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.

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.

Fetal Hypothyroidism Impairs Aortic Vasorelaxation Responses in Adulthood: Involvement of Hydrogen Sulfide and Nitric Oxide Cross talk.

ABSTRACT: Thyroid hormones have a wide range of effects on growth, differentiation, evolution, metabolism, and physiological function of all tissues, including the vascular bed. In this study, the effect of fetal hypothyroidism on impairment of aortic vasorelaxation responses in adulthood was investigated with emphasis on possible involvement of hydrogen sulfide (H2S)/nitric oxide interaction. Two groups of female rats were selected. After mating and observation of vaginal plaque, one group received propylthiouracil (200 ppm in drinking water) until the end of pregnancy and another group had no propylthiouracil treatment during the fetal period. In adult rats, aortic relaxation responses to l-arginine and GYY4137 were assessed in the presence or absence of Nω-nitro-L-arginine methyl ester hydrochloride and dl-propargylglycine in addition to the biochemical measurement of thyroid hormones and some related factors. Obtained findings showed a lower vasorelaxation response for GYY4137 and l-arginine in the fetal hypothyroidism group, and preincubation with Nω-nitro-L-arginine methyl ester hydrochloride or dl-propargylglycine did not significantly aggravate this weakened relaxation response. In addition, aortic levels of sirtuin 3, endothelial nitric oxide synthase, cystathionine gamma-lyase, and H2S were significantly lower in the fetal hypothyroidism group. Meanwhile, no significant changes were obtained regarding serum levels of thyroid hormones including free triiodothyronine;, total triiodothyronine, free thyroxine, total thyroxine, and thyroid-stimulating hormone in adult rats. It can be concluded that hypothyroidism in the fetal period has inappropriate effects on the differentiation and development of vascular bed with subsequent functional abnormality that persists into adulthood, and part of this vascular abnormality is mediated through weakened interaction and/or cross talk between H2S and nitric oxide.

Neuroprotective and anticonvulsant effects of sinomenine in kainate rat model of temporal lobe epilepsy: Involvement of oxidative stress, inflammation and pyroptosis.

Oxidative stress, inflammation and pyroptosis are three of the most important mechanisms in the pathophysiology of temporal lobe epilepsy (TLE). Most people with TLE are refractory to the existing drugs. Sinomenine has shown neuroprotective effects through counteracting oxidative stress, inflammation and pyroptosis. In this study, we evaluated the effect of sinomenine on seizure behavior, oxidative stress, inflammation and pyroptosis markers in addition to its neuroprotective potential in intrahippocampal kainate-induced rat model of TLE. For this purpose, male rats (n = 60) were randomly divided into five groups, i.e., sham, kainate (lesion) with an intrahippocampal injection of kainate, kainate groups receiving sinomenine at doses of 30 or 50 mg/kg, and kainate group receiving valproic acid at a dose of 200 mg/kg (as the positive control). Our obtained data showed that sinomenine administration at a dose of 50 mg/kg can significantly decreases severity of seizures and incidence of status epilepticus (SE), hippocampal aberrant MFS and DNA fragmentation and prevents reduction of neuronal density. It also significantly restored level of ROS, MDA, HO-1 and SOD but its effect on GSH level was not significant. Additionally, sinomenine at a dose of 50 mg/kg partially counteracted the increase of NF-κB, TLR 4, TNFα, GFAP and caspase 1. These results suggest that sinomenine has anticonvulsant and neuroprotective effects by reducing hippocampal oxidative stress, inflammation, pyroptosis and apoptosis in intrahippocampal kainate model of TLE.

Protective effect of diosgenin on LPS/D-Gal-induced acute liver failure in C57BL/6 mice.

Acute liver failure (ALF) is a deadly clinical syndrome, which leads to a rapid loss of normal liver function. Diosgenin is a natural steroidal sapogenin found in various plant families. Various studies have shown that diosgenin have therapeutic or preventive effect in various diseases such as cancer, cardiovascular disorders, type 2 diabetes, and neurodegenerative disorders. In this study, we evaluated effects of diosgenin on mice model of ALF. Animal model of ALF was induced by intraperitoneal injection of lipopolysaccharide (LPS)/d-galactosamine (D-Gal). The male C57BL/6 mice were randomly divided into 3 groups: control group, LPS/D-Gal group, and LPS/D-Gal + diosgenin group (50 mg/kg). Mice in the LPS/D-Gal group received a combination of LPS (50 µg/kg) and D-Gal (400 mg/kg) intraperitoneally. LPS/D-Gal + diosgenin group received diosgenin twice orally 24 h and 1 h before receiving LPS/D-Gal. Markers of liver injury including ALT, AST and ALP were measured in blood samples in addition to determination of oxidative stress and inflammatory markers including MDA, nitrite, ROS, catalase, SOD, Nrf2, IL-1ß, IL-6, TLR4, TNF-α and NF-κB in hepatic tissue. Administration of diosgenin could greatly reduce serum levels of ALT, AST, and ALP. Besides, hepatic levels of MDA, ROS, IL-1ß, IL-6, TLR4, TNF-α, and NF-κB significantly decreased and SOD activity and Nrf2 level increased in comparison with the LPS/D-Gal group. In addition, myeloperoxidase activity as a marker of neutrophil infiltration decreased following diosgenin administration. In summary, diosgenin led to reduction of liver injury indices and oxidative stress and inflammatory events and diosgenin has probably hepatoprotecive effects in ALF.

Protective effect of sesamin in lipopolysaccharide-induced mouse model of acute kidney injury via attenuation of oxidative stress, inflammation, and apoptosis.

CONTEXT: Acute kidney injury (AKI) is considered a major public health concern in today's world. Sepsis-induced AKI is large as a result of exposure to lipopolysaccharide (LPS) that is the major outer membrane component of Gram-negative bacteria. Sesamin is the main lignan of sesame seeds with multiple protective effects. OBJECTIVE: In this research, we tried to demonstrate the protective effect of sesamin pretreatment in LPS-induced mouse model of AKI. METHODS: LPS was injected at a single dose of 10 mg/kg (i.p.) and sesamin was given p.o. at doses of 25, 50, or 100 mg/kg, one hour prior to LPS. RESULTS: Treatment of LPS-challenged mice with sesamin reduced serum level of creatinine and blood urea nitrogen (BUN) and returned back renal oxidative stress-related parameters including glutathione (GSH), malondialdehyde (MDA), and activity of catalase and superoxide dismutase (SOD). Moreover, sesamin alleviated inappropriate changes of renal nuclear factor-kappaB (NF-κB), toll-like receptor 4 (TLR4), cyclooxygenase-2 (COX2), tumor necrosis factor α (TNFα), interleukin-6, DNA fragmentation (an apoptotic index), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In addition, sesamin diminished magnitude of kidney tissue damage due to LPS. CONCLUSION: In summary, sesamin could dose-dependently abrogate LPS-induced AKI via attenuation of renal oxidative stress, inflammation, and apoptosis.

Protective effects of Withania somnifera root on inflammatory markers and insulin resistance in fructose-fed rats.

BACKGROUND: We investigated the effects of Withania somnifera root (WS) on insulin resistance, tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6) in fructose-fed rats. METHODS: Forty-eight Wistar-Albino male rats were randomly divided into four groups (n=12); Group I as control, Group II as sham-treated with WS by 62.5mg/g per diet, Group III fructose-fed rats received 10%W/V fructose, and Group IV fructose- and WS-fed rats. After eight weeks blood samples were collected to measure glucose, insulin, IL-6, and TNF-α levels in sera. RESULTS: Blood glucose, insulin, homeostasis model assessment for insulin resistance (HOMA-R), IL-6, and TNF-α levels were all significantly greater in the fructose-fed rats than in the controls. Treatment with WS significantly (P < 0.05) inhibited the fructose-induced increases in glucose, insulin, HOMA-R, IL-6, and TNF-α. CONCLUSION: Our data suggest that WS normalizes hyperglycemia in fructose-fed rats by reducing inflammatory markers and improving insulin sensitivity.