Protective effect of sinomenine against CCl4-induced acute liver injury through regulation of mitochondrial biogenesis.

Carbon tetrachloride (CCl4)-provoked acute liver injury (ALI) is typified by intensified apoptotic, inflammatory, and oxidative changes besides mitochondrial dysfunction. Sinomenine is an active constituent in the medicinal plant Sinomenium acutum. The main objective of this study was to determine sinomenine-induced hepatoprotection following CCl4 challenge with an emphasis on unraveling the contribution of mitochondrial biogenesis-related factors. To induce ALI, CCl4 was injected i.p. and sinomenine was orally administered at 10, 25, and 50 mg/kg. Serum factors in relation to liver dysfunction were measured in addition to hepatic analysis of apoptotic, mitochondrial biogenesis, oxidative, and inflammatory parameters. Sinomenine pretreatment significantly lowered ALT and AST, MDA, IL-6, apoptosis intensity, and TNF-α and restored mitochondrial biogenesis besides enhancement of SOD, sirtuin-1, and AMPK. Sinomenine also conferred hepatoprotective impact, as was apparent by lower pathologic changes. These effects were accompanied by changes in gene expression for AMPK/sirtuin-1/PGC-1α/PPARγ. The current study showed sinomenine hepatoprotective impact in CCl4-induced ALI that is associated with its regulation of mitochondrial biogenesis and parallel enhancement of AMPK/sirtuin-1.

Exploring the molecular mechanisms underlying neuroprotective effect of ellagic acid in okadaic acid-induced Alzheimer's phenotype.

Pomegranate polyphenol ellagic acid has medicinal potential in neurodegenerative disorders. The advantageous effect of this polyphenol in improving cognition in okadaic acid (OA)-instigated murine model with unraveling some modes of its action was assessed. Rats received ICV okadaic acid (OA) and post-treated with oral ellagic acid for 3 weeks (25 and 100 mg/kg/day). Cognition was analyzed in behavioral tasks besides assessment of oxidative, apoptotic, and inflammatory factors in addition to hippocampal histochemical analysis. Ellagic acid at a dose of 100 mg/kg properly attenuated cognitive abnormalities in novel object recognition (NOR), Y maze, and Barnes maze tests. Additionally, ellagic acid diminished hippocampal changes of malondialdehyde (MDA), protein carbonyl, reactive oxygen species (ROS), glutathione (GSH), glutathione peroxidase, superoxide dismutase (SOD), apoptotic factors caspases 1 and 3, tumor necrosis factor α (TNFα), and acetylcholinesterase (AChE) and beta secretase 1 (BACE 1) besides reversal of AMP-activated protein kinase (AMPK) and hyperphosphorylated tau (p-tau). Moreover, lower glial fibrillary acidic protein (GFAP) and less injury of hippocampal CA1 pyramidal neurons were observed upon ellagic acid. To conclude, neuroprotective potential of ellagic acid was shown which is somewhat attributable to its reversal of oxidative, apoptotic, and neuroinflammatory events in addition to proper regulation of AMPK and p-tau.

Lille Apathy Rating Scale-Patient Version in Stroke Survivors: Psychometric Properties and Diagnostic Accuracy.

OBJECTIVES: This study evaluated the factorial structure, psychometric properties, and diagnostic accuracy of the Persian version of the Lille Apathy Rating Scale-Patient version (LARS-P) in stroke survivors. PARTICIPANTS: This study comprised 105 stroke survivors and 41 healthy controls. METHODS AND SETTING: Exploratory factor analysis was used to determine the factors of the LARS-P. The acceptability, reliability, and validity of the LARS-P were also assessed. Agreement between the LARS-P and the Lille Apathy Rating Scale-informed version (LARS-I) was evaluated using the Bland-Altman plot. The diagnostic accuracy of the LARS-P was determined by categorizing stroke survivors into apathetic and nonapathetic groups based on the "diagnostic criteria of apathy." RESULTS: The exploratory factor analysis showed 3 factors (action initiation and social life; novelty and motivation; and emotional and self-awareness), explaining 67.35% of the variance. Cronbach's alpha was 0.85 for between-items and 0.74 for between-subscales. Intra-class correlation coefficient (ICC)2,1 was >0.88 for test-retest and inter-rater reliability. The LARS-P showed moderate to strong correlations with the LARS-I and Neuropsychiatric Inventory-Apathy subscale (r = 0.70-0.82). In addition, the LARS-P had significant moderate correlations with 2 subscales of the Hospital Anxiety and Depression Scale, modified Rankin Scale, Barthel Index, and Lawton Instrumental Activities of Daily Living (r or Æ¿ = 0.47-0.63). There was a 96.19% agreement between LARS-P and LARS-I. The identified cutoff point (>17) for LARS-P exhibited 77.14% sensitivity and 90% specificity in diagnosing apathetic and nonapathetic stroke survivors. CONCLUSIONS AND IMPLICATIONS: The LARS-P exhibits acceptable psychometric properties in stroke survivors, presenting a promising instrument for assessing apathy through a multidimensional framework.

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.

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.

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.

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.

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.

Generating Human Induced Pluripotent Stem Cell Via Low-Dose Polyethylenimine-Mediated Transfection: An Optimized Protocol.

Human dermal fibroblasts (HDFs) can be reprogrammed through different strategies to generate human induced pluripotent stem cells (hiPSCs). However, most of these strategies require high-cost materials and specific equipment not readily accessible in most laboratories. Hence, liposomal and virus-based techniques can replace with polyethylenimine (PEI)-mediated transfection to overcome these challenges. However, few researchers have addressed the PEI's ability to transfect HDFs. This study used PEI reagent to transfer oriP/EBNA1-based vector into HDFs to produce hiPSC lines. We first described conditions allowing the efficient transfection of HDFs with low cytotoxicity and without specific types of equipment and optimized several parameters relevant to the transfection procedure. We then monitored the effect of different N/P ratios on transfection efficiency and cytotoxicity using flow cytometry and fluorescent microscopy. By the results, we found that transfection efficiency was greatly affected by plasmid DNA concentration, PEI concentration, order of combining reagents, serum presence in polyplexes, and the duration of serum starvations. Moreover, using the optimized condition, we found that the N/P ratio of 3 achieved the highest percentage of HDFs positive for green fluorescent protein plasmid (∼40%) with minimal cell toxicity. We finally generated hiPSCs using the optimized protocol and oriP/EBNA1-based vectors. We confirmed hiPSC formation by characterizing tests: alkaline phosphatase staining, immunocytochemistry assay, real-time PCR analysis, in vitro differentiation into three germ layers, and karyotyping test. In conclusion, our results indicated that 25 kDa branched PEI could efficiently transfect HDFs toward generating hiPSCs via a simple, cost-effective, and optimized condition.

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.

Sinomenine Attenuates Trimethyltin-Induced Cognitive Decline via Targeting Hippocampal Oxidative Stress and Neuroinflammation.

Sinomenine is the main bioactive ingredient of the medicinal plant Sinomenium acutum with neuroprotective potential. This study was designed to assess beneficial effect of sinomenine in alleviation of trimethyltin (TMT)-induced cognitive dysfunction. TMT was administered i.p. (8 mg/kg, once) and sinomenine was daily given p.o. 1 h after TMT for 3 weeks at doses of 25 or 100 mg/kg. Cognitive performance was assessed in various behavioral tests. In addition, oxidative stress- and inflammation-associated factors were measured and histochemical evaluation of the hippocampus was conducted. Sinomenine at a dose of 100 mg/kg significantly and partially increased discrimination index in novel object recognition (NOR), improved alternation in short-term Y maze, increased step-through latency in passive avoidance paradigm, and also reduced probe trial errors and latency in the Barnes maze task. Moreover, sinomenine somewhat prevented inappropriate hippocampal changes of malondialdehyde (MDA), reactive oxygen species (ROS), protein carbonyl, nitrite, superoxide dismutase (SOD), tumor necrosis factor α (TNFα), interleukin 6 (IL 6), acetylcholinesterase (AChE) activity, beta secretase 1 (BACE 1) activity, and mitochondrial membrane potential (MMP) with no significant effect on glutathione (GSH), catalase, glutathione reductase, glutathione peroxidase, and myeloperoxidase (MPO). In addition, lower reactivity (IRA) for glial fibrillary acidic protein (GFAP) as an index of astrocyte activity was observed and loss of CA1 pyramidal neurons was attenuated following sinomenine treatment. This study demonstrated that sinomenine could lessen TMT-induced cognitive dysfunction which is partly due to its attenuation of hippocampal oxidative stress and neuroinflammation.

Therapeutic Potential of Isorhamnetin following Acetaminophen-Induced Hepatotoxicity through Targeting NLRP3/NF-κB/Nrf2.

Acetaminophen (APAP)-induced acute liver injury (ALI) is the principal cause of acute liver failure (ALF) in some countries including the United States and with few available treatments. Isorhamnetin is a bioflavonoid that is found in medicinal plants like Hippophae rhamnoides L. and Ginkgo biloba L. with promising potential to regulate inflammatory responses. In this study, we evaluated the possible effect of isorhamnetin in prevention of APAP-induced ALI and analyzed further the involvement of oxidative stress and inflammation-associated factors. Male C57BL/6 mice were given isorhamnetin (25 or 100 mg/kg b.w., p.o.) three times at 48, 24, and 1 h before APAP administration (300 mg/kg b.w., i.p.). Functional indicators of liver injury were measured as well as analysis of oxidative stress- and inflammation-associated indices and liver histopathology was also conducted. Isorhamnetin at the higher dose of 100 mg/kg significantly lowered serum levels of ALT, ALP, and AST in addition to reduction of ROS, TBARS, IL-6, TNFα, NF-kB, NLRP3, caspase 1, and MPO and significantly prevented reduction of GSH, SOD activity, sirtuin 1, and Nrf2. Additionally, isorhamnetin alleviated pathological changes of the liver tissue and suitably reversed NF-kB and Nrf2 immunoreactivity. These findings show protective effect of isorhamnetin against acetaminophen-induced liver injury through reducing oxidative stress, inflammation, and pyroptosis which is attributed to its regulation of NF-kB, Nrf2, NLRP3, and sirtuin 1.

Sinapic acid ameliorates paracetamol-induced acute liver injury through targeting oxidative stress and inflammation.

BACKGROUND: Acetaminophen (paracetamol, APAP) overdose is the principal cause of acute liver injury (ALI) that leads to liver failure typified with oxidative stress, mitochondrial and lysosomal dysfunction and with few antidotes for this condition. Therefore, more effective therapeutics are urgently required. Sinapic acid is a phenolic phytochemical with significant antioxidant, anti-inflammatory and hepatoprotective potential. RATIONALE AND PURPOSE OF THE STUDY: This study was conducted to evaluate hepatoprotective effect of this phytochemical in acetaminophen-induced model of ALI. METHODS AND RESULTS: Male C57BL/6 mice were treated p.o. with sinapic acid (10 or 50 mg/kg) 3 times at 72, 24, and 1 h before APAP (300 mg/kg; i.p.) challenge. Functional factors of liver dysfunction were determined along with hepatic assessment of oxidative stress and inflammatory indexes and histopathological analysis was also conducted. Sinapic acid (50 mg/kg) properly decreased serum levels of ALT, ALP, and AST besides reducing liver level of ROS, MDA, IL-6, TNF-α, NF-kB, and MPO and improved sirtuin 1, HO-1, Nrf2, SOD activity, and MMP with no significant effect on IL-1ß and catalase activity in addition to decreasing activity of lysosomal enzymes including cathepsin B and ß-galactosidase. Also, sinapic acid at the higher dose ameliorated liver histopathological changes due to APAP and properly reversed NF-kB and Nrf2 immunoreactivity. CONCLUSIONS: These findings show that sinapic acid pretreatment effectively protects liver against adverse and hepatotoxic effect of APAP through its antioxidant- and anti-inflammatory potential linked to NF-kB/Nrf2/HO-1 signaling and also via regulation of sirtuin 1, mitochondrial integrity, and lysosomal stabilization.

Nobiletin prevents amyloid ß1-40-induced cognitive impairment via inhibition of neuroinflammation and oxidative/nitrosative stress.

Alzheimer's disease (AD) is presented as an age-related neurodegenerative disease with multiple cognitive deficits and amyloid ß (Aß) accumulation is the most important involved factor in its development. Nobiletin is a bioflavonoid isolated from citrus fruits peels with anti-inflammatory and anti-oxidative activity as well as anti-dementia property that has shown potency to ameliorate intracellular and extracellular Ab. The aim of the present study was to assess protective effect of nobiletin against Aß1-40-induced cognitive impairment as a consistent model of AD. After bilateral intrahippocampal (CA1 subfield) injection of Aß1-40, rats were treated with nobiletin (10 mg/kg/day; p.o.) from stereotaxic surgery day (day 0) till day + 7. Cognition function was evaluated in a battery of behavioral tasks at week 3 with final assessment of hippocampal oxidative stress and inflammation besides Nissl staining and 3-nitrotyrosine (3-NT) immunohistochemistry. Analysis of behavioral data showed notable and significant improvement of alternation in Y maze test, discrimination ratio in novel object recognition task, and step through latency in passive avoidance test in nobiletin-treated Aß group. Additionally, nobiletin treatment was associated with lower hippocampal levels of MDA and ROS and partial reversal of SOD activity and also improvement of Nrf2 with no significant effect on GSH and catalase. Furthermore, nobiletin attenuated hippocampal neuroinflammation in Aß group as shown by lower tissue levels of TLR4, NF-kB, and TNFa. Histochemical findings showed that nobiletin prevents CA1 neuronal loss in Nissl staining in addition to its alleviation of 3-nitrotyrosine (3-NT) immunoreactivity as a marker of nitrosative stress. Collectively, these findings indicated neuroprotective and anti-dementia potential of nobiletin that is partly attributed to its anti-oxidative, anti-nitrosative, and anti-inflammatory property associated with proper modulation of TLR4/NF-kB/Nrf2 pathways.

Acetyl-L-Carnitine Exerts Neuroprotective and Anticonvulsant Effect in Kainate Murine Model of Temporal Lobe Epilepsy.

The most well-known type of focal epilepsy that is resistant to existing treatments is temporal lobe epilepsy (TLE), with seizure foci in various structures including temporal lobe, hippocampus, amygdala, entorhinal cortex, and subcortex. The most significant processes involved in the pathophysiology of temporal lobe epilepsy (TLE) are oxidative stress, inflammation, and pyroptosis. There are evidences indicating that acetyl-l-carnitine (ALC) has anti-oxidative, anti-inflammatory, and anti-pyroptotic effects. In the present study, rat model of TLE was induced by intrahippocampal kainate and animals received ALC (100 mg/kg, p.o.). ALC properly attenuated intensity of seizures and also incidence of kainate-induced status epilepticus (SE). As well, obtained findings showed that ALC can partially reverse hippocampal levels of MDA, ROS, SOD, TNFa, NF-kB, TLR4, GFAP, and caspase 1. Besides, treatment of kainate group with ALC exerted a protective effect against CA1 neuronal loss and abnormal mossy fiber sprouting (MFS). Conclusively, these results suggest that ALC is capable to attenuate kainate-induced SE which is somewhat mediated through its lowering of oxidative stress, neuroinflammation, and pyroptosis that are related to its neuroprotective effect.

Esculetin Alleviates Acute Liver Failure following Lipopolysaccharide/D-Galactosamine in Male C57BL/6 Mice.

Background: Acute liver failure (ALF) is a fatal clinical situation that rapidly leads to the loss of normal liver function. Esculetin is a natural herbal compound used for the management of various diseases such as cardiovascular and renal disorders. In this study, we evaluated the protective effects of esculetin in a mouse model of ALF. Methods: This article is a report on an experimental study that was conducted at Iran University of Medical Sciences in 2019. Forty-eight male C57BL/6 mice were randomly divided into control, LPS/D-Gal, and LPS/D-Gal+Esculetin (40 mg/kg) groups (n=16 per group). ALF was induced with an intraperitoneal injection of lipopolysaccharide (LPS)/D-galactosamine (D-Gal).The LPS/D-Gal group received a mixture of LPS (50 µg/kg) and D-Gal (400 mg/kg). The LPS/D-Gal+Esculetin group received esculetin by gavage 24 hours and one hour before receiving LPS/D-Gal. Six hours after LPS/D-Gal injection, the mice were sacrificed. Liver injury markers, including alanine aminotransferase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP), were measured in the serum. Oxidative stress indices and inflammatory markers such as interleukin-1 beta (IL-1ß), IL-6, and tumor necrosis factor-alpha (TNF-α) were measured in hepatic tissue. The histopathology of liver tissue was also assessed. The data were analyzed using one-way ANOVA, followed by the post hoc Tukey test. Results: Esculetin lowered oxidative stress and myeloperoxidase activity (P<0.001); reduced the serum levels of ALT (P=0.037), AST (P=0.032), and ALP (P=0.004); and decreased the hepatic levels of IL-1ß (P=0.002), IL-6 (P=0.004), toll-like receptor 4 (P<0.001), TNF-α (P=0.003), and nuclear factor-kappa B (P<0.001) as compared with LPS/D-Gal. Additionally, esculetin ameliorated hepatic tissue injury following LPS/D-Gal challenge. Conclusion: Esculetin can reduce liver injury through the mitigation of oxidative burden, inflammation, and neutrophil infiltration and also exerts hepatoprotective effects against ALF.

Diosgenin ameliorates cellular and molecular changes in multiple sclerosis in C57BL/6 mice.

Multiple sclerosis (MS) is especially known as a demyelinating disease of the central nervous system. Current treatments for MS are mostly based on controlling neuroinflammation and there are no treatments to promote the remyelination process at present. Diosgenin is a known herbal anti-inflammatory and antioxidant agent, which has also been shown to stimulate the growth of myelin in vitro. However, there is no or little evidence about diosgenin effects; specially on myelination, neuroprotection and its corresponding mechanisms in vivo in experimental autoimmune encephalomyelitis (EAE) as the most valid experimental model of MS. In this study, the therapeutic effect of diosgenin on clinical signs of EAE, and the corresponding cellular and molecular mechanisms have been examined with emphasis on myelination and neuroprotection mechanisms. EAE was induced using myelin oligodendrocyte glycoprotein (MOG) antigen in C57BL/6 mice. Diosgenin was gavaged (100 mg/kg) daily with the onset of paralysis signs (half tail paralysis) until the 18th post-immunization day in the treatment group. Blood and spinal cord tissue sampling was performed on post-immunization day 18. Lumbar spinal cord inflammation, demyelination, and axonal degeneration were assessed using Hematoxylin and Eosin (H & E), Luxol Fast Blue (LFB), and Bielschowsky's silver staining methods, respectively. Serum and spinal cord tissue level of tumor necrosis factor alpha (TNFα) and tissue levels of matrix metalloproteinase 9 (MMP-9) and interleukin 17 (IL-17) as inflammatory markers, microtubule-associated proteins 1A/1B light chain 3A (MAP1LC3A), and activity dependent neuroprotector homeobox (ADNP) as neuroprotective markers were assayed using enzyme linked immunosorbent assay (ELISA) method. The clinical score of EAE in the diosgenin treatment group was significantly reduced compared to the EAE group on days 15 to 18 after induction of the EAE (p < 0.001). Inflammation, demyelination and axonal loss scores also decreased significantly in the diosgenin treatment group compared to the EAE group (p < 0.05). Serum and spinal cord tissue level of TNFα and tissue level of MMP-9 considerably decreased in the diosgenin treatment group in comparison with the EAE group (p < 0.01). Diosgenin treatment had no significant effects on the tissue levels of IL-17, ADNP and MAP1LC3A. Therefore, diosgenin improved the clinical signs of EAE through lowering neuroinflammation, demyelination and axonal degeneration, but did not significantly affect the neuroprotective factors in this study. As a result, diosgenin could be a good candidate for new MS treatment strategies that, in addition to their anti-inflammatory effects, also enhance myelination.

Linagliptin Protects Human SH-SY5Y Neuroblastoma Cells against Amyloid-ß Cytotoxicity via the Activation of Wnt1 and Suppression of IL-6 Release

Background: Alzheimer's disease is one of the neurodegenerative disorders typified by the aggregate of amyloid-ß (Aß) and phosphorylated tau protein. Oxidative stress and neuroinflammation, because of Aß peptides, are strongly involved in the pathophysiology of Alzheimer's disease (AD). Linagliptin shows neuroprotective properties against AD pathological processes through alleviation of neural inflammation and AMPK activation. Methods: We assessed the benefits of linagliptin pretreatment (at 10, 20, and 50 nM concentrations), against Aß1-42 toxicity (20 µM) in SH-SY5Y cells. The concentrations of secreted cytokines, such as TNF-α, IL-6, and IL-1ß, and signaling proteins, including pCREB, Wnt1, and PKCε, were quantified by ELISA. Results: We observed that Aß led to cellular inflammation, which was assessed by measuring inflammatory cytokines (TNF-α, IL-1ß, and IL-6). Moreover, Aß1-42 treatment impaired pCREB, PKCε, and Wnt1 signaling in human SH-SY5Y neuroblastoma cells. Addition of Linagliptin significantly reduced IL-6 levels in the lysates of cells, treated with Aß1-42. Furthermore, linagliptin prevented the downregulation of Wnt1 in Aß1-42-treated cells exposed. Conclusion: The current findings reveal that linagliptin alleviates Aß1-42-induced inflammation in SH-SY5Y cells, probably through the suppression of IL-6 release, and some of its benefits are mediated through the activation of the Wnt1 signaling pathway.