Kinin-mediated inflammation in neurodegenerative disorders

The mediatory role of kinins in both acute and chronic inflammation within nervous tissues has been widely described. Bradykinin, the major representative of these bioactive peptides, is one of a few mediators of inflammation that directly stimulates afferent nerves due to the broad expression of specific kinin receptors in cell types in these tissues. Moreover, kinins may be delivered to a site of injury not only after their production at the endothelium surface but also following their local production through the enzymatic degradation of kininogens at the surface of nerve cells. A strong correlation between inflammatory processes and neurodegeneration has been established. The activation of nerve cells, particularly microglia, in response to injury, trauma or infection initiates a number of reactions in the neuronal neighborhood that can lead to cell death after the prolonged action of inflammatory substances. In recent years, there has been a growing interest in the effects of kinins on neuronal destruction. In these studies, the overexpression of proteins involved in kinin generation or of kinin receptors has been observed in several neurologic disorders including neurodegenerative diseases such Alzheimer's disease and multiple sclerosis as well as disorders associated with a deficiency in cell communication such as epilepsy. This review is focused on recent findings that provide reliable evidence of the mediatory role of kinins in the inflammatory responses associated with different neurological disorders. A deeper understanding of the role of kinins in neurodegenerative diseases is likely to promote the future development of new therapeutic strategies for the control of these disorders. An example of this could be the prospective use of kinin receptor antagonists.     

Impact of preconditioning stem cells with all-trans retinoic acid signaling pathway on cisplatin-induced nephrotoxicity by down-regulation of TGFβ1, IL-6, and caspase-3 and up-regulation of HIF1α and VEGF

The survival reduction after transplantation limited the clinical uses of stem cells so the current study explored preconditioning adipose-derived stem cells (ADMSCs) and all-trans retinoic acid (ATRA) effects on cisplatin that caused acute kidney injury (AKI). One hundred and fifty Sprague–Dawley male rats were distributed into five groups: control group; Cisplatin (CIS) group; CIS and ATRA group; CIS and ADMSC group, and CIS, ATRA, and ADMSCs group. Ten rats were euthanized after 3rd, 7th, and 11th days from CIS injection. Renal function, molecular studies, and histopathological analysis were studied. The preconditioning of ADMSCs with ATRA increased the viability of the cells which was reflected in the amelioration of kidney functions after CIS injection by the significant reduction of serum creatinine, microalbuminuria, as well as NO, and the significant rise of creatinine clearance, as well as SOD compared to the group of cisplatin. ATRA also supported ADMSCs by a significant down-regulation of caspase-3, il-6 and TGFβ1, and a significant up-regulation of HIF1, VEGF and CD31 compared to group of cisplatin which reversed the cisplatin effect. ATRA increased renoprotective properties of ADMSCs against cisplatin- induced AKI by reducing the apoptosis, inflammation, and stimulating angiogenesis.     

Ability of a commercial feed additive to modulate expression of innate immunity in sheep immunosuppressed with dexamethasone

In the first study, we tested the ability of a commercial feed additive (OmniGen-AF) to affect markers of innate immunity in immunosuppressed sheep and the ability of a pathogen challenge (mould) to affect the immune response to the additive. Treatments consisted of (1) control, (2) immunosuppressed with dexamethasone (DEX), (3) immunosuppressed plus the feed additive, (4) immunosuppressed plus Aspergillus fumigatus and (5) immunosuppressed, A. fumigatus and the additive. Animal health was monitored and indexes of innate immunity (neutrophil L-selectin and interleukin-1β (IL-1β)) were collected. DEX caused immunosuppression (i.e. reduced abundance of neutrophil L-selectin and IL-1β). This immunosuppressive effect was countered by the provision of the additive in the ration. Provision of mould in the ration increased the ability of the additive to regulate markers of innate immune function. A second study was completed to re-assess the properties of the additive and other feed products. The study consisted of seven treatments: (1) immunosuppressed, (2) immunosuppressed with additive, (3) immunosuppressed with additive in pelleted form (low-temperature pellet) and (4) immunosuppressed with additive in a high-temperature pellet. The remaining three treatments assessed abilities of three other additives to regulate markers of innate immune function. In this study, OmniGen-AF increased expression of neutrophil L-selectin abundance in immunosuppressed animals and this was unaffected by the pelleting temperature. None of the other additives affected markers of innate immunity. In these studies we discovered mechanisms by which a feed product may affect the immune function of ruminant livestock. The product countered DEX-dependent down-regulation of markers of innate immune function and its actions were enhanced by the presence of pathogen (mould) in the ration.     

Desferrioxamine as an Electron Donor. Inhibition of Membranal Lipid Peroxidation Initiated by H202 –Activated Metmyoglobin and Other Peroxidizing Systems

Desferoxamine (DFO) involvement in several peroxidative systems was studied. These sytems included: a) membranal lipid peroxidation initiated by H₂O₂-activated metmyoglobin (or methemoglobin); b) phenol-red oxidation by activated metmyoglobin or horseradish peroxidase (HRP): c) β-carotene-linoleate couple oxidation stimulated by lipoxygenase or hemin. Desferrioxamine was found to inhibit all these systems but not ferrioxamine (FO). Phenol-red oxidation by H₂0₂-horseradish peroxidase was inhibited competitively with DFO. Kinetic studies using the spectra changes in the Soret region of metmyoglobin suggest a mechanism by which H₂0₂ reacts with the iron-heme to form an intermediate of oxy-ferryl myoglobin that subsequently reacts with DFO to return the activated compound to the resting state. These activities of DFO resemble the reaction of other electron donors.     

Molecular and computational approaches to understand resistance of New Delhi metallo β-lactamase variants (NDM-1, NDM-4, NDM-5, NDM-6, NDM-7)-producing strains against carbapenems

The discovery of NDM-1 and its variants has caused the emergence of antibiotic resistance in the community and hospital setting, causing major concern for health care across the globe. New Delhi Metallo-β-lactamase is known to hydrolyse almost all β-lactam antibiotics. Studies have shown the hydrolytic activates of NDM-1 and some of its variants, however a comparative study of these NDM variants has not been explored in detail. Hence, we proposed to check their catalytic activity by performing a comparative study between NDM-1 and its variants. The study was initiated to clone NDM variants (NDM-1, NDM-4, NDM-5, NDM-6 and NDM-7) followed by overexpression of the recombinant proteins to check their hydrolytic properties against β-lactam antibiotics. The minimum inhibitory concentration of carbapenems antibiotics for bla_NDM-5 clone was found four fold increased, whereas no change was observed in the clones having other variants. The hydrolytic activity of carbapenem with NDM-5 variant was found to be augmented as per the kinetics parameter where Km was decreased and kcat, kcat/Km values increased as compared to the NDM-1. Molecular docking studies were employed to identify the variations in the binding ability among all NDM variants with imipenem or meropenem. Simulation studies at 100?ns showed a good stability of NDM-5 with imipenem and meropenem as compared to NDM-1. CD spectroscopy data revealed significant changes in the secondary structure of NDM variants. We conclude that NDM-5 showed higher hydrolytic activity as compared to other variants. This study provides a comparative analysis of the severity of NDM producing strains.     

Role of conformational dynamics in pathogenic protein aggregation

The accumulation of pathogenic protein oligomers and aggregates is associated with several devastating amyloid diseases. As protein aggregation is a multi-step nucleation-dependent process beginning with unfolding or misfolding of the native state, it is important to understand how innate protein dynamics influence aggregation propensity. Kinetic intermediates composed of heterogeneous ensembles of oligomers are frequently formed on the aggregation pathway. Characterization of the structure and dynamics of these intermediates is critical to the understanding of amyloid diseases since oligomers appear to be the main cytotoxic agents. In this review, we highlight recent biophysical studies of the roles of protein dynamics in driving pathogenic protein aggregation, yielding new mechanistic insights that can be leveraged for design of aggregation inhibitors.     

锌转运体ZNT7在Alzheimer病动物模型APP/PS1转基因鼠脑内的表达

目的研究阿尔茨海默病（Alzheimer disease,AD）模型小鼠APP/PS1转基因小鼠脑内锌转运体ZNT7的分布和表达,探讨ZNT7参与Aβ老年斑形成的机理。方法应用免疫组织化学染色观察ZNT7在脑内分布情况,应用Western Blot方法分析ZNT7在APP/PS1转基因小鼠大脑内的表达。结果ZNT7免疫阳性反应产物主要分布在APP/PS1转基因小鼠大脑皮层、纹状体和海马的老年斑内,强阳性的ZNT7免疫产物定位于老年斑的核心。Western Blot分析结果表明ZNT7在APP/PS1转基因小鼠大脑内的表达明显高于野生型小鼠。结论ZNT7在APP/PS1转基因小鼠大脑内的高表达以及在Aβ老年斑的定位,提示ZNT7可能参与了锌离子在老年斑内的聚集,进而参与了APP/PS1转基因小鼠大脑内老年斑的形成。