Pyronaridine combined with diminazene aceturate inhibits Babesia in vitro and in vivo

Objective:To evaluate the combination therapy of pyronaridine tetraphosphate and diminazene aceturate against Babesia in vitro and in vivo.Methods:Bioinformatic analysis was performed using atom pair fingerprints.An in vitro combination test was performed against Babesia bovis and Theileria equi.Moreover,the in vivo chemotherapeutic efficacy of pyronaridine tetraphosphate in combination with diminazene aceturate was investigated against the growth of Babesia microti in mice using a fluorescence inhibitory assay.Results:Pyronaridine tetraphosphate and diminazene aceturate exhibited nearly similar molecular weights.The in vitro combination of pyronaridine tetraphosphate and diminazene aceturate was synergistic on Babesia bovis and additive on Theileria equi.In addition,5 mg/kg pyronaridine tetraphosphate combined with 10 mg/kg diminazene aceturate inhibited Babesia microti growth significantly compared with those observed after treatment with 25 mg/kg diminazene aceturate alone from day 6 post treatment to day 12 post treatment.The combination therapy also normalized the hematological parameters of infected mice.Conclusions:An oral dose of pyronaridine tetraphosphate combined with a subcutaneous dose of diminazene aceturate inhibits Babesia in vitro and in mice,suggesting it might be a new paradigm for the treatment of babesiosis.

Synergistic renoprotective effect of a compiled branched-chain amino acids and Cymbopogon schoenanthus extract against experimentally induced oxido-nitrosative renal insult

Objective: To better investigate the protective role of branched-chain amino acids(BCAAs)and Cymbopogon schoenanthus(CS) extract against the potassium dichromate(PDC)-induced oxido-nitrosative nephrotoxic insult in the experimental rat model. Methods: Thirty male rats were randomly divided into five equal groups: The 1 st group served as control; the 2^(nd)was injected with a single dose of PDC(15 mg/kg b.w i.p.);the 3^(rd), 4^(th), and 5^(th) groups were respectively treated with BCAAs, CS, and their combination for 15 d prior to induction of renal insult via PDC single dose(15 mg/kg b.w s.c.). The experimental period was terminated in all groups 2 d after induction of renal insult. The harvested kdney samples were divided for biochemical assays and histological examination. Results: The PDC-induced nephrotoxic effect caused a depletion of renal oxidative scavengers glutathione, superoxide dismutase with consequent lipo-oxidative cellular membrane deterioration manifested by a rise in malonaldehyde, oxidized glutathione, myeloperoxidase and the concomitant increase in inflammatory response elements tumor necrosis factor α, nitric oxide, and interleukin 1 β.Moreover, the comet assay and increased 8-hydroxy-2-deoxyguanosine proved an accelerated apoptotic DNA fragmentation. These local renal changes were met with global altered blood biochemistry. The BCAAs and CS or their compiled administration showed an ameliorative effect against PDC-induced nephrotoxic in a synergistic pattern. Conclusions: Both BCAAs and CS or their combined administration afford potential competitors against renal insult induced by polyvalent anion pollutants in experimentally studied animals model. As a route for novel drug discovery, further investigation should be attempted to optimize their augmenting reno-protecting potential.

A Comparative Study on the Hemato-Biochemical and Immunological Effects of the Hexavalent FMD Vaccine Alone or in Combination with Trivalent FMD Vaccine in Cattle

Foot and mouth disease is the most contagious disease of mammals and has a great potential for causing severe economic loss in susceptible cloven-hoofed animals. Routine prophylactic vaccination in Egypt from 2012 till now has been conducted with Trivalent and/or hexavalent vaccine of MERIAL, against virus strains (O manisa + O-3039 + A Iran 05 + A Saudi 95 + Asia 1 + Sat2). This study aimed to evaluate the hemato-biochemical and immunological changes associated with the use of hexavalent vaccine alone or in combination with trivalent FMD vaccine. This study was carried out on 24 cattle divided into three groups eight cattle each. Group I served as control. Group II were selected from farms vaccinated with hexavalent FMD vaccine. Group III were selected from farms vaccinated with a combination of trivalent and hexavalent FMD vaccine. The results showed that both vaccinated groups showed a significant increase in total leukocytic count. Sera from hexavalent-trivalent vaccinated cattle demonstrated a significant increase in serum cortisol concentrations. Significant increase in serum activity of aspartate aminotransferase was recorded in animals vaccinated with a combination of hexavalent and trivalent vaccine. In addition, both regimes resulted in a significant increase in serum blood urea nitrogen compared to control. Both regimes induced a significant increase in serum levels of ceruloplasmin while phagocytic activity of neutrophils and phagocytic index was enhanced only by the hexavalent vaccine. Both vaccinated groups had significantly increased serum values of gamma globulins. These results suggested that hexavalent vaccine produced higher levels of safety and protective effects against FMD in cattle as compared to those produced by a combination of hexavalent and trivalent vaccines. It is also advisable to include the hexavalent vaccine within the program of obligatory and imperative vaccination against FMD.

Click chemistry in the design of AIEgens for biosensing and bioimaging

The development of rapid,selective,and sensitivefluorescent sensors is essential for visualizing and quantifying biological molecules and processes in vitro,ex vitro,and in vivo,which is important for not only fundamental biological studies but the accurate diagnosis of diseases.The emergingfield of activity-based sensing(ABS),a sensing method that utilizes molecular reactivity for analyte detection possesses many advantages including high specificity,sensitivity and accuracy.The aggrega-tion caused quenching phenomenon which occurs in most conventionalfluorophores results in reduced labeling efficiency of the target analytes and low photobleaching resistance,therefore limiting the applications of the ABS strategy.In contrast,aggre-gation induced emission(AIE)active luminogens(AIEgens)provide exceptional molecular frameworks for ABS.Of the many reaction classes utilized in the AIEgen ABS approach,click chemistry has become increasing popular.In this review,the sensing concepts of the ABS approach with AIEgens and the principles of click chemistry are discussed,followed by a systematic summary of the application of specific click chemistry reactions in AIEgen ABS protocols for the detection of an array of target analytes.Furthermore,the utility of click chemistry in the construction of AIEgens for bioimaging will also be showcased throughout the review.

S100A8/A9 induces autophagy and apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes that involves BNIP3

建筑群由 S100 钙绑定蛋白质家庭，的二个成员形成了 S100A8/A9，在不同起源的各种各样的房间施加导致 apoptosis 活动。这里，我们内在的分子的机制包含的现在的证据两个都规划了房间死亡我(PCD 我， apoptosis ) 并且象死亡一样的 PCD II (autophagy ) 。有 S100A8/A9 的房间的处理引起了 Beclin-1 表示以及 Atg12-Atg5 形成的增加。S100A8/A9-induced 房间死亡被特定的 PI3-kinase 班 III 禁止者部分禁止， 3-methyladenine (3 麻省) ，并且由液泡 H+-ATPase 禁止者， bafilomycin-A1 (Baf-A1 ) 。S100A8/A9 挑起了 BNIP3 的 translocation， BH3 仅仅 pro-apoptotic Bcl2 家庭成员，到线粒体。与这发现一致，螖 T M-BNIP3 overexpression 部分禁止了 S100A8/A9-induced 细胞死亡，减少的反应的氧种(ROS ) 产生，并且部分在 S100A8/A9-treated 细胞在 mitochondrial transmembrane 潜力免于减少。另外，任何一个螖 T M-BNIP3 overexpression 或 N-acetyl-L-cysteine 合作处理减少了在与 S100A8/A9 对待的房间的 lysosomal 激活。我们的数据显示 S100A8/A9-promoted 房间死亡通过线粒体的串音发生，经由 ROS 和这个过程的 lysosomes 包含 BNIP3。

Cocktail of Theileria equi antigens for detecting infection in equines

Objective:To use two diagnostic antigens belonging to the frequently associated in Theileria domain,Theileria equi(T.equi)protein 82(Te 82)and T.equi 104 k Da microneme-rhoptry antigen precursor(Te 43),to diagnose T.equi infection in horses as compared with equi merozoite antigen-2(EMA-2).Methods:In the current study,we applied a cocktail-ELISA containing two antigens(EMA-2+Te 82)to diagnose T.equi infection either in experimentally infected horses or in field infection.Results:Our findings have revealed that a cocktail formula of EMA-2+Te 82 provided a more practical and sensitive diagnostic candidate for diagnosing T.equi infection in horses as compared with Te 82 or Te 43 alone.Conclusions:The ELISA technique using a cocktail formula of EMA-2+Te 82 offers a practical and sensitive diagnostic tool for diagnosing T.equi infection in horses and using of this promising cocktail formula will be applicable for epidemiological surveys and will help control the infection in horses.

The effect of tailing lipidation on the bioactivity of antimicrobial peptides and their aggregation tendency Special Issue:Emerging Investigators

Antimicrobial peptides(AMPs)are potentially powerful alternatives to conven-tional antibiotics in combating multidrug resistance,given their broad spectrum of activity.They mainly interact with cell membranes through surface electrostatic potentials and the formation of secondary structures,resulting in permeability and destruction of target microorganism membranes.Our earlier work showed that two leading AMPs,MSI-78(4–20)and pardaxin(1–22),had potent antimicrobial activ-ity against a range of bacteria.It is known that the attachment of moderate-length lipid carbon chains to cationic peptides can further improve the functionality of these peptides through enhanced interactions with the membrane lipid bilayer,inducing membrane curvature,destabilization,and potential leakage.Thus,in this work,we aimed to investigate the antimicrobial activity,oligomerization propensity,and lipid-membrane binding interactions of a range of N-terminal lipidated analogs of MSI-78(4–20)and pardaxin(1–22).Molecular modeling results suggest that aggregation of the N-lipidated AMPs may impart greater structural stability to the peptides in solu-tion and a greater depth of lipid bilayer insertion for the N-lipidated AMPs over the parental peptide.Our experimental and computationalfindings provide insights into how N-terminal lipidation of AMPs may alter their conformations,with subsequent effects on their functional properties in regard to their self-aggregation behavior,membrane interactions,and antimicrobial activity.

Binding of transition metals to S100 proteins

The S100 proteins are a unique class of EF-hand Ca^(2+) binding proteins distributed in a cell-specific, tissue-specific, and cell cycle-specific manner in humans and other vertebrates. These proteins are distinguished by their distinctive homodimeric structure, both intracellular and extracellular functions, and the ability to bind transition metals at the dimer interface. Here we summarize current knowledge of S100 protein binding of Zn^(2+), Cu^(2+) and Mn^(2+) ions, focusing on binding affinities, conformational changes that arise from metal binding, and the roles of transition metal binding in S100 protein function.