study reveals that MET effectively induces lesion reduction and elevated molecular processes that support myelin recovery via direct activation of AMPK and indirect regulation of AMPK/Nrf2/mTOR pathway in OLGs. These findings facilitate the development of new therapeutic strategies based on AMPK activation for MS in the near future. KEYWORDS: AMPK; Cuprizone; Multiple sclerosis; Nrf2; mTO

The Effects of Different Dose of Chronic Ritalin on the Brain of Prepubertal Female Balb/C Mice

Background Methylphenidate (MPH) is commonly prescribed for children who have been diagnosed with attention deficit hyperactivity disorder (ADHD); however, the action mechanisms of methylphenidate have not been fully elucidated. Studies have shown a relationship between apoptosis signaling pathways and psychiatric disorders, as well as therapeutic targets for such disorders. So, we examined the effects of chronic methylphenidate administration on the brain of mice. Materials and Methods Animals were administered MPH at doses of 2, 5 and 10 mg/kg for 60 days.  At the age of three months and in estrous phase, brian tissues were removed and washed in cold phosphate-buffered saline and some of them were frozen at -80oC for Western blot analysis. We measured the levels of pro-apoptotic protein, Bax and anti-apoptoticprotein, Bcl-2, in the brain of neonate female Balb/c mice. The rest of the brains were fixed in formalin (10% phosphate-buffered, pH = 7.4). Then samples were embedded in paraffin according to routine histologic procedures. Results: Our results showed that MPH with a dose of 10 mg/kg causes a considerable increase in the level of the Bax protein as compared with other groups. In contrast, in the partial cortex of female mice under treatment with high dose of MPH (10 mg/kg) could less Bcl2 levels as compared with 5 mg/kg MPH. However, 5 mg/kg MPH have a significant effect on Bcl2 levels compare with each of mentioned doses (

Dalteparin as a Novel Therapeutic Agent to Prevent Diabetic Encephalopathy by Targeting Oxidative Stress and Inflammation

Introduction: Hepcidin is the main modulator of systemic iron metabolism, and its role in the brain has been clarified recently. Studies have shown that hepcidin plays an important role in neuronal iron load and inflammation. This issue is of significance because neuronal iron load and inflammation are pathophysiological processes that are highly linked to neurodegeneration. Moreover, the activity of hepcidin has recently been manipulated to recover the neuronal impairment caused by brain inflammation in animal models. Methods: Streptozotocin (STZ) was used to induce type 1 diabetes. Male Wistar rats (n = 40) with a weight range of 200–250 g were divided into control, diabetic, diabetic + insulin, and diabetic + dalteparin groups. Dalteparin (100 mg/kg IP) and insulin (100 mg/kg SC) were administered for 8 weeks. At the end of the experiment, Y-maze and passive avoidance tasks were carried out. The animals were perfused randomly and their hippocampal tissue was isolated for the analysis of markers such as lipid peroxidation like Malondialdehyde (MDA), hepcidin expression, iron, and ferritin. Blood samples were taken for the measurement of serum inflammatory cytokine Interleukin (IL)-6. Results: The findings indicated that treatment with dalteparin reduced IL-6, MDA, ferritin, and hepcidin expression in diabetic rats compared to treatment with insulin (P<0.05). Moreover, treatment with dalteparin did not decrease the iron level or prevented its decline. Conclusion: Treatment with dalteparin improved the cognitive dysfunctions and symptoms of Alzheimer disease in STZ-induced diabetic rats by appropriately modulating and reducing oxidative stress and neuroinflammation. This may enhance the existing knowledge of therapeutics to reduce cognitive impairment in diabetes and is suggested to be a potential therapeutic agent in diabetes

The Effect of Aqueous Extract of Fennel (Foeniculum Vulgare) on Kidney in BALB/C Adult Male Mic

Background & Objective: Fennel as a medicinal plant has a long history of use in traditional herbal medicine. But there have been few reports of this drug toxicity in different tissues. In this study, the effect of aqueous extract of fennel on the kidneys of adult male BALB/C mice and renal blood factors was investigated. Materials & Methods: In this study, 40 adult male BALB/C mice in the range of 20-22 g were used. Mice were divided into 5 groups. Group 1: Control, Group 2: Sham, that received normal saline intraperitoneal (IP) for 14 days. Experimental groups received doses of 50, 100 and 200 mg/kg of body weight of the aqueous extract of fennel IP for 14 days. After 14 days of treatment, the mice were anesthetized and after blood sampling from the heart, their kidneys were removed for pathology examination. Histological sections were prepared and stained with H & E and investigated by the optical microscope. Data were analyzed using SPSS software. Result: The mean number of glomeruli, cortex thickness, vascular occlusion, leukocyte infiltration and other histologic indices in the group received 200 mg/kg of an aqueous extract of fennel had a significant difference with control group. However, weight, BUN, creatinine and medulla thickness indices did not have any significant difference with the control group. Conclusion: The results showed that aqueous extract of fennel at doses of 50 and 100 mg/kg had no toxic effects on parenchyma and renal cells, but dose of 200 mg/kg had toxic effects on the kidney

The Association Between Fennel Extract, Serum Lipid Profile, and Leptin Receptor Expression

Introduction: Obesity is among the most severe challenges of our era, with significant health consequences and a high economic burden for health systems. Therefore, many countries have developed political agendas to cope with this ever-rising challenge. Along with chemical medications developed to manage obesity, researchers have focused on some natural ingredients and herbal extracts that are effective in reducing weight. The current study investigated the association between Foeniculum vulgar (fennel) extracts and body weight, lipid profile, and leptin.  Methods: In total, 35 adult male BALB/c mice were investigated in sham, fennel 50 mg/kg, fennel 100 mg/kg, and fennel 200 mg/kg (n=7) groups. The mice were administered fennel extracts for fourteen days while weighted at the intervention’s beginning and end. Then, their weight, lipid profile, serum leptin, and expression of leptin protein in the hypothalamus were measured. Results: After providing the intervention, leptin receptor protein expression was increased in all groups, while serum leptin didn’t change significantly. Moreover, a significant decrease was observed in the cholesterol dose of 100 mg/kg/day, triglycerides in 100 and 200 mg/kg/day, and LDL in 50 and 100 mg/kg/day. Serum HDL was increased significantly in a dose of 100 mg/kg/day.  Conclusion: Fennel extract can decrease the lipid profile by changing the expression of the leptin receptor

DNA Methylation in Cancer: Epigenetic View of Dietary and Lifestyle Factors

Background: Alterations in DNA methylation play an important role in cancer development and progression. Dietary nutrients and lifestyle behaviors can influence DNA methylation patterns and thereby modulate cancer risk. Introduction: To comprehensively review available evidence on how dietary and lifestyle factors impact DNA methylation and contribute to carcinogenesis through epigenetic mechanisms. Materials and methods: A literature search was conducted using PubMed to identify relevant studies published between 2005 and 2022 that examined relationships between dietary/lifestyle factors and DNA methylation in cancer. Studies investigating the effects of dietary components (eg, micronutrients, phytochemicals), physical activity, smoking, and obesity on global and gene-specific DNA methylation changes in animal and human cancer models were included. Data on specific dietary/lifestyle exposures, cancer types, DNA methylation targets and underlying mechanisms were extracted. Results: Multiple dietary and lifestyle factors were found to influence DNA methylation patterns through effects on DNA methyltransferase activity, methyl donor availability, and generation of oxidative stress. Altered methylation of specific genes regulating cell proliferation, apoptosis, and inflammation were linked to cancer development and progression. Conclusion: Dietary and lifestyle interventions aimed at modulating DNA methylation have potential for both cancer prevention and treatment through epigenetic mechanisms. Further research is needed to identify actionable targets for nutrition and lifestyle-based epigenetic therapies

Effect of Aqueous Extract of Foeniculum Vulgare on Thyroid Hormones and the Expression of its Receptors in the Ovaries of BALB/C Mice

Background & Objective: Fennel (Foeniculum vulgare) is one of the ancient plants that has various medicinal effects. The main hormones produced by the thyroid gland are thyroxine (T4) and triiodothyronine (T3), which regulate the body's growth and development. Thyroid hormones have two receptors called TRα and TRβ in different tissues. The present study aimed to investigate the effect of fennel aqueous extract on serum levels of thyroid hormones and the expression of thyroid receptors in ovarian tissue. Materials & Methods: In this study, 40 female Balb/C mice weighing 18-20 g were used. Mice were divided into 5 groups of 8 including control, sham and intraperitoneal (IP) injection of 50, 100 and 200 mg/kg aqueous fennel extract for 14 days. The blood samples were then taken from the heart to measure thyroid hormone. The ovarian tissue was also sampled for real time thyroid receptor expression by PCR. Results: Serum thyroid hormones, T3 and T4 were not changed by aqueous extract of fennel. The expression of receptor β did not have any significant change, but the expression of receptor α increased significantly by the 200 mg/kg of aqueous extract of fennel. The weights of the rats in 200 mg/kg of fennel decreased significantly. Conclusion: Fennel may increase ovarian response to thyroid hormones in high dose

Evaluation of the neuroprotective effects of electromagnetic fields and coenzyme Q 10 on hippocampal injury in mouse

Electromagnetic fields (EMFs) are reported to interfere with chemical reactions involving free radical production. Coenzyme Q(10) (CoQ10) is a strong antioxidant with some neuroprotective activities. The purpose of this study was to examine and compare the neuroprotective effects of EMF and CoQ10 in a mouse model of hippocampal injury. Hippocampal injury was induced in mature female mice (25-30g), using an intraperitoneal injection of trimethyltin hydroxide (TMT; 2.5mg/kg). The experimental groups were exposed to EMF at a frequency of 50Hz and intensity of 5.9mT for 7hr daily over 1 week or treated with CoQ10 (10mg/kg) for 2 weeks following TMT injection. A Morris water maze apparatus was used to assess learning and spatial memory. Nissl staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) tests were also performed for the histopathological analysis of the hippocampus. Antiapoptotic genes were studied, using the Western blot technique. The water maze test showed memory improvement following treatment with CoQ10 and coadministration of CoQ10+EMF. The Nissl staining and TUNEL tests indicated a decline in necrotic and apoptotic cell count following treatment with CoQ10 and coadministration of CoQ10+EMF. The Western blot study indicated the upregulation of antiapoptotic genes in treatment with CoQ10, as well as coadministration. Also, treatment with EMF had no significant effects on reducing damage induced by TMT in the hippocampus. According to the results, EMF had no significant neuroprotective effects in comparison with CoQ10 on hippocampal injury in mice. Nevertheless, coadministration of EMF and CoQ10 could improve the neuroprotective effects of CoQ10

Evaluation of the neuroprotective effects of electromagnetic fields and coenzyme Q10 on hippocampal injury in mouse

Electromagnetic fields (EMFs) are reported to interfere with chemical reactions involving free radical production. Coenzyme Q10 (CoQ10) is a strong antioxidant with some neuroprotective activities. The purpose of this study was to examine and compare the neuroprotective effects of EMF and CoQ10 in a mouse model of hippocampal injury. Hippocampal injury was induced in mature female mice (25–30 g), using an intraperitoneal injection of trimethyltin hydroxide (TMT; 2.5 mg/kg). The experimental groups were exposed to EMF at a frequency of 50 Hz and intensity of 5.9 mT for 7 hr daily over 1 week or treated with CoQ10 (10 mg/kg) for 2 weeks following TMT injection. A Morris water maze apparatus was used to assess learning and spatial memory. Nissl staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) tests were also performed for the histopathological analysis of the hippocampus. Antiapoptotic genes were studied, using the Western blot technique. The water maze test showed memory improvement following treatment with CoQ10 and coadministration of CoQ10 + EMF. The Nissl staining and TUNEL tests indicated a decline in necrotic and apoptotic cell count following treatment with CoQ10 and coadministration of CoQ10 + EMF. The Western blot study indicated the upregulation of antiapoptotic genes in treatment with CoQ10, as well as coadministration. Also, treatment with EMF had no significant effects on reducing damage induced by TMT in the hippocampus. According to the results, EMF had no significant neuroprotective effects in comparison with CoQ10 on hippocampal injury in mice. Nevertheless, coadministration of EMF and CoQ10 could improve the neuroprotective effects of CoQ10. keywords:CoQ10 electromagnetic fields (EMFs) neuroprotective effect trimethyltin hydroxide (TMT