Pharmacological inhibition of lipid peroxidation attenuates calpain-mediated cytoskeletal degradation after traumatic brain injury

Free radical-induced lipid peroxidation (LP) is critical in the evolution of secondary injury following traumatic brain injury (TBI). Previous studies in our laboratory demonstrated that U-83836E, a potent LP inhibitor, can reduce post-TBI LP along with an improved maintenance of mouse cortical mitochondrial bioenergetics and calcium (Ca(2+)) buffering following severe (1.0 mm; 3.5 m/s) controlled cortical impact TBI (CCI-TBI). Based upon this preservation of a major Ca(2+) homeostatic mechanism, we have now performed dose-response and therapeutic window analyses of the ability of U-83836E to reduce post-traumatic calpain-mediated cytoskeletal (α-spectrin) proteolysis in ipsilateral cortical homogenates at its 24 h post-TBI peak. In the dose-response analysis, mice were treated with a single i.v. dose of vehicle or U-83836E (0.1, 0.3, 1.3, 3.0, 10.0 or 30.0 mg/kg) at 15 min after injury. U-83836E produced a dose-related attenuation of α-spectrin degradation with the maximal decrease being achieved at 3.0 mg/kg. Next, the therapeutic window was tested by delaying the single 3 mg/kg i.v. dose from 15 min post-injury out to 1, 3, 6 or 12 h. No reduction in α-spectrin degradation was observed when the treatment delay was 1 h or longer. However, in a third experiment, we re-examined the window with repeated U-83836E dosing (3.0 mg/kg i.v. followed by 10 mg/kg i.p. maintenance doses at 1 and 3 h after the initial i.v. dose) which significantly reduced 24 h α-α-spectrin degradation even when treatment initiation was withheld until 12 h post-TBI. These results demonstrate the relationship between post-TBI LP, disruptions in neuronal Ca(2+) homeostasis and calpain-mediated cytoskeletal damage.     

Identifying simultaneous matrix metalloproteinases/soluble epoxide hydrolase inhibitors

Molecular and Cellular Biochemistry - Matrix metalloproteinase (MMP) and soluble epoxide hydrolase (sEH) have completely unrelated biological functions; however, their dysregulation produce similar...     

Protective role of Codiaeum variegatum against genotoxicity induced by carmustine in somatic and germ cells of male mice

Molecular Biology Reports - Carmustine (Cr) is an important chemotherapeutic drug, widely used in the treatment of brain tumors. Herein, the protective role of Codiaeum variegatum leaves ethyl...     

Bacteriophage influence Campylobacter jejuni types populating broiler chickens

The characteristics that allow one Campylobacter jejuni genotype to succeed over another under the influence of bacteriophage predation have been examined in experimental broiler chickens following the observation that this succession appeared to occur in naturally colonized broiler chicken flocks. Examination of three C. jejuni strains from a single flock indicated that horizontal transfer of at least 112 kb of genomic DNA from strain F2C10 (bacteriophage sensitive) to strain F2E1 (bacteriophage insensitive) had created strain F2E3. Transfer of this DNA was associated with acquisition of sensitivity to 6 of 25 lytic bacteriophage isolated from the same flock. All strains tested were capable of colonizing broiler chickens but cocolonization revealed that the bacteriophage sensitive strains F2E3 and F2C10 had a competitive advantage over the bacteriophage insensitive strain F2E1. With the addition of lytic bacteriophage the situation was completely reversed, with F2E1 dominating. The inability to replicate bacteriophage is associated with a significant fitness cost that renders the insensitive strain competitive only in the presence of bacteriophage. We demonstrate that interstrain recombination in vivo can generate genome diversity in C. jejuni and that bacteriophage predation is a strong selective pressure that influences the relative success of emergent strains in broiler chickens.     

Olfactory associative behavioral differences in three honey bee Apis mellifera L. races under the arid zone ecosystem of central Saudi Arabia

Apis mellifera jemenitica is the indigenous race of honey bees in the Arabian Peninsula and is tolerant to local drought conditions. Experiments were undertaken to determine the differences in associative learning and memory of honey bee workers living in the arid zone of Saudi Arabia, utilizing the proboscis extension response (PER). These experiments were conducted on the indigenous race (A. m. jemenitica) along with two introduced European races (A. m. carnica and A. m. ligustica). The data revealed that A. m. jemenitica is amenable to PER conditioning and may be used in conditioning experiments within the olfactory behavioral paradigm. The results also demonstrated that the three races learn and retain information with different capacities relative to each other during the experimental time periods. Native Arabian bees (A. m. jemenitica) exhibited significantly lower PER percentage during second and third conditioning trials when compared to exotic races. Apis mellifera jemenitica also exhibited reduced memory retention at 2?h and 24?h when compared to A. m. carnica and A. m. ligustica. Therefore, the native Arabian bees were relatively slow learners with reduced memory retention compared to the other two races that showed similar learning and memory retention. Three or five conditioning trials and monthly weather conditions (October and December) had no significant effects on learning and memory in A. m. jemenitica. These results emphasized a novel line of research to explore the mechanism and differences in associative learning as well as other forms of learning throughout the year among bee races in the harsh arid conditions of Saudi Arabia. This is the first study in Saudi Arabia to demonstrate inter-race differences regarding olfactory associative learning between native Arabian bees and two introduced European honey bee races.     

3-Trifluoromethylpyrazolones derived nucleosides: Synthesis and antiviral evaluation

Dengue (DENV) viral infection is a global public health problem that infrequently develops life threatening diseases such as dengue hemorrhagic fever (DFS) and dengue shock syndrome (DSS). Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic human corona virus with 38% fatality rate of infected patients. A series of 4-arylhydrazono-5-trifluoromethyl-pyrazolones, their ribofuranosyl, and 5′-deoxyribofuranosyl nucleosides were synthesized, geometry optimized using Density functional theory (DFT), and evaluated for their antiviral activity. 2-Nitrophenylhydrazonopyra-zolone derivative 5 showed significant activity against MERS-CoV (EC₅₀ = 4.6?μM). The nucleoside analog 8 showed moderate activity against DENV-2 (EC₅₀ = 10?μM), while the activity was abolished with the corresponding 5′-deoxyribonucleoside analogs. The identified hits in this study set this category of compounds for further future optimizations.     

Antioxidant Capacity of Melatonin on Preimplantation Development of Fresh and Vitrified Rabbit Embryos: Morphological and Molecular Aspects

Embryo cryopreservation remains an important technique to enhance the reconstitution and distribution of animal populations with high genetic merit. One of the major detrimental factors to this technique is the damage caused by oxidative stress. Melatonin is widely known as an antioxidant with multi-faceted ways to counteract the oxidative stress. In this paper, we investigated the role of melatonin in protecting rabbit embryos during preimplantation development from the potential harmful effects of oxidative stress induced by in vitro culture or vitrification. Rabbit embryos at morula stages were cultured for 2 hr with 0 or 10⁻³ M melatonin (C or M groups). Embryos of each group were either transferred to fresh culture media (CF and MF groups) or vitrified/devitrified (CV and MV groups), then cultured in vitro for 48 hr until the blastocyst stage. The culture media were used to measure the activity of antioxidant enzymes: glutathione-s-transferase (GST) and superoxide dismutase (SOD), as well as the levels of two oxidative substrates: lipid peroxidation (LPO) and nitric oxide (NO). The blastocysts from each group were used to measure the expression of developmental-related genes (GJA1, POU5F1 and Nanog) and oxidative-stress-response-related genes (NFE2L2, SOD1 and GPX1). The data showed that melatonin promoted significantly (P<0.05) the blastocyst rate by 17% and 12% in MF and MV groups compared to their controls (CF and CV groups). The GST and SOD activity significantly increased by the treatment of melatonin in fresh or vitrified embryos, while the levels of LPO and NO decreased (P<0.05). Additionally, melatonin considerably stimulated the relative expression of GJA1, NFE2L2 and SOD1 genes in MF and MV embryos compared to CF group. Furthermore, melatonin significantly ameliorated the reduction of POU5F1 and GPX1 expression induced by vitrification. The results obtained from the current investigation provide new and clear molecular aspects regarding the mechanisms by which melatonin promotes development of both fresh and vitrified rabbit embryos.     

18β-Glycyrrhetinic acid exerts protective effects against cyclophosphamide-induced hepatotoxicity: potential role of PPARγ and Nrf2 upregulation

18β-Glycyrrhetinic acid (18β-GA) has been proposed as a promising hepatoprotective agent. The current study aimed to investigate the protective action and the possible mechanisms of 18β-GA against cyclophosphamide (CP)-induced liver injury in rats, focusing on the role of peroxisome proliferator-activated receptor gamma (PPARγ) and NF-E2-related factor-2 (Nrf2). Rats were administered 18β-GA at doses 25 and 50 mg/kg 2 weeks prior to CP injection. Five days after CP administration, animals were sacrificed and samples were collected. CP induced hepatic damage evidenced by the histopathological changes and significant increase in serum pro-inflammatory cytokines, liver marker enzymes, and liver lipid peroxidation and nitric oxide (NO) levels. 18β-GA counteracted CP-induced oxidative stress and inflammation as assessed by restoration of the antioxidant defenses and diminishing of pro-inflammatory cytokines, lipid peroxidation, and NO production. These hepatoprotective effects appear to depend on activation of Nrf2 and PPARγ, and subsequent suppression of nuclear factor-kappa B. In conclusion, the present study provides evidence that 18β-GA exerts hepatoprotective effects against CP through induction of antioxidant defenses and suppression of inflammatory response. This report also confers new information that 18β-GA protects liver against the toxic effect of chemotherapeutic alkylating agents via activation of Nrf2 and PPARγ.     

The feeding responses evoked by cholecystokinin are mediated by vagus and splanchnic nerves

Total or selective branch vagotomy attenuates the reduction of cumulative food intake by cholecystokinin (CCK)-8 and CCK-33 respectively. However, the role of the sympathetic innervation of the gut and the role of the vagus nerve in feeding responses, which include meal size (MS) and intermeal interval (IMI), evoked by CCK-8 and CCK-33 have not been evaluated. Here, we tested the effects of total subdiaphragmatic vagotomy (VGX) and celiaco-mesenteric ganglionectomy (CMGX) on the previous feeding responses by CCK-8 and CCK-33 (0, 1, 3, and 5 nmol/kg given intraperitoneally). We found (1) that both peptides reduced meal size and CCK-8 (5 nmol) and CCK-33 (1 and 3 nmol) prolonged IMI, (2) that VGX attenuated the reduction of MS but failed to attenuate the prolongation of IMI by both peptides and (3) that CMGX attenuated the reduction of meal size by CCK-8 and the prolongation of IMI by both peptides. Therefore, the feeding responses evoked by CCK-8 require intact vagus and splanchnic nerves: the reduction of MS by CCK-33 requires an intact vagus nerve, and the prolongation of IMI requires the splanchnic nerve. These findings demonstrate the differential peripheral neuronal mediation of the feeding responses evoked by CCK-8 and CCK-33.