Neuroprotective Therapeutic Potential of microRNA-149-5p against Murine Ischemic Stroke.

Ischemic stroke resulting from blockade of brain vessels lacks effective treatments, prompting exploration for potential therapies. Among promising candidates, microRNA-149 (miR-149) has been investigated for its role in alleviating oxidative stress, inflammation, and neurodegeneration associated with ischemic conditions. To evaluate its therapeutic effect, male Wistar rats were categorized into five groups, each consisting of 27 rats: sham, MCAO, lentiviral control, lentiviral miR-149, and miR149-5p mimic. Treatments were microinjected intracerebroventricularly (ICV) (right side), and ischemia was induced using middle cerebral artery occlusion (MCAO) procedure. Post-MCAO, neurological function, histopathological changes, blood-brain barrier (BBB) permeability, cerebral edema, and mRNA levels of Fas ligand (Faslg) and glutamate ionotropic NMDA receptor 1 (GRIN1) were assessed, alongside biochemical assays. MiR-149 administration improved neurological function, reduced brain damage, preserved BBB integrity, and attenuated cerebral edema. Upregulation of miR149-5p decreased Faslg and GRIN1 expression in ischemic brain regions. MiR-149 also reduced oxidative stress, enhanced antioxidant activity, decreased caspase-1 and - 3 activity, and modulated inflammatory factors in ischemic brain regions. Moreover, DNA fragmentation as an index of cell death decreased following miR-149 treatment. In conclusion, the study underscores miR-149 potential as a neuroprotective agent against ischemic stroke, showcasing its efficacy in modulating various mechanisms and supporting its candidacy as a promising therapeutic target for innovative strategies in stroke treatment.

Reversing valproic acid-induced autism-like behaviors through a combination of low-frequency repeated transcranial magnetic stimulation and superparamagnetic iron oxide nanoparticles.

Transcranial magnetic stimulation (TMS) is a neurostimulation device used to modulate brain cortex activity. Our objective was to enhance the therapeutic effectiveness of low-frequency repeated TMS (LF-rTMS) in a rat model of autism spectrum disorder (ASD) induced by prenatal valproic acid (VPA) exposure through the injection of superparamagnetic iron oxide nanoparticles (SPIONs). For the induction of ASD, we administered prenatal VPA (600 mg/kg, I.P.) on the 12.5th day of pregnancy. At postnatal day 30, SPIONs were injected directly into the lateral ventricle of the brain. Subsequently, LF-rTMS treatment was applied for 14 consecutive days. Following the treatment period, behavioral analyses were conducted. At postnatal day 60, brain tissue was extracted, and both biochemical and histological analyses were performed. Our data revealed that prenatal VPA exposure led to behavioral alterations, including changes in social interactions, increased anxiety, and repetitive behavior, along with dysfunction in stress coping strategies. Additionally, we observed reduced levels of SYN, MAP2, and BDNF. These changes were accompanied by a decrease in dendritic spine density in the hippocampal CA1 area. However, LF-rTMS treatment combined with SPIONs successfully reversed these dysfunctions at the behavioral, biochemical, and histological levels, introducing a successful approach for the treatment of ASD.

Therapeutic Potential of Diosgenin in Amelioration of Carbon Tetrachloride-Induced Murine Liver Injury.

Diosgenin is a sapogenin with antidiabetic, antioxidant, and anti-inflammatory properties. The current study investigated whether diosgenin could ameliorate carbon tetrachloride (CCL4)-induced liver injury. To cause liver injury, CCL4 was injected intraperitoneally twice a week for 8 weeks. Daily oral administration of diosgenin at doses of 20, 40, and 80 mg/kg was started one day before CCL4 injection and continued for 8 weeks. Finally, serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and also albumin were assessed. Catalase and superoxide dismutase (SOD) activities in addition to glutathione (GSH) and malondialdehyde (MDA) levels were also quantified in the liver homogenate and routine histological evaluation was also conducted. Elevated serum levels of liver enzymes and decreased serum level of albumin caused by CCL4 were significantly restored following diosgenin administration at doses of 40 and 80 mg/kg. Long-term administration of CCL4 increased inflammatory and apoptotic factors such as IL-1ß, caspase 3, TNF-α, and IL-6 and decreased SOD and catalase activities as well as GSH level in liver homogenates; while MDA level was increased. Treatment with diosgenin increased SOD and catalase activities and GSH levels in the liver of injured animals. In addition, liver MDA, IL-1ß, caspase 3, TNF-α, and IL-6 level or activity decreased by diosgenin treatment. Additionally, diosgenin aptly prevented aberrant liver histological changes. According to obtained results, diosgenin can dose-dependently diminish CCl4-induced liver functional deficits and histological changes in a dose-dependent manner, possibly due to its antioxidant and anti-inflammation properties, and its beneficial effect is comparable to known hepatoprotective agent silymarin.

Protective Effect of Baclofen on Ovarian Cystogenesis and Morphine-Induced Lipid Profile Change in Female Rats.

Introduction: Morphine induces ovarian cysts that cause obesity and disrupt sex hormone secretion. Baclofen, a gamma-aminobutyric acid receptor agonist, can help regulate sex hormones and reduce harmful blood lipids by protecting against morphine-induced gamma-aminobutyric acid inhibition. We investigated the prophylactic effect of baclofen in rats receiving morphine by comparing with the untreated groups. Materials and Methods: Forty eight female Wistar rats were randomly divided into several groups, including control (saline 1 mL/kg, i.p.), morphine (5 mg/kg, i.p.), baclofen (10, 20, and 30 mg/kg, i.p.), and baclofen (10, 20, and 30 mg/kg) before morphine (5 mg/kg). Twenty four hours after the treatment, blood and serum samples were taken to check the levels of gonadotropins (LH & FSH) and lipid profile. The ovaries and uterus were also studied, and a proinflammatory nitric oxide (NO) diagnostic test was completed. The results were analyzed using analysis of variance (α = 0.05). Results: In comparison with the control group, the levels of LH and not FSH decreased in the morphine group and the number of ovarian cysts was more in the morphine group. These problems were not observed in the group of baclofen alone and baclofen + morphine. However, the triglyceride level increased slightly in the baclofen 30 mg/kg + morphine group. But the LDL level somewhat decreased. The proinflammatory NO system did not show significant activation in the ovary and uterus, except for the baclofen 10 mg/kg + baclofen group. Conclusion: Morphine can cause ovarian cysts by lowering LH but baclofen prophylaxis can protect reproductive properties by adapting major metabolic changes.

Kolaviron neuroprotective effect against okadaic acid-provoked cognitive impairment.

Alzheimer's disease (AD) is acknowledged as the main causative factor of dementia that affects millions of people around the world and is increasing at increasing pace. Okadaic acid (OA) is a toxic compound with ability to inhibit protein phosphatases and to induce tau protein hyperphosphorylation and Alzheimer's-like phenotype. Kolaviron (KV) is a bioflavonoid derived from Garcinia kola seeds with anti-antioxidative and anti-inflammation properties. The main goal of this study was to assess whether kolaviron can exert neuroprotective effect against okadaic acid-induced cognitive deficit. Rats had an intracerebroventricular (ICV) injection of OA and pretreated with KV at 50 or 100 mg/kg and examined for cognition besides histological and biochemical factors. OA group treated with KV at 100 mg/kg had less memory deficit in passive avoidance and novel object discrimination (NOD) tasks besides lower hippocampal levels of caspases 1 and 3, tumor necrosis factor α (TNFα) and interleukin 6 (IL-6) as inflammatory factors, reactive oxygen species (ROS), protein carbonyl, malondialdehyde (MDA), and phosphorylated tau (p-tau) and higher level of acetylcholinesterase (AChE) activity, mitochondrial integrity index, superoxide dismutase (SOD), and glutathione (GSH). Moreover, KV pretreatment at 100 mg/kg attenuated hippocampal CA1 neuronal loss and glial fibrillary acidic protein (GFAP) reactivity as a factor of astrogliosis. In summary, KV was able to attenuate cognitive fall subsequent to ICV OA which is partly mediated through its neuroprotective potential linked to mitigation of tau hyperphosphorylation, apoptosis, pyroptosis, neuroinflammation, and oxidative stress and also improvement of mitochondrial health.

Literature review on hepatoprotective effects of diosgenin: possible mechanisms of action.

Liver diseases are among the major causes of death worldwide. Alcohol consumption, obesity, diabetes mellitus, viral infection, and drug-induced liver injury are common risk factors for the development of liver diseases. Diosgenin is a herbal steroidal sapogenin with hepatoprotective properties. This phytosteroid modulates lipid profile and prevents liver injury and fibrosis, metabolic associated fatty liver disease (MAFLD), steatohepatitis, and diabetes mellitus. Different mechanisms have been presented underlying the therapeutic properties of diosgenin. Diosgenin with antioxidant activity and ability to inhibit pro-inflammatory and apoptotic mediators as well as modulating gut microbiota is able to protect the liver. This literature overview summarizes the previously published studies regarding the hepatoprotective function of diosgenin against liver injury in different conditions with an emphasis on possible underlying mechanisms.

Simvastatin improves learning and memory impairment via gut-brain axis regulation in an ovariectomized/D-galactose Alzheimer's rat model.

AIM: Alzheimer's disease (AD) is the most prevalent form of dementia with multiple etiology and no effective remedy. Statins are a group of medicines that are basically used to lower cholesterol. However, several studies have recently done to assess the potential relationship between statins use and dementia but presented controversial results. METHODS: In this study, using ovariectomy and D-galactose injection, a model of AD was induced in female rats, and then the protective effects of oral administration of simvastatin were investigated. shuttle box and Y-maze tests were done to assess the animals' learning and memory performance. Using GC-MC, ELISA, Immunohistochemistry and tissue staining techniques, changes in the amount of short-chain fatty acids (SCFAs), plasma and hippocampus neuroinflammatory markers and histological changes in the intestine and hippocampus were assessed in sham, disease and treatment groups. KEY FINDINGS: Oral administration of simvastatin improved the gut microbiome activity (increased the amount of SCFAs in fecal samples) and strengthened the tight junctions of intestinal cells. Moreover, simvastatin reduced the amount of TNF-α and IL-1ß in plasma and hippocampus. Also, cell death and Amyloid plaques notably decreased in the simvastatin-treated hippocampal tissue. All these physiological changes led to better performance in behavioral tasks in the treatment group in comparison to the disease group. SIGNIFICANCE: These findings provide evidence that simvastatin may improve gut-brain axis followed by improvement in learning and memory via an anti-inflammatory effect.

Chronic acetyl-L-carnitine treatment alleviates behavioral deficits and neuroinflammation through enhancing microbiota derived-SCFA in valproate model of autism.

Autism spectrum disorder is characterized by a variety of cellular and molecular abnormalities which leads to autism-associated behaviors. Besides behavioral defects, these individuals also suffer from various associated disorders such as gastrointestinal deficit, altered gut microbiota composition and their metabolite. This study examined the effect of ALC on microbiota SCFA production and its effects on brain inflammation in VPA autism model. After prenatal exposure to valproate (600 mg/kg, i.p.) on embryonic day 12.5, followed by ALC treatment (100 mg/kg during postnatal days 23-51, p.o.), ASD-like behaviors, SCFAs amount in feces, intestine integrity (Occludin and ZO-1 tight junction proteins), systemic and brain inflammation (TNF-α and IL-1ß) were assessed. Then, Golgi-Cox staining and Western blot for Iba1 protein were utilized to identify the changes in microglia profile in cerebral cortex. In the VPA model, we found that induction of autism was associated with demoted levels of SCFAs in feces and disintegration of intestine tissue which led to elevated level of TNF-α in the plasma. Further, we characterized an increased number of microglia in our histology evaluation and Iba1 protein in cerebral cortex. We also observed elevated level of TNF-α and IL-1ß in the cerebral cortex of VPA rat. All these abnormalities were significantly alleviated by ALC treatment. Overall, our findings suggest that alleviation of behavioral abnormalities by ALC therapy in the VPA model of autism is associated with an improvement in the gut microbiota SCFAs, intestinal barrier and recovery of microglia and inflammation in the brain.

Valproate-induced murine autism spectrum disorder is associated with dysfunction of amygdala parvalbumin interneurons and downregulation of AMPK/SIRT1/PGC1α signaling.

Autism spectrum disorder (ASD) is a neurodevelopmental condition that is characterized by difficulty in social behavior and restricted behaviors. Also, in ASD, several accompanying disorders such as anxiety are observed. Considering the important role of amygdala in the pathophysiology of ASD, the present study focused on the neuronal changes and it possible signaling pathway in amygdala. After prenatal exposure to valproate (VPA; 600 mg/kg, i.p, on embryonic day 12.5), amount of ROS, MMP, caspase-3 activity, AMPK, SIRT1 and PGC1α proteins, and parvalbumin interneurons in the amygdala were assessed following evaluation of ASD and anxiety-like behaviors. Amygdala analysis revealed ROS accumulation and decreased MMP in autistic rats. In addition, caspase-3 activation elevated and immunoreactivity for parvalbumin interneurons decreased. These were accompanied by anxiety and autistic-like behaviors in open field test, elevated zero maze and U-Shaped 2 Choice Field maze. Also, our data showed that in the valproate group, protein levels of AMPK, SIRT1 and PGC1α reduced. Collectively, our results indicate that prenatal exposure to valproate leads to anxiety and autistic-like behaviors, partly through its targeting amygdala parvalbumin interneurons dysfunction and this might be affected by disturbed AMPK/SIRT1/PGC1α signaling pathway.

Acamprosate effect on neuropathic pain in rats: With emphasis on the role of ERK/MAPK pathway and SCN9A sodium channel.

BACKGROUND: Neuropathic pain is a chronic pain owing to nerve damage or diseases of the central nervous system (CNS). The expression of SCN9A, which encodes the Nav1.7 voltage-gated sodium channel and ERK have been found to change significantly in many cases of neuropathic pain. Here, we investigated effects of acamprosate on neuropathic pain, taking into account the crucial roles of SCN9A, the ERK signaling pathway, and inflammatory markers in a rat model of chronic constriction injury (CCI). METHODS: Acamprosate (300 mg/kg) was injected intraperitoneally (i.p.) for 14 days. The tail-immersion, acetone, and formalin tests were used to determine behavioral tests such as heat allodynia, cold allodynia, and chemical hyperalgesia, respectively. Lumbar spinal cord was extracted and processed for Nissl staining. The amount of spinal SCN9A expression and ERK phosphorylation were examined using ELISA assay. RESULTS: The expression of SCN9A, ERK, inflammatory cytokines (IL-6 and TNF-α), allodynia and hyperalgesia significantly increased on days 7 and 14 following CCI. The treatment not only reduced neuropathic pain but also blocked CCI's effects on SCN9A upregulation and ERK phosphorylation. CONCLUSION: This research demonstrated that acamprosate reduces the neuropathic pain induced by CCI of the sciatic nerve in rats by preventing cell loss, inhibiting spinal SCN9A expression, ERK phosphorylation, and inflammatory cytokines, suggesting potential therapeutic implications of acamprosate administration for the treatment of neuropathic pain.

Capsaicin protects against septic acute liver injury by attenuation of apoptosis and mitochondrial dysfunction.

Capsaicin is the main pungent bioactive constituent in red chili with promising therapeutic properties due to its anti-oxidative and anti-inflammatory effects. No evidence exists on the beneficial effect of capsaicin on apoptosis and mitochondrial function in acute liver injury (ALI) under septic conditions. For inducing septic ALI, lipopolysaccharide (LPS, 50 µg/kg) and d-galactose (D-Gal, 400 mg/kg) was intraperitoneally injected and capsaicin was given orally at 5 or 20 mg/kg. Functional markers of liver function and mitochondrial dysfunction were determined as well as hepatic assessment of apoptotic, oxidative, and inflammatory factors. Capsaicin at the higher dose appropriately decreased serum level of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in addition to reducing hepatic level of malondialdehyde (MDA), reactive oxygen species (ROS), nitrite, NF-kB, TLR4, IL-1ß, TNF-α, caspase 3, DNA fragmentation and boosting sirtuin 1, Nrf2, superoxide dismutase (SOD) activity, and heme oxygenase (HO-1). These beneficial effects of capsaicin were associated with reversal and/or improvement of gene expression for pro-apoptotic Bax, anti-apoptotic Bcl2, mitochondrial and metabolic regulators PGC-1α, sirtuin 1, and AMPK, and inflammation-associated factors. Additionally, capsaicin exerted a hepatoprotective effect, as revealed by its reduction of liver histopathological changes. These findings evidently indicate hepatoprotective property of capsaicin under septic conditions that can be attributed to its down-regulation of oxidative and inflammatory processes besides its potential to attenuate mitochondrial dysfunction and apoptosis.

Ursolic acid enhances the effect of exercise training on vascular aging by reducing oxidative stress in aged type 2 diabetic rats.

Ursolic acid (UA) mediates the vasorelaxant activity via nitric oxide (NO) release, and upregulation of endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs) in disease conditions with increased oxidative stress (OS). The present study aimed to reflect on the impact of 8 weeks of a combination of UA supplementation and resistance/endurance training in old male Wistar rats having a high-fat diet and/or low-dose streptozotocin-induced type 2 diabetes (HFD/STZ-induced T2D), with an emphasis on Sirtuin 1 (SIRT1)-endothelial nitric oxide synthase (eNOS) axis and OS indices in their aortic tissues. A total number of56 21-month-old male Wistar rats with HFD/STZ-induced T2D were randomized into seven groups (n = eight animals per group): (1) sedentary old nondiabetic (Control [C]); (2) sedentary HFD/STZ-induced T2D (Diabetic [D]); (3) sedentary HFD/STZ-induced T2D plus UA (Diabetic + Ursolic Acid [DU]); (4) endurance-trained HFD/STZ-induced T2D (Diabetic + Endurance Training [DE]); (5) resistance-trained HFD/STZ-induced T2D (Diabetic + Resistance Training [DR]); (6) endurance-trained HFD/STZ-induced T2D plus UA (Diabetic + Endurance Training + Ursolic Acid [DEU]); and (7) resistance-trained STZ-diabetic plus UA (Diabetic + Resistance Training + Ursolic Acid [DRU]) rats. The ladder-based resistance training group performed the ladder resistance training at 60% of the maximum voluntary carrying capacity (MVCC), 14-20 climbs in each session, with a one-min rest between each two trials, 5 days a week. The treadmill-based endurance exercise training protocol consisted of repeated bouts of high- and low-intensity training with 60-75% maximal running speed and 30%-40% maximal running speed in the course of 8 weeks, respectively. The animals in the supplement groups also took 500 mg of UA/kg of high-fat diet/day, resulting in a daily UA intake of approximately 250 mg UA per kg of body weight rat/day. The resistance/endurance training plus the UA consumption could partially reverse the levels of malondialdehyde (MDA), nitric oxide (NO), as well as total antioxidant capacity (TAC). It was concluded that oral 0.5% UA supplementation can prevent vascular aging biomarkers in a HFD/STZ-induced T2D model. Further studies are also required to clarify how chronic consumption of UA with/without training protocols reverses vascular aging process.

Metformin mitigates amyloid ß1-40-induced cognitive decline via attenuation of oxidative/nitrosative stress and neuroinflammation.

Metformin is an antidiabetic medicine widely used for management of type 2 diabetes with neuroprotective effects and promising potential to attenuate cognitive impairment. The efficacy of metformin in attenuation of Alzheimer's disease (AD) pathology has not been well-documented. Thus, this study was designed to assess protective effect of metformin against Aß1-40-instigared cognitive impairment. After intra-CA1 microinjection of aggregated Aß1-40, rats received oral metformin (50 and/or 200 mg/kg/day) for two weeks. Cognition function was analyzed in various behavioral tasks besides measurement of hippocampal oxidative stress, apoptosis, and inflammation along with H&E staining and 3-nitrotyrosine (3-NT) immunohistochemistry. Obtained data showed significant improvement of discrimination score in novel object recognition test, higher alternation score in Y maze, greater latency in passive avoidance task, and lower working and reference memory errors in radial arm maze in metformin-treated Aß-injured group. Moreover, metformin treatment attenuated hippocampal levels of nitrite, MDA, protein carbonyl, ROS, TNFα, GFAP, DNA fragmentation intensity, caspase 3 activity, AChE activity, and increased SOD activity and level of IL-10 as an anti-inflammatory factor. In addition, metformin treatment was associated with lower CA1 neuronal loss and it also decreased intensity of 3-NT immunoreactivity as an indicator of nitrosative stress. Taken together, obtained findings showed neuroprotective and anti-dementia property of metformin in male rats and this may have potential benefit in attenuation of cognitive decline and related complications in patients with neurodegenerative disorders such as AD besides diabetes mellitus.

Scutellarin alleviates lipopolysaccharide-provoked septic nephrotoxicity via attenuation of inflammatory and oxidative events and mitochondrial dysfunction.

BACKGROUND: Sepsis-associated acute kidney injury (AKI) is highlighted by high incidence of mortality and morbidity. Scutellarin is a flavone extracted from certain medicinal plants with anti-inflammatory and anti-oxidative properties. This research study was done to investigate the beneficial effect of scutellarin on lipopolysaccharide (LPS) murine model of AKI. MATERIALS AND METHODS: Five groups of mice were used including control (without LPS injection), LPS group (LPS injection, 10 mg/kg), and LPS + Scutellarin25, 50, and/or 100 groups (receiving scutellarin orally at different doses of 25, 50, or 100 mg/kg before LPS injection). RESULTS: Scutellarin pretreatment effectively lowered kidney function markers (BUN, creatinine, and cystatin C), improved superoxide dismutase (SOD) besides enhancement of level, and/or gene expression for nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase 1 (HO-1) and also reduced oxidative stress factors including reactive oxygen species (ROS) and malondialdehyde (MDA). In addition, scutellarin reduced tissue level and/or gene expression of inflammatory markers comprising toll-like receptor 4 (TLR4), nuclear factor-kappaB (NF-κB), and tumor necrosis factor α (TNF-α) and properly raised anti-inflammatory factor IL-10. Moreover, scutellarin enhanced mitochondrial membrane potential (MMP) and attenuated histopathological changes in renal tissue subsequent to LPS challenge. Beneficial effects of scutellarin was associated with improvement of gene expression regarding peroxisome proliferator-activated receptor gamma (PPARγ) and its coactivator PGC-1α as specific markers of mitochondrial biogenesis. CONCLUSION: These results indicate that scutellarin could protect against LPS-provoked AKI through restraining inflammation and oxidative stress and maintenance of mitochondrial health and biogenesis which is partly mediated through its regulation of Nrf2/PPAR-γ/PGC-1α/NF-kB/TLR4.

Ferulic Acid Attenuates Kainate-induced Neurodegeneration in a Rat Poststatus Epilepticus Model.

BACKGROUND AND AIMS: Increasing research evidence indicates that temporal lobe epilepsy (TLE) induced by kainic acid (KA) has high pathological similarities with human TLE. KA induces excitotoxicity (especially in the acute phase of the disease), which leads to neurodegeneration and epileptogenesis through oxidative stress and inflammation. Ferulic acid (FA) is one of the well-known phytochemical compounds that have shown potential antioxidant and anti-inflammatory properties and promise in treating several diseases. The current study set out to investigate the neuroprotective effects of FA in a rat model of TLE. METHODS: Thirty-six male Wistar rats were divided into four groups. Pretreatment with FA (100 mg/kg/day p.o.) started one week before the intrahippocampal injection of KA (0.8 µg/µl, 5µl). Seizures were recorded and evaluated according to Racine's scale. Oxidative stress was assessed by measuring its indicators, including malondialdehyde (MDA), nitrite, and catalase. Histopathological evaluations including Nissl staining and immunohistochemical staining of cyclooxygenase-2 (COX-2), and neural nitric oxide synthases (nNOS) were performed for the CA3 region of the hippocampus. RESULTS: Pretreatment with FA significantly attenuates the severity of the seizure and prevents neuronal loss in the CA3 region of the hippocampus in rats with KA-induced post-status epilepticus. Also, nitrite concentration and nNOS levels were markedly diminished in FA-pretreated animals compared to non-pretreated epileptic rats. CONCLUSION: Our findings indicated that neuroprotective properties of FA, therefore, could be considered a valuable therapeutic supplement in treating TLE.

Hepatoprotective Effect of Myricetin following Lipopolysaccharide/DGalactosamine: Involvement of Autophagy and Sirtuin 1.

BACKGROUND: Acute liver injury (ALI) is a critical and fatal disorder associated with excessive oxidative stress and inflammation, ultimately leading to the death of hepatocytes. Myricetin is a bioflavonoid in some berries, including blueberries and strawberries, with anti-inflammatory, antioxidant and anti-apoptotic properties. OBJECTIVE: In the current research, the hepatoprotective potential of myricetin was studied in the LPS/D-GalN model of ALI in C57BL/6 mice. METHODS: For inducing liver injury, D-GalN (400 mg/kg) and LPS (50 µg/kg) were injected via intraperitoneal route and myricetin was orally administered (25 or 100 mg/kg/day) for two days before inducing injury. Functional indices of liver dysfunction along with hepatic apoptotic, autophagic, oxidative stress and inflammatory factors were measured. RESULTS: Myricetin (100 mg/kg) reduced the fatality rate of animals and pathological liver changes and suitably lowered serum levels of total bilirubin, 8-OH-dG, ALT, AST and ALP in addition to decreasing apoptotic, oxidative and inflammatory factors, NOX, NLRP3, caspase 3, MPO and enhancing some antioxidants. Besides, myricetin improved the hepatic level and activity of sirtuin 1 and reversed inappropriate alterations of autophagic parameters, including LC3 II, Beclin 1, and P62. The beneficial effects of myricetin were attenuated after co-treatment with the autophagy inhibitor 3- methyladenine. CONCLUSION: This study indicates the hepatoprotective potential of myricetin that can be ascribed to its down-regulation of oxidative, apoptotic, and inflammatory factors and upregulation of antioxidants besides its partial regulation of sirtuin 1 and autophagic pathway.

Preliminary report of Iranian Registry of Alzheimer's disease in Tehran province: A cross-sectional study in Iran.

Background and Aims: Alzheimer's disease (AD) is the main cause of dementia and over the 55 million people live with dementia worldwide. We aimed to establish the first database called the Iranian Alzheimer's Disease Registry to create a powerful source for future research in the country. In this report, the design and early results of the Iranian Alzheimer's Disease Registry will be described. Methods: We performed this multicenter investigation and patients' data including age, sex, educational level, disease status, Mini-Mental State Examination (MMSE), and Geriatric Depression Scale (GDS) from 2018 to 2021 were collected, registered, and analyzed by GraphPad Prism software. Results: Totally 200 AD patients were registered in our database. 107 (54%) were women and age of 147 (74%) were over 65. The mean age for men and women was 76.20 ± 8.29 and 76.40 ± 8.83 years, respectively. 132 (66%) were married and 64 (32%) were illiterate. Also, 94 (47%) were in the moderate stage of disease, and 150 (75%) lived at home together with their families. The most frequent neurological comorbidity was psychosis (n = 72, 36%), while hypertension was the most common non-neurological comorbidity (n = 104, 52%). The GDS score of women in the mild stage (5.23 ± 2.9 vs. 6.9 ± 2.6, p = 0.005) and moderate stage (5.36 ± 2.4 vs. 8.21 ± 2.06, p = <0.001) of the disease was significantly greater than men. In univariate analysis, MMSC score was remarkably associated with stroke (ß = -2.25, p = 0.03), psychosis (ß = -2.18, p = 0.009), diabetes (ß = 3.6, p = <0.001), and hypercholesteremia (ß = 1.67, p = 0.05). Also, the MMSE score showed a notable relationship with stroke (ß = -2.13, p = 0.05) and diabetes (ß = 3.26, p = <0.001) in multivariate analysis. Conclusion: Iranian Alzheimer's Disease Registry can provide epidemiological and clinical data to use for purposes such as enhancing the current AD management in clinical centers, filling the gaps in preventative care, and establishing effective monitoring and cure for the disease.

Protective effect of N-acetyl cysteine on the mitochondrial dynamic imbalance in temporal lobe epilepsy: Possible role of mTOR.

Understanding the underlying molecular mechanisms involved in epilepsy is critical for the development of more effective therapies. It is believed that mTOR (Mechanistic Target of Rapamycin kinases) activity and the mitochondrial dynamic balance change during epilepsy. mTOR affects mitochondrial fission by stimulating the translation of mitochondrial fission process 1 (MTFP1). In This study, the protective role of N-acetylcysteine was studied in temporal lobe epilepsy (TLE) through the regulation of mTOR and mitochondrial dynamic proteins. Rats received N-acetylcysteine (oral administration) seven days before induction of epilepsy, followed by one day after epilepsy. TLE was induced by microinjection of kainite into the left lateral ventricle. The total mTOR and Drp1 levels in the hippocampus were evaluated by western blotting. MFN1 was assessed using immunohistochemistry, and the expression of Fis.1 and MTFP1 (fission-related proteins) and OPA (fusion-related protein) were detected by real-time PCR. The mitochondrial membrane potential was measured by Rhodamin 123. The results showed that 72 h after induction of epilepsy, the mTOR protein level increased, and the balance of the mitochondrial dynamic was disturbed; however, oral administration of NAC decreased the mTOR protein level and improved the mitochondrial dynamic. These findings indicate that NAC plays a neuroprotective role in temporal lobe epilepsy, probably through decreasing the mTOR protein level, which can improve the imbalance in the mitochondrial dynamic.

Paeonol exerts neuroprotective and anticonvulsant effects in intrahippocampal kainate model of temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is presented the most common form of focal epilepsy with involvement of oxidative stress and neuroinflammation as important factors in its development. About one third of epileptic patients are intractable to currently available medications. Paeonol isolated from some herbs with traditional and medicinal uses has shown anti-oxidative and anti-inflammatory effects in different models of neurological disorders. In this research, we tried to evaluate the possible protective effect of paeonol in intrahippocampal kainate murine model of TLE. To induce TLE, kainate was microinjected into CA3 area of the hippocampus and paeonol was administered at two doses of 30 or 50 mg/kg. The results of this study showed that paeonol at the higher dose significantly reduces incidence of status epilepticus, hippocampal aberrant mossy fiber sprouting and also preserves neuronal density. Beneficial protective effect of paeonol was in parallel with partial reversal of some hippocampal oxidative stress markers (reactive oxygen species and malondialdehyde), caspase 1, glial fibrillary acidic protein, heme oxygenase 1, DNA fragmentation, and inflammation-associated factors (nuclear factor-kappa B, toll-like receptor 4, and tumor necrosis factor α). Our obtained data indicated anticonvulsant and neuroprotective effects of paeonol which is somewhat attributed to its anti-oxidative and anti-inflammation properties besides its attenuation of apoptosis, pyroptosis, and astrocyte activity.

Therapeutic effect of lycopene in lipopolysaccharide nephrotoxicity through alleviation of mitochondrial dysfunction, inflammation, and oxidative stress.

BACKGROUND: Sepsis-associated acute kidney injury (AKI) accompanies a higher mortality in intensive care patients. High-dose lipopolysaccharides (LPS) as an endotoxin is usually used to model AKI in rodents. Lycopene is a fat-soluble carotenoid with proved protective effects in different condition. Rationale and purpose of the study. This research work was designed to assess the effect of lycopene in LPS murine AKI. METHODS AND RESULTS: LPS was injected (intraperitoneally) at 10 mg/kg to induce AKI and lycopene was given (orally) at 5 or 20 mg/kg. Pretreatment of LPS group with lycopene (20 mg/kg) lowered serum BUN, creatinine, and cystatin C and alleviated renal indices of oxidative stress consisting of malondialdehyde and reactive oxygen species and elevated level of catalase activity, superoxide dismutase activity, and glutathione peroxidase activity. In addition, lycopene (20 mg/kg) attenuated renal neutrophil infiltration and reduced renal inflammation, improved mitochondrial membrane potential, and increased gene expression for PGC1-α as a key regulator of mitochondrial biogenesis. In addition, lycopene appropriately reduced level and gene expression of inflammation-related transcription factors including NF-kB and TLR4 and improved level and gene expression of Nrf2 as an important transcription factor related to antioxidant system. Besides, lycopene prevented histopathological changes following LPS in periodic acid-Schiff staining. CONCLUSIONS: Collectively, this study revealed that lycopene has favorable effects by means of amelioration of mitochondrial dysfunction, oxidative stress, and inflammation and accordingly could protect against LPS-induced AKI.