Possible Mechanism Of Protective Effect Research Articles

Nutraceutical Potential of Vitexin: A Flavone Glycoside

Vitexin is an apigenin flavone glycoside and it is extensively present in numerous edible and medicinal plants. It is considered as important as other flavonoids. It possessed a variety of biological properties, including anti-oxidation, anti-inflammation, anticancer, neuron-protective, cardio-protective, hepatopancreatic protective effects. Other reported health relevant effects, includes fat reduction and glucose metabolism. The possible mechanism of protective effect through activation or inhibition of the different signaling pathways like AMPKa, Nrf-2, mTOR, PUMA, MMP, PARP, JNK, p38, Bcl-2/Bax ratio etc. The molecular targets of vitexin are very critical to utilize its potential effect as emerging chemopreventive and chemotherapeutic agent.

Protection Against Blood-Brain Barrier Permeability as a Possible Mechanism for Protective Effects of Thymoquinone Against Sickness Behaviors Induced by Lipopolysaccharide in Rats

Background: Blood-brain barrier (BBB), as well-known protection for the brain, plays an active role in normal homeostasis. It might be changed by a range of inflammatory mediators to have a role in sickness behaviors. Objectives: Regarding the anti-inflammatory effects of thymoquinone (TQ), its protection against BBB permeability, as a possible mechanism for protective effects against sickness behaviors elicited by lipopolysaccharide (LPS), was evaluated in rats. Methods: The animals were grouped as follows and treated (n = 10 in each): (1) control (saline); (2) LPS 1 mg/kg, was injected two hours before behavioral tests for two weeks; (3-5) 2, 5, and 10 mg/kg TQ, respectively was injected 30 min before LPS injection. Open-field (OF), elevated plus-maze (EPM) and Forced Swimming test (FST) were done. Finally, the animals were anesthetized to evaluate for BBB permeability using Evans blue (EB) dye method. Results: Compared with control, LPS decreased the peripheral distance and crossing and also total crossing and distance in OF, (P < 0.01 - P < 0.001). The central crossing and distance and central time in all three treatment groups were more than LPS (P < 0.05 - P < 0.001). LPS also reduced the entries and the time spent in the open arm while increased the time spent in the closed arm in EPM (P < 0.05 - P < 0.001). The effects of LPS were reversed by TQ (P < 0.05 - P < 0.001). In FST, the immobility time and active time were increased and decreased by LPS compared with control (P < 0.001), respectively. In all three TQ-treated groups, the active and climbing times were more while the immobility time was fewer than the LPS (P < 0.05 - P < 0.001). The animals of the LPS group showed more EB dye content in their brain tissue than the control group (P < 0.05 - P < 0.001). TQ significantly reduced EB dye content of the brain tissues (P < 0.05 - P < 0.001). Conclusions: According to this study, protection against BBB permeability as a possible mechanism for the protective effects of TQ against sickness behaviors induced by LPS might be suggested.

Tert-butylhydroquinone mitigates Carbon Tetrachloride induced Hepatic Injury in mice.

Tert-butylhydroquinone (tBHQ) is an antioxidant compound that exhibits cytoprotective effect in many tissues under pathological condition. However, its role in carbon tetrachloride (CCL4) induced liver injury is still unclear. Here we established a carbon tetrachloride induced hepatic injury model in mice to determine whether tBHQ can mitigate CCL4 induced liver damage. In our study, we found tBHQ exhibited protective effects in CCL4 treated mice model. TBHQ markedly improved hepatic function and decreased hepatic histopathological damage in vivo. In addition, tBHQ reduced levels of pro-inflammatory cytokines in mice model. Moreover, tBHQ mitigated apoptosis of hepatocytes, oxidative stress and lipid peroxidation in vivo and in vitro. We also found the possible mechanism of protective effects of tBHQ was associated with activation of Nrf2/ heme oxygenase-1 (HO-1) pathway. In conclusion, our study revealed tBHQ can be a potential therapeutic drug in treatment of acute hepatic injury.

Neuroprotective effect of Qinggan Lishui formula on retinal ganglion cell apoptosis in a microbead-induced rat chronic glaucoma model

OBJECTIVETo investigate a possible mechanism for protective effects of a decoction of the Qinggan Lishui formula (QF) on retinal ganglion cells (RGCs) in a rat model of microbead-induced chronic intraocular hypertension (COH). METHODSThe COH model was generated by injecting microbeads (superparamagnetic iron oxide) into the anterior chamber of rat eyes. QF was given by intragastric administration (gavage) once daily at a dose of 6.2 g/kg until day 28, following microbead injection. Cholera toxin B subunit (CTB) retrograde labeling and immunohistochemistry were used to evaluate changes in the number of RGCs in the retina. Terminal dUTP nick end labeling (TUNEL) staining was used to assess apoptotic changes in RGCs. RESULTSMicrobead injection induced a steady increase in intraocular pressure (IOP) of rats. Elevated IOP resulted in a progressive reduction in the number of CTB-labeled RGCs, 2-4 weeks after microbead injection. QF administration may moderately reduce IOP in the rat COH model and attenuate reduction of the number of CTB-labeled RGCs in COH rats. Furthermore, elevated IOP resulted in a progressive increase in the number of TUNEL-positive RGCs, 2–4 weeks after microbead injection, suggestive of an increase in the extent of RGC apoptosis. There was a significant reduction in the number of TUNEL-positive signals in QF-treated COH retinas, compared with untreated COH retinas. CONCLUSIONQF decoction may provide a protective effect for RGCs in COH retinas by reducing RGC loss; these effects may be mediated by inhibition of RGC apoptosis.

Activity of neuron-specific enolase in patients with acute ishemic stroke on the background of correction of infusion solutions

The article analyzes the impact of a single course of treatment with various infusion solutions on the intensity of the flow of destructive changes in the neurons of the brain to the dynamics of the activity of the neuron-specific enolase, which is an early marker of damage of the nervous tissue. The level of neuron-specific enolase in serum of patients with acute stroke is correlated with the volume of cerebral infarction. To a thorough determine the presence of the protective effect in the infusion solutions on the brain was interest to investigate the effect of a single course of treatment with various solutions on the intensity of the flow of destructive changes in the neurons of the brain with the dynamics of neuron-specific enolase in acute disorder of cerebral circulation. Analyzed isoosmolar 0.9% NaCl solution and colloidal isoosmolar hydroxyethylstarch 130/04 solution administered intravenous drip in a conventionally effective dose of 2.5 ml / kg p 2 / day (5 ml / kg per day) (determined experimentally) immediately upon confirmation of the diagnosis and further a daily basis and every 12 h for 7 days. Control group were patients treated with infusion solutions only 0.9% NaCl, control group – 0.9% NaCl + hydroxyethylstarch 130/04. Using of the isoosmolar 0.9% NaCl solution for 7 days in addition to standard therapy promotes a statistically significant increase in the activity of the neuron-specific enolase on the seventh day of stroke, which is associated with increasing of necrotic tissue in the ischemic area of the brain in patients with acute disorder of cerebral circulation in ischemic type. Infusion therapy in patients with acute disorder of cerebral circulation in ischemic type with isoosmolar 0,9% NaCl + colloid isoosmolar solution of hydroxyethyl starch 130/04, against a background of standard therapy, been accompanied by a significant decrease in the neuron-specific enolase compared with the control group which indicates the presence in hydroxyethyl starch 130/04 corrective influence on the dynamics of the processes of neuronal death in acute ischemic stroke. A possible mechanism of protective effect of hydroxyethyl starch 130/04 implemented by improving perfusion of the penumbra, the disclosure of collaterals, properties of endothelial protection in acute disorder of cerebral circulation.

T32: Human papilloma virus association with survival of head and neck cancer patients

The most important development in head and neck oncology of the past decade is the demonstration that patients with human papillomavirus (HPV)-mediated oropharyngeal cancers have significantly improved outcomes, compared to HPV-negative counterpart patients. We examined racial disparities among 102 oropharyngeal carcinoma (OPC) patients (30 African Americans, 72 Whites) comparing the present of HPV16/18 E6 and E7 oncoproteins, and p16Ink4A overexpression, with times to disease progression (DP) and disease specific survival (DSS). Expression of HPV16/18 transcripts was assessed by reverse transcription and polymerase chain reaction using type-specific E6/E7 primers; p16Ink4A was evaluated by immunohistochemistry. African Americans were significantly more likely to present with high T stage disease and receive nonsurgical treatment. HPV16/18 was present in 63% of patients; no racial differences were observed. Silenced p16Ink4A in OPC was significantly more common in African Americans (15/24) than Whites (20/69) ( p = 0.004), and HPV16 + African Americans (6/24) than HPV + Whites (2/42) ( p = 0.023). Kaplan Meier analysis for DSS revealed a protective effect for p16Ink4A overexpression ( p = 0.0028), HPV16+ ( p = 0.036), and Whites ( p = 0.0039). Shorter DSS was associated with primary definitive chemoradiation ( p = 0.019) and T3/T4 disease ( p = 0.0001). A protective effect with respect to disease progression was observed for HPV16+ ( p = 0.007), Whites ( p = 0.0006) and p16Ink4A overexpression ( p = 0.0001). African Americans with OPC experience poorer outcomes likely due to p16Ink4A silencing, higher T stage, and nonsurgical treatment, but not lower rates of transcriptionally active HPV16/18. We studied patients with oral cavity squamous cell carcinoma for HPV16 and HPV18, local immune response, p16 expression and outcome. Overexpression of p16INK4a was uncommon in oral cavity squamous cell carcinoma (17/112 or 15.2%). HPV16 and HPV18 were detected in 22.6% and 11% patients respectively. We demonstrated that the presence of transcriptionally active HPV16 in oral cavity squamous cell carcinomas does not correlate with p16INK4a overexpression, enhanced local tumor immunity, or improved outcome. To investigate the possible mechanism of protective effect of HPV and p16INK4a, we have developed primary cancer cell lines from resections with known patterns of invasion. Given that cell lines derived from HPV-mediated oropharyngeal squamous cell carcinomas are less invasive than their HPV-negative counterparts, we tested the hypothesis that viral oncoproteins E6, E7, and p16INK4a can affect tumor invasion. We demonstrated that p16INK4a overexpression in two cancer cell lines (UAB-3 and UAB-4), derived from oral cavity squamous cell carcinomas with the most aggressive invasive phenotype, dramatically decrease tumor invasiveness by altering expression of extracellular matrix remodeling genes. Pathway analysis integrating changes in RNA expression and kinase activities reveals different potential p16INK4a-sensitive pathways. In summary, we presented clinical data from a large cohort of head and neck squamous cell carcinoma patients with respect to transcriptionally active HPV16, p16INK4a overexpression, local adaptive tumor immunity, and outcome. Observed differences in clinical outcomes could be perhaps due to differential immune responses and gene activation profile. The detection of a HPV-positivity in HNSCC has important clinical implications as independent prognostic factor for treatment deintensification and improved survival of HPV-mediated oropharyngeal cancers. In our knowledge the further studies are needed to dissect the HPV-positive HNSCC in more detail to find the effective prognostic markers as well as molecular targets to affect tumor behavior.

Allogeneic Cytokine-Induced Killer Cells Eliminate Host Dendritic Cells Due To The Enhanced Killing Activity By IFN-Gamma, Leading To Less Graft-Versus-Host Disease

Cytokine-induced killer (CIK) cells are ex vivo–expanded T lymphocytes expressing both natural killer (NK)– and T-cell markers. We have reported that adoptive transfer of allogeneic CIK cells in a murine model caused minimal graft-versus-host disease (GVHD) with retention of antitumor activity mediated by NKG2D, which is an activating receptor expressed on NK cells. It was reported previously that IFN-gamma was a critical cytokine for preventing GVHD because CIK cells generated from IFN-gamma knock out mice caused lethal GVHD. One possible mechanism of protective effect against GVHD was that a large amount of IFN-gamma secreted by CIK cells could promote Fas-mediated apoptosis of recipient antigen activated donor T cells. However the mechanism of suppression of GVHD with CIK cells is not fully understood. Host residual dendritic cells (DCs) are most important cells in initiating GVHD reaction. Therefore, we hypothesize that CIK cells eliminate host DCs as same as kill tumor cells, and then reduce GVHD severity. To test this, 51Cr release assay was performed using BM derived DCs as target cells. We showed that allogeneic CIK cells had cytolytic activity against DCs, in marked contrast killing activity of IFN-gamma deficient CIK cells was much less compared to that of WT CIK cells (p< 0.05). Expression level of surface markers including NKG2D and CD8/CD4 ratio was not different between WT and IFN-gamma KO CIK cells. To further explore the mechanism why IFN-gamma deficient CIK cells reduced killing activity against DCs, IFN-gamma neutralizing antibody was added into killing mixture with WT CIK cells. However killing activity of WT CIK cells against DCs with IFN-gamma antibody did not changed compared to that of WT CIK alone. These results suggested that IFN-gamma itself did not affect killing activity directly, but IFN-gamma was essential cytokine to enhance killing activity during the culture of CIK cells. Next concern was whether CIK cells eliminated host DCs in vivo or not, we compared the residual number of host-type splenic DCs between the mice receiving bone marrow (BM) cells plus WT CIK cells and IFN-gamma deficient CIK cells. As shown in the figure below, the number of host DCs in the spleen in the mice receiving WT CIK cells was significantly lower compared to those of the mice receiving IFN-gamma KO CIK cells (p<0.05). In conclusion, allogeneic CIK cells eliminated host DCs due to the enhanced killing activity by IFN-gamma, leading to much less GVHD. Disclosures: No relevant conflicts of interest to declare.

Possible mechanism of protective effect of thalidomide in STZ-induced-neuropathic pain behavior in rats

Diabetes-induced neuropathic pain is recognized as one of the most difficult type of pain to treat and conventional analgesics are well known to be partially effective or associated with potential toxicity. Recently, it has been demonstrated that thalidomide, besides its teratogenic potential, reduced chronic pain in an SNL experimental pain model. The present study was designed to investigate the effect of thalidomide on streptozotocin (STZ)-induced neuropathic pain in rats. Streptozotocin (20 mg/kg, i.p, daily × 4 days) was administered to induce diabetes in the rats. Nociceptive latency was measured using tail-flick and paw-withdrawal test. Thermal hyperalgesia and mechanical allodynia were measured using planter test and dynamic aesthesiometer (Ugo-Basile, Italy), respectively. Urinary and serum nitrite concentration was estimated using Greiss reagent method. Spleen homogenate supernatant was prepared from spleen of 28th day diabetic rats and administered to normal rats (400 ul, i.v) daily for 28 days. Pain threshold progressively decreased in STZ-treated rats, as compared with control rats. 3 weeks after induction of diabetes, the rat exhibited thermal hyperalgesia and mechanical allodynia. The analgesic effect of morphine (8 mg/kg, s.c.) was significantly decreased in both diabetic and in SHS-treated non-diabetic rats. Administration of thalidomide (25 and 50 mg/kg, i.p), a TNF-α inhibitor, significantly prevented hyperglycemia-induced thermal hyperalgesia and mechanical allodynia and also attenuated the increase in serum and urinary nitrite concentration, as compared with untreated diabetic rats. Also, thalidomide (25 and 50 mg/kg, i.p) 1 h before or concurrently with morphine significantly restored the analgesic effect of morphine in diabetic rats. It may be concluded that thalidomide has a beneficial effect in neuropathic pain by decreasing cytokines (TNF-α) and nitric oxide level and may provide a novel promising therapeutic approach for managing painful diabetic neuropathy.

Synthesis of some novel N4-(naphtha[1,2- d]thiazol-2-yl)semicarbazides as potential anticonvulsants

A series of N 4-(naphtha[1,2- d]thiazol-2-yl)semicarbazides were designed and synthesized to meet the structural requirements essential for anticonvulsant activity. Anticonvulsant activity was determined after intraperitoneal (i.p.) administration to mice by maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ)-induced seizure tests and minimal motor impairment was determined by rotorod test. A majority of the compounds exhibited significant anticonvulsant activity after intraperitoneal administration. Some of the selected compounds were evaluated orally in rats for activity in scPTZ test at several time points (50 mg/kg). The most active compounds carry bromo, fluoro and nitro substituents at 4-position in the phenyl ring. The biochemical estimations of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) from brain homogenate not only clearly implicated the role of free radicals in PTZ-induced convulsion but also explained the possible mechanism of protective effect of semicarbazides, through the reduced formation of MDA and increased formation of SOD and GSH-Px.

Prevention of Apoptosis-Inducing Factor Translocation is a Possible Mechanism for Protective Effects of Hepatocyte Growth Factor against Neuronal Cell Death in the Hippocampus after Transient Forebrain Ischemia

Hepatocyte growth factor (HGF) is one of the prospective agents for therapy against a variety of neurologic and neurodegenerative disorders, although the precise mechanisms for the effect of HGF remain to be elucidated. We showed that treatment with HGF protected hippocampal cornu ammonis (CA) subregion 1 neurons from apoptotic cell death after transient forebrain ischemia. Accumulating evidence indicates that ischemia-induced neuronal damage occurs via caspase-independent pathways. In the present study, we focused on the localization of apoptosis-inducing factor (AIF), which is an important protein in the signal-transduction system through caspase-independent pathways, to investigate the possible mechanism for the protective effect of HGF after transient forebrain ischemia. Hepatocyte growth factor attenuated the increase in the expression of AIF protein in the nucleus after transient forebrain ischemia. We further explored the upstream components of AIF translocation. Primary DNA damage induced by Ca(2+) influx and subsequent NO formation are thought to be the initial events for AIF translocation, which results in the subsequent DNA damage by AIF. Hepatocyte growth factor prevented the primary oxidative DNA damage, as was estimated by using anti-8-OHdG (8-hydroxy-2'-deoxyguanosine) antibody. Oxidative DNA damage after ischemia is known to lead to the activation of poly(ADP-ribose) polymerase (PARP) and p53, resulting in AIF translocation. Marked increases in the PAR polymer formation and the expression of p53 protein after ischemia were effectively prevented by HGF treatment. In the present study, we first showed that HGF was capable of preventing neuronal cell death by inhibiting the primary oxidative DNA damage and then preventing the activation of the PARP/p53/AIF pathway.

Direct reduction of N-acetoxy-PhIP by tea polyphenols: a possible mechanism for chemoprevention against PhIP–DNA adduct formation

The chemopreventive effect of tea against 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP)–DNA adduct formation and its mechanism were studied. Rats were exposed to freshly prepared aqueous extracts of green tea (3% (w/v)) as the sole source of drinking water for 10 days prior to administration with a single dose of PhIP (10 mg/kg body weight) by oral gavage. PhIP–DNA adducts in the liver, colon, heart, and lung were measured using the 32 P -postlabelling technique. Rats pre-treated with tea and given PhIP 20 h before sacrifice had significantly reduced levels of PhIP–DNA adducts as compared with controls given PhIP alone. The possible mechanism of protective effect of tea on PhIP–DNA adduct formation was then examined in vitro. It was found that an aqueous extract of green and black tea, mixtures of green and black tea polyphenols, as well as purified polyphenols could strongly inhibit the DNA binding of N-acetoxy-PhIP, a putative ultimate carcinogen of PhIP formed in vivo via metabolic activation. Among these, epigallocatechin gallate was exceptionally potent. HPLC analyses of these incubation mixtures containing N-acetoxy-PhIP and the tea polyphenols each revealed the production of the parent amine, PhIP, indicating the involvement of a redox mechanism. In view of the presence of relatively high levels of tea polyphenols in rat and human plasma after ingestion of tea, this study suggests that direct reduction of the ultimate carcinogen N-acetoxy-PhIP by tea polyphenols is likely to be involved in the mechanism of chemoprotection of tea against this carcinogen.

Possible mechanism for protective effect of theflavonoid quercetin

Possible mechanism for protective effect of theflavonoid quercetin

Intermittent perfusion of ischemic myocardium. Possible mechanisms of protective effects on mechanical function in isolated rat heart.

Intermittent restoration of coronary flow during ischemia reduced myocardial damage and improved recovery of function. The mechanisms of the protective effects of intermittent perfusion were investigated in isolated rat hearts. Ventricular function was assessed as the product of developed pressure (left ventricular systolic pressure minus end-diastolic pressure) and heart rate. Recovery of function was calculated by division of the product at the end of reperfusion by that before ischemia. After 40 minutes of sustained global ischemia, intracellular Na+ (Nai) increased from 11 to 74 mumol/g dry wt. During 30 minutes of reperfusion, these hearts took up a large amount of 45Ca2+ (10 mumol/g dry wt), recovered only 24% of preischemic function, and had an increased left ventricular end-diastolic pressure (48 mm Hg). When the 40-minute period of ischemia was interrupted at 10-minute intervals by intermittent perfusion (three periods of 3 minutes) with either oxygenated or hypoxemic buffer, Nai increased to only 12 or 17 mumol/g dry wt, and reperfusion resulted in much lower 45Ca2+ uptake (0.5 and 0.5 mumol/g dry wt, respectively). Recovery of function was 100% of the preischemic value. When hypoxemic buffer without glucose was used for intermittent perfusion, Nai increased to 50 mumol/g dry wt, ATP was depleted, and reperfusion resulted in reduced recovery of function (76%) and moderately increased 45Ca2+ uptake (2.1 mumol/g dry wt). The role of Na(+)-K+ pump activity in maintaining low Nai was assessed by removing K+ from oxygenated or hypoxemic buffers used during intermittent perfusion. Under these conditions, Nai rose to 64 or 102 mumol/g dry wt, 45Ca2+ uptake increased to 4.4 or 9.4 mumol/g dry wt, and recovery of function was poor. There was a highly significant correlation between Nai during ischemia and reperfusion Ca2+ overload (r = 0.87) or impaired recovery of function (r = 0.96). These results indicate that prevention of an increase in Nai by maintenance of Na(+)-K+ pump activity is associated with a reduction of Ca2+ overload through Na+/Ca2+ exchange.