2-BFI attenuates ischemic injury by modulating mTOR signaling and neuroinflammation in rats.

Ischemic stroke is one of the major diseases that cause mortality and morbidity of human beings, but there is still lack of effective treatment and prevention. We found that 2-(2-Benzofuranyl)-2-Imidazoline (2-BFI) is potently protective against stroke and acute inflammatory immune disease. Moreover, the mammalian target of rapamycin (mTOR) signaling contributes effectively to the modulation of post-stroke neuroinflammatory response. However, whether the protection of 2-BFI against ischemic injury is through mTOR-mediated neuroinflammatory response remains unestablished. Here, we used 2-BFI to treat ischemic rats induced by distal middle cerebral artery occlusion (dMCAO). We found that 2-BFI administration after dMCAO improved the neurological deficits and decreased the infarct volume. 2-BFI reduced phosphorylation of mTOR and p70S6, increased IL-10 and TGF-ß, and decreased IFN-γ levels in ischemic rats. Our results demonstrated that 2-BFI attenuates ischemic injury by inhibiting the activation of mTOR signaling and modulating neuroinflammation after stroke in rats.

Effect of methyl jasmonate and 3-bromopyruvate combination therapy on mice bearing the 4 T1 breast cancer cell line.

Cancer cells apply the Warburg pathway to meet their increased metabolic demands caused by their rapid growth and proliferation and also creates an acidic environment to promote cancer cell invasion. 3-bromopyruvate (3-BrP) as an anti-cancer agent disrupts glycolytic pathway. Moreover, one of the mechanism of actions of Methyl Jasmonate (MJ) is interference in glycolysis. Hence, the aim of this study was to evaluate MJ and 3-BrP interaction. MTT assay was used to determine IC50 and synergistic concentrations. Combination index was applied to evaluate the drug- drug interaction. Human tumor xenograft breast cancer mice was used to evaluate drug efficacy in vivo. Tumor size was considered as a drug efficacy criterion. In addition to drug efficacy, probable side effects of these drugs including hepatotoxicity, renal failure, immunotoxicity, and losing weight were evaluated. Serum alanine aminotransferase and aspartate aminotransferase for hepatotoxicity, serum urea and creatinine level for the possibility of renal failure and changes in body weight were measured to evaluate drug toxicity. IL10 and TGFß secretion in supernatant of isolated splenocytes from treated mice were assessed to check immunotoxicity. 3-BrP synergistically augmented the efficacy of MJ in the specific concentrations. This polytherapy was more effective than monotherapy of 3-BrP, MJ, and also surprisingly cyclophosphamide as a routine treatment for breast cancer in the tumor bearing mice. These results have been shown by decrease in tumor volume and increase of tumor growth inhibition percentage. This combination therapy didn't have any noticeable side effects on kidney, liver, and immune system and body weight.

Affibody molecules: engineered proteins for therapeutic, diagnostic and biotechnological applications.

Affibody molecules are a class of engineered affinity proteins with proven potential for therapeutic, diagnostic and biotechnological applications. Affibody molecules are small (6.5 kDa) single domain proteins that can be isolated for high affinity and specificity to any given protein target. Fifteen years after its discovery, the Affibody technology is gaining use in many groups as a tool for creating molecular specificity wherever a small, engineering compatible tool is warranted. Here we summarize recent results using this technology, propose an Affibody nomenclature and give an overview of different HER2-specific Affibody molecules. Cumulative evidence suggests that the three helical scaffold domain used as basis for these molecules is highly suited to create a molecular affinity handle for vastly different applications.

Benzodiazepines protect against ethanol-induced gastric mucosal damage in vitro.

The protective effects of drugs acting at the benzodiazepine receptors against ethanol-induced gastric damage were investigated using a newly developed in vitro model of the ethanol-induced gastric damage. The rat stomachs were isolated from the whole animal and kept in Kreb's solution at 37 degrees C. Gastric damage was induced by administration of 1 mL of 50% V/V ethanol into the isolated rat stomach. Administration of the benzodiazepine agonist, clonazepam (25, 50, 100 microg), or the partial benzodiazepine inverse agonist Ro15-4513 (50 or 100 microg), significantly protected against ethanol-induced gastric damage when these agents were administered 15 min before ethanol. The protective effects of these drugs were blocked by the benzodiazepine receptor antagonist flumazenil (200-400 microg). Flumazenil alone was found to aggravate ethanol-induced gastric damage (200-400 microg). The results of this study give evidence for the involvement of central-type benzodiazepine receptors located in the stomach in the protective action of benzodiazepines against ethanol-induced gastric damage.

Inhibitors of 17alpha-hydroxylase/17,20-lyase (CYP17): potential agents for the treatment of prostate cancer.

Prostate cancer (PCa) is now the most prevalent cancer in men in the U.S.A. and Europe. At present the major treatment options include surgical or medical castration. These strategies depend on the abolition of the production of testosterone by the testes. However, as these procedures do not affect adrenal androgen production, they are frequently combined with androgen receptor antagonist to block their action. Inhibition of the key enzyme which catalyzes the biosynthesis of androgens from pregnane precursors, 17alpha-hydroxylase/17,20-lyase (hereafter referred to as CYP17 ) could prevent androgen biosynthesis from both sources. Thus total blockade of androgen production by CYP17 inhibitors may provide effective treatment of prostate cancer patients. Indeed, this strategy is now an area of intense interest within research institutions and the pharmaceutical industry. This review highlights development in the design and evaluation of both steroidal and non-steroidal CYP17 inhibitors since 1965. Major emphasis is given to the potent CYP17 inhibitors and those which may show clinical promise. The review could function as a comprehensive working reference of research accomplishment in the field and what problems remain to be tackled in the future.

Nucleoside trapping during reperfusion prevents ventricular dysfunction, "stunning," in absence of adenosine. Possible separation between ischemic and reperfusion injury.

A previous study has shown that endogenous adenosine trapping during ischemia (by blocking adenine nucleoside transport and inhibiting adenosine breakdown) prevents myocardial stunning. In this study, we tested the hypothesis that delay of administration of inhibitors until reperfusion would similarly prevent myocardial stunning in the absence of entrapped adenosine. In both studies, a selective nucleoside transport blocker, p-nitrobenzyl-thioinosine, was used in combination with a potent adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine, to entrap adenosine (preischemic treatment) or inosine (postischemic treatment) in an in vivo canine model of reversible global ischemia. Twenty-five anesthetized adult dogs were instrumented (by sonomicrometry) to monitor left ventricular performance from the relationship between stroke work and end-diastolic length as a sensitive and load-independent index of contractility. Hearts of animals supported by cardiopulmonary bypass were subjected to 30 minutes of normothermic global ischemia and 60 minutes of reperfusion. Saline solution containing the pharmacologic agents were infused into the bypass circuit before ischemia (group 1) or during reperfusion (group 2). Control group (group 3) received saline before and after ischemia. Myocardial biopsy specimens were obtained before, during, and after ischemia, and levels of adenine nucleotides, nucleosides, oxypurines, and the oxidized form of nicotinamide-adenine dinucleotide were determined. Left ventricular contractility fully recovered within 30 minutes of reperfusion in the groups treated with erythro-9-(2-hydroxy-3-nonyl)adenine and p-nitrobenzyl-thioinosine (p < 0.05 versus control group). Myocardial adenosine triphosphate was depleted by 50% in all groups at the end of ischemia. Adenosine triphosphate recovered during reperfusion only in the group that was treated with inhibitors before ischemia (group 1). At the end of ischemia, adenosine levels were low (< 10% of total nucleosides) in the control group (group 3) and in the group treated only after ischemia (group 2). A high level of adenosine (> 90% of total nucleosides) was present in group 1. We infer that selective pharmacologic blockade of nucleoside transport, only after ischemic injury, accelerated functional recovery during reperfusion, even without trapping of endogenous adenosine during ischemia and without adenosine triphosphate recovery during reperfusion. Recovery of myocardial adenosine triphosphate required preischemic treatment and adenosine entrapment during ischemia and reperfusion. Therefore, nucleoside trapping may be used to prevent reperfusion-mediated injury after reversible ischemic injury.

[The affinity lavage of the abdominal cavity in diffuse peritonitis with liquid sorbents based on cross-linked dextrans]. / Affinnyi lavazh briushnoi polosti pri razlitom peritonite zhidkimi sorbentami na osnove sshitykh dekstranov.

Experiments were conducted on 35 Wistar rats with generalized purulent peritonitis. Twenty-four hours after infection the authors introduced into the animals' abdominal cavity gels of cross-linked dextrans with immobilized polymixin (50 mg/g dry weight) and terrilithin (100 PE/g dry weight), as well as a combination of these sorbents with 24-hour exposure in a 5 ml volume. The object of the study was the detoxification effect. The authors revealed a phenomenon of agglutination of red cells of an ox or rat sensitized by plasma of sick animals in mixing with sephadex G-200 granules with polymixin W immobilized on them. The agglutination titers determined the activity of the sorbent taking part in lavage of the abdominal cavity. The study showed that cross-linked dextrans with immobilized polymixin B and terrilithin introduced into the abdominal cavity in peritonitis are capable of extracting substrates possessing affinity to them, the polymixin sorbent raises the quality of careful mechanical lavage. Combination of gels based on cross-linked dextrans with enzymatic and affinity functions in relation to toxins leads to detoxification and restoration of the disturbed biochemical values by 87%.