Targeted Temperature Management for Subarachnoid Hemorrhage: Excellent Outcome After Severe Vasospasm-A Case Series.

Targeted temperature management (TTM) might improve outcome of patients with severe subarachnoid hemorrhage (SAH) in which vasospasm, delayed cerebral ischemia (DCI), and increased intracranial pressure (ICP) are frequent and severe complications. A series of patients (n = 3) with severe aneurysmatic SAH were treated by TTM if they developed ICP crisis and/or severe vasospasm diagnosed by angiography. Once these complications were detected, body core temperature (BCT) was rapidly decreased to 35°C or 33°C, if necessary. BCT induced and maintained by surface cooling remained at the desired level for at least 72 hours. Rewarming was performed by 1°C, only if the target parameters ICP and velocities in the serial Doppler sonography indicating macrovascular vasospasm improved to regular levels. In case of increase of ICP or middle cerebral arteries velocities BCT was decreased again to the last effective level. The patients developed vasospasm between days 6 and 12 after SAH. All aneurysms were treated by coiling. BCT was reduced between days 6 and 12 after SAH. Total duration of BCT <36.5°C was between 5.5 and 8 days. It remained <35°C for 4-6 days, and at 33°C for 3 days on average. ICP could be sufficiently controlled in all patients, because no ICP crisis was observed during TTM and after rewarming. Two patients developed minor DCI. Side effects of prolonged ventilation of 7-18 days included pneumonia for two patients that could be treated sufficiently. Other complications were one case of ventriculitis and two temporary deliriums. Outcome of the patients was good because no focal neurological symptoms could be detected after rehabilitation. TTM represents a promising treatment approach for severe SAH in which standard treatment is often limited and experimental. It deserves further clinical investigation in a larger cohort.

Genistein Alleviates Neuroinflammation and Restores Cognitive Function in Rat Model of Hepatic Encephalopathy: Underlying Mechanisms.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome resulting from acute liver failure. Previously, we demonstrated hepatoprotective effects of genistein in D-galactosamine (D-GalN)-induced fulminant hepatic failure (FHF). In this study, we evaluated behavioural and neuroprotective effects of genistein in rat model of HE. HE was induced by intraperitonial administration of D-GalN (250 mg/kg BW) twice a week for 30 days Genistein was given as co-treatment through oral gavage daily at dose of 5 mg/kg BW. D-GalN administration significantly resulted in acute liver failure which was further associated with hyperammonemia, neurological dysfunction, as evident from behavioural and functional impairment and reduced learning ability in Morris water maze. Genistein significantly alleviated behavioural and functional impairment and restored learning ability in Morris water maze. Considerable histopathological changes, including portal inflammation, sinusoidal dilation, necrotic lesions and swelled astrocytes with pale nuclei, were seen in the liver and brain sections of D-GalN-challenged rats while genistein co-treated rats revealed normal cellular and morphological architecture as no pathological features were seen. Furthermore, pro-inflammatory markers (interleukin (IL)-10, IL-4, IL-1ß and TNF-α) and membrane expression of subunits α1 of GABAA receptor and GluR2 of AMPA marked significant increase, while subunits GluR1 of AMPA receptors showed reduced expression in D-GalN-challenged rats leading to neuroinflammation and dysregulated neurotransmission. Genistein significantly normalized altered expression of pro-inflammatory cytokines and membrane receptor of GABA and GluR. Our study suggests strong therapeutic potential of genistein in animal model of HE. Genistein can be used a strong anti-oxidant to attenuate neurotoxic effects of xenobiotics.

Oxazolo[4,5-b]pyridine-Based Piperazinamides as GSK-3ß Inhibitors with Potential for Attenuating Inflammation and Suppression of Pro-Inflammatory Mediators.

Recent studies reveal that glycogen synthase kinase-3ß (GSK-3ß) acts as a pro-inflammatory enzyme, and by inhibiting this kinase, inflammation can be controlled. In this regard, a series of 17 piperazine-linked oxazolo[4,5-b]pyridine-based derivatives was synthesized and evaluated for in vitro GSK-3ß inhibitory and in vivo anti-inflammatory activity. The compounds 7d, 7e, 7g, and 7c displayed the best GSK-3ß inhibitory activity among all the synthesized compounds, with corresponding IC50 values of 0.34, 0.39, 0.47, and 0.53 µM. Among the compounds 7d, 7e, 7g, and 7c examined for in vivo anti-inflammatory activity in the rat paw edema model, compound 7d exhibited maximum inhibition, reducing the paw volume by 62.79 and 65.91% at 3 and 5 h post-carrageenan administration, respectively, in comparison to indomethacin (76.74% at 3 h and 79.54% at 5 h after carrageenan administration). Furthermore, these compounds (7d, 7e, 7g, and 7c) were also found to substantially inhibit pro-inflammatory mediators, i.e., TNF-α, IL-1ß, and IL-6, ex vivo in comparison to indomethacin and did not pose any gastric ulceration risk, indicating the potential of this oxazolopyridine scaffold for the development of GSK-3ß inhibitors and their application as anti-inflammatory agents.

Genistein attenuates D-GalN induced liver fibrosis/chronic liver damage in rats by blocking the TGF-ß/Smad signaling pathways.

BACKGROUND AND AIM: Genistein is a major isoflavonoid abundantly found in soy. Earlier genistein has been reported to possess protective effect against a multitude of disorders including cancer. Previously we demonstrated the protective effects of Genistein in d-Galactosamine (D-GalN) induced fulminant hepatic failure (FHF) in rats. In present study, we evaluated the hepatoprotective activity of Genistein in rat model of chronic liver damage and liver fibrosis. METHODS: Liver fibrosis was induced by intraperitoneal injection of D-GalN (250 mg/kg BW) twice a week for 12 weeks. Genistein (5 mg/kg BW) was given via intra-gastric route as co-treatment daily for 12 weeks. RESULTS: Genistein co-treatment significantly attenuated D-GalN-induced chronic liver damage and liver fibrosis as evident from a significant amelioration in functional impairment, including inhibition of the activation of Hepatic stellate cells (HSC), decreased expression in alpha smooth muscle actin (α-SMA) and accumulation of collagen matrix, and an elevation in serum alanine transaminase (ALT) and aspartate transaminase (AST) level. In addition Genistein co-treatment was associated with elevated expression of hepatic Smad7, which ultimately blunts the expression of TGF-ß and the activation of TGF-ß/Smad signaling. Furthermore Genistein significantly prevented the histopathological changes induced by D-GalN. CONCLUSION: Our results suggest that Genistein could be a novel therapeutic/nutraceutical agent in treating chronic liver damage and liver fibrosis. In addition our study also suggests a possible mechanism of action in which Smad7-induced inhibition of TGF-ß/Smad2/3 can be a central mechanism by which Genistein protects liver from chronic injury.

Regression of fibrosis/cirrhosis by Glycine propionyl-l-carnitine treatment in d-Galactosamine induced chronic liver damage.

BACKGROUND AND PURPOSE: Liver fibrosis and cirrhosis are leading causes of morbidity and mortality, with majority of preventable cases attributed to excessive alcohol consumption, viral hepatitis, or non-alcoholic fatty liver disease. We previously reported the hepatoprotective effect of Glycine propionyl-l-carnitine (GPLC) against the fulminant hepatic failure (FHF) induced by d-Galactosamine (D-GalN). In this study we evaluated the protective effect of GPLC against D-GalN induced chronic liver damage. EXPERIMENTAL APPROACH: Animals received D-GalN twice a week for 12 weeks at a dose of 250 mg/kg body weight (BW). GPLC was given daily for 12 weeks as co-treatment along with D-GalN at a dose of 35 mg/kg BW. KEY RESULTS: D-GalN injection resulted in a considerable decrease in body weight, hepatocellular disintegration, necrosis and lipid peroxidation as evident from altered levels of SOD, CAT and MDA while GPLC significantly restored the reduced body weight and ameliorated hepatocellular damage and lipid peroxidation. D-GalN administration resulted in DNA damage as evident from TUNEL positive cells in disease control rats while; GPLC significantly alleviated the genotoxic effects of D-GalN. Further histopathological analysis revealed significant tissue and cellular damage, and increased collagen content in D-GalN challenged rats. GPLC however ameliorated the damage as evident from normal cellular and morphological architecture in GPLC co-treated rats. Hydroxyproline and nitrotyrosine (NTY) levels marked a significant decrease in GPLC co-treated rats relative to disease control. GPLC significantly blocked D-GalN induced pro-inflammatory cytokine (TNF-α, IL-6) production and at the same time inhibited the expression of α-smooth muscle actin (α-SMA), collagen-I (COL-I) and transforming growth factor-ß (TGF-ß) significantly. CONCLUSION AND IMPLICATIONS: Our results demonstrate significant protective activity of GPLC in chronic liver damage and other complications related to it. This study is a novel study to demonstrate the hepatoprotective effect of GPLC in chronic liver damage.

Bioactivity of genistein: A review of in vitro and in vivo studies.

Genistein is a soy derived isoflavanoid compound with multitude of health benefits. This compound is found to be a potent agent in both prophylaxis and treatment of cancer and various other chronic diseases. Ranging from its antioxidant activity to its effect on various cancer types, genistein has been a compound of interest in a number of studies carried out so far. The great interest that has focused on genistein led to the identification of numerous intracellular targets of its action in the live cells. Retardation of atherogenic activity and increasing the antioxidant defense of a cell has been attributed to genistein while as it has also been reported that genistein possesses suppressive effects on both the cell-mediated and humoral components of the adaptive immune system. At the molecular level, genistein reduces the number of developing CD4(+) and CD8(+) thymocytes suggesting a possible mechanism for genistein effects on cell-mediated immunity. Genistein may inhibit cancer progression by inducing apoptosis or inhibiting proliferation. In addition, genistein has its prominent role in preventing the DNA damage. Apolipoprotein B secretion gets reduced when the subjects are administered with genistein. Genistein confers a better protection to ischemic conditions thereby giving a significant cardioprotection. At cellular level adipocyte differentiation is another property of genistein which makes it a better neutraceutical which can reduce the atherogenic condition and hypercholesterolemia. Expression of human endothelial nitric oxide synthase is associated with genistein supplementation. The advantage of using genistein is its multidirectional action and its lesser toxicity.

Genistein modulates the expression of NF-κB and MAPK (p-38 and ERK1/2), thereby attenuating d-Galactosamine induced fulminant hepatic failure in Wistar rats.

Genistein is an isoflavanoid abundantly found in soy. It has been found to play an important role in the prevention of various chronic diseases including cancer. In this study, we evaluated potential therapeutic properties of Genistein against d-Galactosamine (d-GalN) induced inflammation and hepatotoxicity in male Wistar rats. Fulminant hepatic failure (FHF) was induced in rats by intraperitoneal injection of d-GalN (700mg/kgBW). Genistein (5mg/kgBW/day) was given as pre-treatment for 30days via intra-gastric route followed by d-GalN (700mg/kgBW) injection. The hepatoprotective and curative effects of Genistein were evident from a significant decrease in the serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels as well as prevention of histological damage by pre-treatment of Genistein. Genistein pre-treatment significantly inhibited the increased protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), thereby reducing nitric oxide (NO) and prostaglandin-E2 (PGE) levels, respectively. In addition Genistein significantly suppressed the production of d-GalN-induced proinflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin (IL)-1ß. These inhibitory effects were associated with the suppression of nuclear factor-kappa B (NF-ĸB) activation, IKKα/ß and Mitogen activated protein kinase (MAPK) phosphorylation by Genistein in d-GalN-treated animals. In conclusion, our results suggest that Genistein may serve as a potential supplement in the prevention of hepatic and inflammatory diseases. Furthermore Genistein is able to maintain the redox potential and strengthens the antioxidant defense system of a cell.

Ellagic acid, an NF-κB inhibitor, ameliorates renal function in experimental diabetic nephropathy.

Diabetic nephropathy (DN) is a serious complication confronted by diabetic patients. Available data indicate that the development of DN is linked to inflammation. In this context, nuclear factor-kappa B (NF-κB) has received much attention. Ellagic acid (2,3,7,8-tetrahydroxy-chromeno[5,4,3-cde]chromene-5,10-dione), found abundantly in plant extracts and fruits, possesses numerous medicinal properties. We investigated the nephroprotective effects of oral treatment of ellagic acid in high fat diet/low dose streptozotocin (HFD/STZ)-induced type 2 diabetic Wistar albino rats. Ellagic acid treatment for 16weeks post induction of diabetes significantly attenuated renal dysfunction and oxidative stress. Ellagic acid significantly inhibited the renal NF-кB activation. Moreover, ellagic acid significantly lowered renal pathology and suppressed transforming growth factor-beta (TGF-ß) and fibronectin expressions in renal tissues. Ellagic acid also significantly reduced the serum levels of pro-inflammatory cytokines, interleukin-1beta (IL-1ß), IL-6 and tumor necrosis factor-alpha (TNF-α). In cultured rat NRK 52E proximal tubular epithelial cells, ellagic acid treatment inhibited high glucose-induced activation of NF-κB and pro-inflammatory cytokine synthesis. These results suggest that ellagic acid exhibited renal protective effect in diabetic rats partly through antihyperglycemia which was accompanied by attenuation of inflammatory processes via inhibition of NF-κB pathway.

Chrysin, an anti-inflammatory molecule, abrogates renal dysfunction in type 2 diabetic rats.

Diabetic nepropathy (DN) is considered as the leading cause of end-stage renal disease (ESRD) worldwide, but the current available treatments are limited. Recent experimental evidences support the role of chronic microinflammation in the development of DN. Therefore, the tumor necrosis factor-alpha (TNF-α) pathway has emerged as a new therapeutic target for the treatment of DN. We investigated the nephroprotective effects of chrysin (5, 7-dihydroxyflavone) in a high fat diet/streptozotocin (HFD/STZ)-induced type 2 diabetic Wistar albino rat model. Chrysin is a potent anti-inflammatory compound that is abundantly found in plant extracts, honey and bee propolis. The treatment with chrysin for 16weeks post induction of diabetes significantly abrogated renal dysfunction and oxidative stress. Chrysin treatment considerably reduced renal TNF-α expression and inhibited the nuclear transcription factor-kappa B (NF-кB) activation. Furthermore, chrysin treatment improved renal pathology and suppressed transforming growth factor-beta (TGF-ß), fibronectin and collagen-IV protein expressions in renal tissues. Chrysin also significantly reduced the serum levels of pro-inflammatory cytokines, interleukin-1beta (IL-1ß) and IL-6. Moreover, there were no appreciable differences in fasting blood glucose and serum insulin levels between the chrysin treated groups compared to the HFD/STZ-treated group. Hence, our results suggest that chrysin prevents the development of DN in HFD/STZ-induced type 2 diabetic rats through anti-inflammatory effects in the kidney by specifically targeting the TNF-α pathway.

Glycine propionyl l-carnitine attenuates d-Galactosamine induced fulminant hepatic failure in wistar rats.

Glycine propionyl l-carnitine (GPLC) is a propionyl ester of carnitine that includes an additional glycine component. The present study evaluated hepatoprotective effect of GPLC in d-Galactosamine (d-GalN) induced fulminant hepatic failure. Rats were intraperitonially administered d-GalN (700mg/kgBW). GPLC was given as a pre-treatment (35mg/kgBW/day) for 1month followed by a single dose of d-GalN on the 31st day. d-GalN administration resulted in increased mortality and serum ALT and AST activities. These increases were significantly attenuated by GPLC. d-GalN treatment increased hepatic lipid peroxidation and a decrease in reduced glutathione content was observed. GPLC pre-treatment significantly decreased lipid peroxidation and augmented the level of GSH. d-GalN increased the circulating level of TNF-α and ATM-Kinase and MAP-Kinase expression. GPLC supplementation inhibited the increase in serum TNF-α and ATM-Kinase and MAP-Kinase expression. d-GalN treatment increased the level of Bax and Caspase-3 m-RNA while as a decline was observed in Bcl2 m-RNA. GPLC prevented the increase in Caspase-3 and Bax m-RNA and at the same time augmented the expression of Bcl2 m-RNA. Our findings suggest that GPLC alleviates d-GalN induced liver injury by strengthening antioxidative defense system and reducing apoptotic signalling pathways.