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

Benefit of magnesium-25 carrying porphyrin-fullerene nanoparticles in experimental diabetic neuropathy

Diabetic neuropathy (DN) is a debilitating disorder occurring in most diabetic patients without a viable treatment yet. The present work examined the protective effect of 25Mg-PMC16 nanoparticle (porphyrin adducts of cyclohexil fullerene-C60) in a rat model of streptozotocin (STZ)-induced DN. 25Mg-PMC16 (0.5 lethal dose50 [LD50]) was administered intravenously in two consecutive days before intraperitoneal injection of STZ (45 mg/kg). 24Mg-PMC16 and MgCl2 were used as controls. Blood 2,3-diphosphoglycerate (2,3-DPG), oxidative stress biomarkers, adenosine triphosphate (ATP) level in dorsal root ganglion (DRG) neurons were determined as biomarkers of DN. Results indicated that 2,3-DPG and ATP decreased whereas oxidative stress increased by induction of DN which all were improved in 25Mg-PMC16-treated animals. No significant changes were observed by administration of 24Mg-PMC16 or MgCl2 in DN rats. It is concluded that in DN, oxidative stress initiates injuries to DRG neurons that finally results in death of neurons whereas administration of 25Mg-PMC16 by release of Mg and increasing ATP acts protectively

Alteration of hepatocellular antioxidant gene expression pattern and biomarkers of oxidative damage in diazinon-induced acute toxicity in Wistar rat

In the present survey, the plasma level of diazinon after acute exposure was measured by HPLC method at a time-course manner. In addition, the impact of diazinon on the expression of the key genes responsible for hepatocellular antioxidative defense, including PON1, GPx and CAT were investigated. The increase in oxidative damages in treated rats was determined by measuring LPO, protein carbonyl content and total antioxidant power in plasma. After administration of 85 mg/kg diazinon in ten groups of male Wistar rats at different time points between 0-24 hours, the activity of AChE enzyme was inhibited to about 77.94 %. Significant increases in carbonyl groups and LPO after 0.75 and 1 hours were also observed while the plasma antioxidant power was significantly decreased. Despite the dramatic reduction of GPX and PON1 gene expression, CAT gene was significantly upregulated in mRNA level by 1.1 fold after 4 hours and 1.5-fold after 24 hours due to diazinon exposure, compared to control group. Furthermore, no significant changes in diazinon plasma levels were found after 4 hours in the treated rats. The limits of detection and quantification were 137.42 and 416.52 ng/mL, respectively. The average percentage recoveries from plasma were between 90.62 % and 95.72 %. In conclusion, acute exposure to diazinon increased oxidative stress markers in a time-dependent manner and the changes were consistent with effects on hepatic antioxidant gene expression pattern. The effect of diazinon even as a non-lethal dose was induced on the gene expression of antioxidant enzymes. The change in antioxidant defense system occurs prior to diazinon plasma peak time. These results provide biochemical and molecular evidence supporting potential acute toxicity of diazinon and is beneficial in the evaluation of acute toxicity of other organophosphorus pesticides as well

Stability of Doxycycline Absorbed on Root Canal Dentin After Obturation with Gutta-Percha/AH26 and Resilon/RealSeal at Different Time Intervals

Objective: Eradication of microorganisms present in the root canal system is paramount for the successful outcome of root canal therapy. The purpose of this study was to compare the of doxycycline absorbed from MTAD into root canal dentin after obturation with gutta-percha/AH26 and Resilon/RealSeal at different time intervals.Materials and Methods: Fifty-one extracted human teeth were instrumented. Thirty samples were obturated with either gutta-percha/AH26 or Resilon/self-etch RealSeal after final irrigation with MTAD. Fifteen samples were kept unobturated (positive control); six samples were obturated with either gutta-percha/AH26 or Resilon/self-etch RealSeal without MTAD irrigation (negative control).After aging for 1, 3 or 6 weeks, dentin debri were collected, the Doxycycline compound was extracted and its amount was quantified using high performance liquid chromatography. The statistical significance of the change in Doxycycline concentrations was tested with two-way ANOVA.Results: The mean concentration of Doxycycline in dentin for one, three and six-week guttapercha/AH26 samples was 1.8±0.36, 1.22±0.22 and 0.67±0.11 respectively, whereas these concentrations in Resilon/RealSeal samples were 1.60±0.26, 0.80±0.14 and 0.59±0.01 respectively. Regarding the positive control group, these concentrations were 2.09±0.11, 1.54±0.12 and 0.72±0.07 respectively for 1, 3 and 6-week intervals. No Doxycycline was detected in negative control groups. The Doxycycline concentrations showed a significant difference forobturating materials (p=0.008). These concentrations were higher in the gutta-percha/AH26 samples than Resilon/RealSeal samples in each time interval.Conclusion: The remaining amount of Doxycycline bonded to dentin was higher when root canals were obturated with gutta-percha/AH26 compared to Resilon/RealSeal. The stability of Doxycycline showed a time dependent decrease

Emerging Role of Enhancer RNAs as Potential Diagnostic and Prognostic Biomarkers in Cancer

Enhancers are distal cis-acting elements that are commonly recognized to regulate gene expression via cooperation with promoters. Along with regulating gene expression, enhancers can be transcribed and generate a class of non-coding RNAs called enhancer RNAs (eRNAs). The current discovery of abundant tissue-specific transcription of enhancers in various diseases such as cancers raises questions about the potential role of eRNAs in disease diagnosis and therapy. This review aimed to demonstrate the current understanding of eRNAs in cancer research with a focus on the potential roles of eRNAs as prognostic and diagnostic biomarkers in cancers

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

Bionanocomposite Active Packaging Material Based on Soy Protein Isolate/Persian Gum/Silver Nanoparticles; Fabrication and Characteristics

In this study, nanocomposite active films were fabricated containing silver nanoparticles (SNPs) embedded within soy protein isolate (SPI)/Persian gum (PG) matrices. The physical, mechanical, and antibacterial properties of these composite films were then characterized. In addition, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD) were used to provide information about the microstructure, interactions, and crystallinity of the films. Pure SPI films had poor physicochemical attributes but the addition of PG (0.25, 0.5, or 1 wt%) improved their water vapor permeability, mechanical properties, and water solubility (WS). The moisture content (MC) of the films decreased after the introduction of PG, which was attributed to fewer free hydroxyl groups to bind to the water molecules. Our results suggest there was a strong interaction between the SPI and the PG and SNPs in the films, suggesting these additives behaved like active fillers. Optimum film properties were obtained at 0.25% PG in the SPI films. The addition of PG (0.25%) and SNPs (1%) led to a considerable increase in tensile strength (TS) and a decrease in elongation at break (EB). Furthermore, the incorporation of the SNPs into the SPI/PG composite films increased their antibacterial activity against pathogenic bacteria (Escherichia coli and Staphylococcus aureus), with the effects being more prominent for S. aureus. Spectroscopy analyses provided insights into the nature of the molecular interactions between the different components in the films. Overall, the biodegradable active films developed in this study may be suitable for utilization as eco-friendly packaging materials in the food industry

Bionanocomposite Active Packaging Material Based on Soy Protein Isolate/Persian Gum/Silver Nanoparticles; Fabrication and Characteristics

In this study, nanocomposite active films were fabricated containing silver nanoparticles (SNPs) embedded within soy protein isolate (SPI)/Persian gum (PG) matrices. The physical, mechanical, and antibacterial properties of these composite films were then characterized. In addition, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD) were used to provide information about the microstructure, interactions, and crystallinity of the films. Pure SPI films had poor physicochemical attributes but the addition of PG (0.25, 0.5, or 1 wt%) improved their water vapor permeability, mechanical properties, and water solubility (WS). The moisture content (MC) of the films decreased after the introduction of PG, which was attributed to fewer free hydroxyl groups to bind to the water molecules. Our results suggest there was a strong interaction between the SPI and the PG and SNPs in the films, suggesting these additives behaved like active fillers. Optimum film properties were obtained at 0.25% PG in the SPI films. The addition of PG (0.25%) and SNPs (1%) led to a considerable increase in tensile strength (TS) and a decrease in elongation at break (EB). Furthermore, the incorporation of the SNPs into the SPI/PG composite films increased their antibacterial activity against pathogenic bacteria (Escherichia coli and Staphylococcus aureus), with the effects being more prominent for S. aureus. Spectroscopy analyses provided insights into the nature of the molecular interactions between the different components in the films. Overall, the biodegradable active films developed in this study may be suitable for utilization as eco-friendly packaging materials in the food industry

Molecular Evidence on the Inhibitory Potential of Metformin against Chlorpyrifos-Induced Neurotoxicity

Chlorpyrifos (CPF) is an organophosphorus (OP) pesticide, resulting in various health complications as the result of ingestion, inhalation, or skin absorption, and leads to DNA damage and increased oxidative stress. Metformin, derived from Galega officinalis, is reported to have anti-inflammatory and anti-apoptotic properties; thus, this study aimed to investigate the beneficial role of metformin in neurotoxicity induced by sub-acute exposure to CPF in Wistar rats. In this study, animals were divided into nine groups and were treated with different combinations of metformin and CPF. Following the 28 days of CPF and metformin administration, brain tissues were separated. The levels of inflammatory biomarkers such as tumor necrosis factor alpha (TNFα) and interleukin 1β (IL-1β), as well as the expression of 5HT1 and 5HT2 genes, were analyzed. Moreover, the levels of malondialdehyde (MDA), reactive oxygen species (ROS), and the ADP/ATP ratio, in addition to the activity of acetylcholinesterase (AChE) and superoxide dismutase (SOD), were tested through in vitro experiments. This study demonstrated the potential role of metformin in alleviating the mentioned biomarkers, which can be altered negatively as a result of CPF toxicity. Moreover, metformin showed protective potential in modulating inflammation, as well as oxidative stress, the expression of genes, and histological analysis, in a concentration-dependent manner