Substituted phenyl containing 1,3,4-oxadiazole-2-yl-but-2-enamides: synthesis and preliminary evaluation as promising anticonvulsants

A series of 3-(4-substitutedphenyl)-N-(5-(4-substitutedphenyl-1,3,4-oxadiazol-2-yl)but-2-enamide were synthesized using pharmacophoric elements for in vivo anticonvulsant activity yielding two potent candidates (4d and 4j) in the Phase I and Phase II screening employing maximal electroshock seizure and subcutaneous pentylenetetrazole test having minimal neurotoxicity. Their Phase II screen depicted an increment of nearly 2–10 times for MES and 7–67 folds for scPTZ in the therapeutic index and protective index—the two mainstays in the drug discovery.     

Bradykinin induces NO and PGF2α production via B2 receptor activation from cultured porcine basilar arterial endothelial cells

Our previous in vitro study demonstrated that bradykinin (BK) induced relaxation and contraction of porcine basilar artery (PBA) mediated via activation of endothelial B₂ receptors. The main relaxing and contracting factors appeared to be nitric oxide (NO) and prostaglandin (PG) H₂, respectively, but not thromboxane A₂. After obtaining these findings, we succeeded in cultivating endothelial cells isolated from the PBA. Although PGH₂ has different functionally active isoforms, including PGD₂, PGE₂, and PGF_2α, we have not yet clarified which of them is responsible for BK-induced contraction. Therefore, we attempted to quantify NO and PG production from cultured porcine basilar arterial endothelial cells (PBAECs) and to identify which of the PGs was involved in this contraction. The cultured PBAECs produced NO spontaneously, and BK enhanced this production in a concentration-dependent manner. The NO synthase inhibitor Nω-nitro-l-arginine (L-NNA) and the B₂ receptor antagonist HOE-140, but not the B₁ receptor antagonist des-Arg⁹, [Leu⁸]-BK, completely abolished it. In a functional study, PGD₂, PGE₂, and PGF_2α induced concentration-dependent contractions in isolated porcine basilar arterial rings, the order of maximum contraction being PGF_2α?>?PGE₂?>?PGD₂. The cultured PBAECs produced PGD₂, PGE₂, and PGF_2α spontaneously, and BK significantly enhanced the production of PGF_2α, but not that of PGD₂ and PGE₂. The B₂, but not B₁, antagonist completely abolished the BK-enhanced production of PGF_2α. These results suggest that BK induces production of NO and PGF_2α simultaneously from PBAECs via B₂ receptor activation.     

Keyhole limpet hemocyanin augmented the killing activity,cytokine production and proliferation of NK cells,and inhibited the proliferation of Meth A sarcoma cells in vitro

Objective:

Keyhole limpet hemocyanin (KLH) is a popular tumor vaccine carrier protein and an immunostimulant. The present study aimed to investigate the immunoregulatory activity of KLH on cytotoxicity, cytokines production, and proliferation of natural killer (NK) cells. Moreover, antiproliferative activity of KLH on Meth A sarcoma cells was studied.

Materials and Methods:

Cytotoxicity was determined with killing ability of NK cells against yeast artificial chromosome (YAC)-1 cells. Interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) productions by NK cells were measured by enzyme-linked immunosorbent assay (ELISA). Proliferations of NK and Meth A cells were determined by [³H]thymidine incorporated proliferation and 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) methods, respectively.

Results:

KLH at 6.25, 12.5, and 25 μg/well augmented cytotoxicity of NK cells against YAC-1 cells by 2.5, three, and five-times, respectively. KLH at 25 μg/well enhanced IFN-γ and TNF-α productions by 17- and 23-folds, respectively. The proliferation of NK cells was three times stimulated by KLH. The proliferation of Meth A cells was markedly inhibited by all the doses; the highest (4-folds higher) inhibition was observed at a dose of KLH (25 μg/well).

Conclusion:

The study demonstrated the anticancer activity of KLH acting through the induction of NK cells and inhibition of cancer cells. KLH, therefore, may be a good candidate for an anticancer agent alone or in combination with other chemotherapeutic agents.KEY WORDS: Anticancer activity, cytotoxicity, cytokines, Keyhole limpet hemocyanin, Natural Killer cells, Meth A sarcoma cells, YAC-1 cells     

The Effect of Tropical Environment on Fatigue Failure in Royal Malaysian Airforce (RMAF) Aircraft Structure and Operational Readiness

The environmental condition in which the Royal Malaysian Airforce is currently operating its aircraft is prone to corrosion. This is due to the high relative humidity and temperature. With most of its aircraft being in the legacy aircraft era, the aircraft’s main construction consists of the aluminium 2024 material. However, this material is prone to corrosion, thus reducing fatigue life and leading to fatigue failure. Using the concept of either Safe Life or Damage Tolerance as its fatigue design philosophy, the RMAF adopts the Aircraft Structure Integrity Program (ASIP) to monitor its structural integrity. With the current problem of not having the structural limitation on corrosion-damaged structure, the RMAF has embarked on its fatigue testing method. Finite Element (FE) studies and flight tests were conducted, and the outcome is summarized. The conclusion is that the longeron tested on the aircraft can withstand the operational load, and its yield strength is below the ultimate yield strength of the material. These research outcomes will also enhance the ASIP for other aircraft platforms in the RMAF fleet for its structure life assessment or service life extension program.     

Prevalence of Neutralizing Antibodies to Canine Distemper Virus and Response to Vaccination in Client-Owned Adult Healthy Dogs

Re-vaccinations against canine distemper virus (CDV) are commonly performed in 3-year intervals. The study’s aims were to determine anti-CDV antibodies in healthy adult dogs within 28 days of vaccination against CDV, and to evaluate factors associated with the presence of pre-vaccination antibodies and with the antibody response to vaccination. Ninety-seven dogs, not vaccinated within 1 year before enrollment, were vaccinated with a modified live CDV vaccine. A measurement of the antibodies was performed before vaccination (day 0), on day 7, and 28 after the vaccination by virus neutralization. A response to vaccination was defined as a ≥4-fold titer increase by day 28. Fisher’s exact test was used to determine factors associated with a lack of antibodies and vaccination response. In total, 94.8% of the dogs (92/97; CI 95%: 88.2–98.1) had antibodies (≥10) prior to vaccination. A response to vaccination was not observed in any dog. Five dogs were considered humoral non-responders; these dogs neither had detectable antibodies before, nor developed antibodies after vaccination. Young age (<2 years) was significantly associated with a lack of pre-vaccination antibodies (p = 0.018; OR: 26.825; 95% CI: 1.216–1763.417). In conclusion, necessity of re-vaccination in adult healthy dogs should be debated and regular vaccinations should be replaced by antibody detection.     

Tuning the mechanical properties of silicene nanosheet by auxiliary cracks: a molecular dynamics study

Silicene has become a topic of interest nowadays due to its potential application in various electro-mechanical nanodevices. In our previous work on silicene, fracture stresses of single crystal and polycrystalline silicene have been investigated. Existence of defects in the form of cracks reduces the fracture strength of silicene nanosheets to a great extent. In this study, an engineering way has been proposed for improving the fracture stress of silicene nanosheets with a pre-existing crack by incorporating auxiliary cracks symmetrically in a direction perpendicular to the main crack. We call this mechanism the “Failure shielding mechanism”. An extensive molecular dynamics simulation based analysis has been performed to capture the atomic level auxiliary crack-main crack interactions. It is found that the main crack tip stress distribution is significantly changed with the presence of auxiliary cracks for loading along both armchair and zigzag directions. The effects of temperature and the crack propagation speed of silicene have also been studied. Interestingly, in the case of loading along the zigzag direction, SW defect formation is observed at the tip of main crack. This leads to a reduction of the tip stress resulting in a more prominent failure shielding in case of zigzag loading than in armchair loading. Moreover, the position and length of the cracks as well as the loading directions have significant impacts on the tip stress distribution. Finally, this study opens the possibilities of strain engineering for silicene by proposing an engineering way to tailor the fracture strength of silicene.

Inclusion of auxiliary cracks increases the fracture stress of silicene nanosheets with a pre existing crack.     

Adsorption of methylene blue and tetracycline onto biomass-based material prepared by sulfuric acid reflux

The adsorptive removal of environmental pollutants is an effective method for the treatment of contaminated water. Thus, the preparation of adsorbents from low-cost, readily available, and renewable resources has garnered immense attention in recent years. In this study, a facile one-step method for the preparation of a high-capacity adsorbent is demonstrated by refluxing pine cones in concentrated sulfuric acid. With sulfuric acid reflux, the pine cones undergone carbonization as well as functionalization with sulfonic acid groups. The adsorbent demonstrated high adsorption capacity for two emerging organic pollutants, methylene blue (MB) and tetracycline (TC). Different variables such as pH, temperature, contact time, and initial concentration of the pollutants were analyzed and showed that the adsorption capacity for MB increased in a basic pH and vice versa for TC. Also, the elevated temperature favored the adsorption for both MB and TC. The maximum adsorption capacity was found to be 1666.66, and 357.14 mg g⁻¹ for MB and TC, respectively. In comparison to the pristine pine cone, the sulfuric acid treated pine cone demonstrated an extraordinary improvement in the adsorption capacity. The adsorption of MB and TC was performed from the tap water matrix and similar adsorption capacities were found. A packed glass column was also prepared to demonstrate the adsorption of MB from tap water under flow conditions.

Facile conversion of pine cones into a high-capacity adsorbent for the removal of methylene blue and tetracycline from water.     

Scorpion Toxin,BmP01, Induces Pain by Targeting TRPV1 Channel

The intense pain induced by scorpion sting is a frequent clinical manifestation. To date, there is no established protocol with significant efficacy to alleviate the pain induced by scorpion envenomation. One of the important reasons is that, little information on pain-inducing compound from scorpion venoms is available. Here, a pain-inducing peptide (BmP01) has been identified and characterized from the venoms of scorpion (Mesobuthus martensii). In an animal model, intraplantar injection of BmP01 in mouse hind paw showed significant acute pain in wild type (WT) mice but not in TRPV1 knock-out (TRPV1 KO) mice during 30 min recording. BmP01 evoked currents in WT dorsal root ganglion (DRG) neurons but had no effect on DRG neurons of TRPV1 KO mice. Furthermore, BmP01 evoked currents on TRPV1-expressed HEK293T cells, but not on HEK293T cells without TRPV1. These results suggest that (1) BmP01 is one of the pain-inducing agents in scorpion venoms; and (2) BmP01 induces pain by acting on TRPV1. To our knowledge, this is the first report about a scorpion toxin that produces pain by targeting TRPV1. Identification of a pain-inducing compound may facilitate treating pain induced by scorpion envenomation.     

Effect of metal doping on the visible light absorption,electronic structure and mechanical properties of non-toxic metal halide CsGeCl3

Non-toxic metal halide perovskites have become forefront for commercialization of the perovskite solar cells and optoelectronic devices. In the present study, for the first time we show that particular metal doping in CsGeCl₃ halide can considerably enhance the absorbance both in the visible and ultraviolet light energy range. We have carried out DFT based first principles calculations on Mn-doped and Ni-doped CsGeCl₃ halide. We investigate the detailed structural, optical, electronic and mechanical properties of all the doped compositions theoretically. The study of the optical properties shows that the absorption edge of both Ni and Mn-doped CsGeCl₃ is shifted toward the low energy region (red shift) relative to the pristine one. An additional peak is observed for both doped profiles in the visible light energy region. The study of the mechanical properties demonstrates that both the doped samples are mechanically stable and ductile as the pristine CsGeCl₃. The study of the electronic properties shows that the excitation of photoelectrons is easier due to the formation of intermediate states in Mn-doped CsGeCl₃. As a result Mn-doped CsGeCl₃ exhibits higher absorptivity in the visible region than the Ni-doped counterpart. A combinational analysis indicates that CsGe_1−xMn_xCl₃ is the best lead free candidate among the inorganic perovskite materials for solar cell and optoelectronic applications.

We have studied the optical, electronic and mechanical properties of Ni and Mn-doped CsGeCl₃ using DFT calculations.