Efficacy of glucagon-like peptide-1 mimetics for neural regeneration

Glucagon-like peptide 1（GLP-1）is secreted from enteroendocrine L cells in response to nutrient ingestion and exhibits insulinotropic properties by stimulating specific G protein-linked receptors（GLP-1Rs）on pancreaticβcells.Several GLP-1 mimetics,such as exenatide（exendin-4（Ex-4））,liraglutide,and lixisenatide,have been developed and approved as treatments for patients with type 2 diabetes.These peptides show bioactiv-ities almost identical to those of GLP- 1 and have a substantially longer plasma half-life than GLP-1 because of their resistance to dipeptidyl peptidase-4, a GLP-1 degrading enzyme.

Application of Renneted Skim Milk as a Fat Mimetics in Nonfat Yoghurt

For a long time, fermented dairy products have been consumed for human’s nutrition and health. Recently, consumption of whole dairy products, such as full fat yoghurt, has declined due to the awareness of probable harmful effects of fat on consumers’ health, resulting change of market interest in favor of low or non fat dairy products. It is a challenge for food scientists to produce a suitable fat substitute providing the functionality of the missing fat. The present investigation was carried out to examine the effect of 0 to 50% renneted skim milk (RSM) as a fat mimetic upon the physico-chemical, physical, rheological and sensory characteristics of nonfat yoghurt in comparison to control samples (full fat and skim yoghurt). By increasing RSM content, the chemical characteristics (titratable acidity, pH as well as the content of fat and total protein) of yoghurts did not alter except decrease of total solid in sample with 50% RSM. The yoghurts with more content of RSM exhibited higher b*and a* values, while the highest L* value, viscosity, water holding capacity (WHC), firmness and lowest syneresis were found in sample containing 30% RSM. It seems that new interaction in gel network of yoghurts containing RSM, exhibited greater ability to bind water than control skim yoghurt. In addition, probably new bridges between milk proteins (interacting partially hydrolyzed casein with casein) can increase the number of bounds between protein particles leading to lower syneresis. However, excessive RSM content (higher than 30%) did not increase the L* value, viscosity and WHC of samples probably because of too much aggregation of casein. Sensory results revealed that sample containing 30% RSM was exactly alike to full fat yoghurt in terms of overall sensory attributes. New formulation of palatable skim yoghurt was developed using 3% RSM successfully.

Dimeric Dipeptide Mimetics of NGF and BDNF Are Promising Agents for Post-Stroke Therapy

The dimeric dipeptide mimetics of the brain derived neurotrophic factor (BDNF) loops 1 and 4 and nerve growth factor (NGF) loop 4 were designed and synthesized at the Zakusov Research Institute of Pharmacology. There are respectively bis-(N-monosuccinyl-L-methionyl-L-serine) heptamethylenediamide(GSB-214), bis-(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide (GSB-106) and bis-(N-monosuccinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2). All of the ob-tained compounds activated a corresponding specific NGF or BDNF tyrosine kinase receptor (TrkA or TrkB), but had different postreceptor signaling patterns. GSB-106 activated the ERK and AKT, whereas GSB-214 and GK-2 only activated the AKT kinase. Here we report a comparative analysis of neuroprotective activity of these dipeptides in a model of ischemic stroke induced by transient middle cerebral artery occlusion (MCAO). The all three dimeric dipeptides showed a statistically significant decrease of infarct volumes with the treatment beginning 4 hour after surgery. In the experiment with BDNF mimetics, GSB-106 reduced this volume by 66% and GSB-214 by 26%. NGF GK-2 reduced the cerebral infarct volume by 45%. Thus, BDNF mimetic, which activated both the ERK and AKT, and NGF mimetic, which selectively activated PI3K/AKT, showed high neuroprotective efficacy. In addition, we studied neuroprotective effects of GK-2 at the beginning of the treatment 6, 8 and 24 hours after reperfusion. The neuroprotective effect of GK-2 persisted in all these conditions. The effectiveness of GK-2 at a delayed start of administration suggests that the dipeptide has neuroregenerative properties. The results obtained suggest a potential role for the dimeric dipeptide NGF and BDNF mimetics as therapeutic agents useful in the treatment of a stroke.

Ceria Nanoparticles as Enzyme Mimetics

In the past decades, enzyme mimetics based on ceria nanoparticles （nanoceria） have been developed as potential substitutes for nature enzymes. The mixed valence states of cerium and the patterns of oxygen vacancies on crystal planes result in different enzyme mimetic activities. In this review we survey the bio-applications of nanoceria-based enzyme mimetics as well as the underlying mechanisms. Factors influencing the enzyme mimetic activities and future perspective of nanoceria-based enzyme mimetics are also addressed.

Multi-shell nanocomposites based multienzyme mimetics for efficient intracellular antioxidation

Oxidative stress is associated with many acute and chronic inflammatory diseases.Development of nanomaterial-based enzyme mimetics for reactive oxygen species(ROS)scavenging is challenging,but holds great promise for the treatment of inflammatory diseases.Herein,we report the highly ordered manganese dioxide encapsulated selenium-melanin(Se@Me@MnO_(2))nanozyme with high efficiency for intracellular antioxidation and anti-inflammation.The Se@Me@MnO_(2)nanozyme is sequentially fabricated through the radical polymerization and the in-situ oxidation-reduction.In vitro experimental results demonstrated that the Se@Me@MnO_(2) nanozyme exhibits multiple enzyme activities to scavenge ROS,including catalase(CAT),glutathione peroxidase(GPx)and superoxide dismutase(SOD).Mechanism researches illustrated that the Se core possesses GPx-like catalytic activity,the Me and the MnO_(2) possess both the SOD-like and the CAT-like activities.What’s more,due to the stable unpaired electrons existing in the nanozyme,the Se,Me and MnO_(2) provide synergistic and fast electron transfer effect to achieve the quickly scavenging of hydrogen peroxide,hydroxyl radical,and superoxide anion.Further in vivo experimental results showed that this biocompatible nanozyme exhibits cytoprotective effects by resisting ROS-mediated damage,thereby alleviating the inflammation.This multienzyme mimetics is believed to be an excellent ROS scavenger and have a good potential in clinical therapy for ROS-related diseases.

Research progress of nanoparticles as enzyme mimetics

Natural enzymes as biological catalysts possess remarkable advantages,especially their highly efficient and selective catalysis under mild conditions.However,most natural enzymes are proteins,thus exhibiting an inherent low durability to harsh reaction conditions.Artificial enzyme mimetics have been pursued extensively to avoid this drawback.Quite recently,some inorganic nanoparticles(NPs) have been found to exhibit unique enzyme mimetics.In addition,their much higher stability overcomes the inherent disadvantage of natural enzymes.Furthermore,easy mass-production and low cost endow them more benefits.As a new member of artificial enzyme mimetics,they have received intense attention.In this review article,major progress in this field is summarized and future perspectives are highlighted.

Vc-Functionalized Fe3O4 Nanocomposites as Peroxidase-like Mimetics for H2O2 and Glucose Sensing

A simple and efficient colorimetric biosensing for hydrogen peroxide and glucose with peroxidase-like vitamin C（Vc） functionalized Fe3O4 magnetic nanoparticles（Vc/Fe3O4MNPs） as a catalyst is reported. Compared with Fe3O4 MNPs and other catalysts, Vc/Fe3O4 MNPs exhibited superior catalytic properties. Kinetic studies indicated that vitamin C incorporated on Fe3O4 MNPs improved the affinity toward H2O2. As low as 0,29 μmol/L H2O2 can be detected with a wide linear range of 0.5-100 μmol/L H2O2; moreover, as low as 0.288 μmol/L glucose can be detected with a linear range of 0.5-25 μmol/L glucose. The detection method was highly sensitive in sensing H2O2 and glucose. The robustness of Vc/Fe3O4 MNPs rendered them suitable for wide ranging applications.

Time-dependent model for two-phase flow in ultra-high water-cut reservoirs:Time-varying permeability and relative permeability

For the ultra-high water-cut reservoirs,after long-term water injection exploitation,the physical properties of the reservoir change and the heterogeneity of the reservoir becomes increasingly severe,which further aggravates the spatial difference of the flow field.In this study,the displacement experiments were employed to investigate the variations in core permeability,porosity,and relative permeability after a large amount of water injection.A relative permeability endpoint model was proposed by utilizing the alternating conditional expectation(ACE)transformation to describe the variation in relative permeability based on the experimental data.Based on the time dependent models for permeability and relative permeability,the traditional oil-water two-phase model was improved and discretized using the mimetic finite difference method(MFD).The two cases were launched to confirm the validation of the proposed model.The impact of time-varying physical features on reservoir production performance was studied in a real water flooding reservoir.The experimental results indicate that the overall relative permeability curve shifts to the right as water injection increases.This shift corresponds to a transition towards a more hydrophilic wettability and a decrease in residual oil saturation.The endpoint model demonstrates excellent accuracy and can be applied to time-varying simulations of reservoir physics.The impact of variations in permeability and relative permeability on the reservoir production performance yields two distinct outcomes.The time-varying permeability of the reservoir results in intensified water channeling and poor development effects.On the other hand,the time-varying relative permeability enhances the oil phase seepage capacity,facilitating oil displacement.The comprehensive time-varying behavior is the result of the combined influence of these two parameters,which closely resemble the actual conditions observed in oil field exploitation.The time-varying simulation technique of reservoir physical properties proposed in this paper can continuously and stably characterize the dynamic changes of reservoir physical properties during water drive development.This approach ensures the reliability of the simulation results regarding residual oil distribution.

Double enzyme mimetic activities of multifunctional Ag nanoparticle-decorated Co_(3)V_(2)O_(8)hollow hexagonal prismatic pencils for application in colorimetric sensors and disinfection

Since the catalytic activity of most nanozymes is still far lower than the corresponding natural enzymes,there is urgent need to discover novel highly efficient enzyme-like materials.In this work,Co_(3)V_(2)O_(8)with hollow hexagonal prismatic pencil structures were prepared as novel artificial enzyme mimics.They were then decorated by photo-depositing Ag nanoparticles(Ag NPs)on the surface to further improve its catalytic activities.The Ag NPs decorated Co_(3)V_(2)O_(8)(ACVPs)showed both excellent oxidase-and peroxidase-like catalytic activities.They can oxidize the colorless 3,3’,5,5’-tetramethylbenzidine rapidly to induce a blue change.The enhanced enzyme mimetic activities can be attributed to the surface plasma resonance(SPR)effect of Ag NPs as well as the synergistic catalytic effect between Ag NPs and Co_(3)V_(2)O_(8),accelerating electron transfer and promoting the catalytic process.ACVPs were applied in constructing a colorimetric sensor,validating the occurrence of the Fenton reaction,and disinfection,presenting favorable catalytic performance.The enzyme-like catalytic mechanism was studied,indicating the chief role of⋅O_(2)-radicals in the catalytic process.This work not only discovers a novel functional material with double enzyme mimetic activity but also provides a new insight into exploiting artificial enzyme mimics with highly efficient catalytic ability.

Nano-crystallites Imine-based Copper(II) Complexes as Mimetics for Copper Oxidase Proteins: Synthesis,Characterization,DFT and Oxidase Mimicking Activity

Three tridentate imine ligands containing N2S donors were synthesized via Schiff condensation between derivatives of both amino triazine and 2-carbonyl pyridine.The reaction of these ligands with CuCl2 in a molar ratio of 1:1 provides three Cu(II) complexes with the general formula [CuLn·Cl_(2)].Analytical,electrical,magnetic,and spectroscopic studies were used to assign the molecular formulae of these metallic chelates.Density function theory (DFT) calculations confirmed the structural analysis results obtained from spectroscopic studies.The various characterization techniques used demonstrated the penta-coordinated slightly distorted square pyramidal structure for the present Cu(II) complexes 1,2,and 3.Measurements of cyclic voltammetry were done in methanol to define the electrochemical behavior of the current Cu(II) complexes.The biomimetics of catechol oxidase (C.O.);phenoxazinone synthase (PHS) have been studied in the aerobic oxidation of some phenolic substrates,such as 3,5-di-tert-butylcatechol (3,5-DTBCH2);ortho-aminophenol (o-APH3).The three candidate oxidase mimetics showed promising activity in the order 3 > 1 > 2.The catalytic activity related to the structural properties of existing oxidase mimetics was discussed.The driving force (-ΔG°) controlling the redox reactions of the present biomolecules was calculated from the redox data of Cu(II) complexes 1,2,and 3.The potential catalytic reaction pathway for the oxidation of the studied phenolic substrates was discussed.

An overview on antidiabetic medicinal plants having insulin mimetic property

Diabetes mellitus is one of the common metabolic disorders acquiring around 2.8%of the world's population and is anticipated to cross 5.4%by the year 2025.Since long back herbal medicines have been the highly esteemed source of medicine therefore,they have become a growing part of modern,high-tech medicine.In view of the above aspects the present review provides profiles of plants(65 species) with hypoglycaemic properties,available through literature source from various database with proper categorization according to the parts used,mode of reduction in blood glucose(insulinomimetic or insulin secretagugues activity) and active phyloconsliluents having insulin mimetics activity.From the review it was suggested that,plant showing hypoglycemic potential mainly belongs to the family Leguminoseae,Lamiaceae,Liliaceae,Cucurbitaceae, Asteraceae,Moraceae,Rosaceae and Araliaceae.The most active plants are Allium sativum. Gymnema sylvestre,Citrullus colocynthis,Trigonella foenum greacum,Momordica charantia and Ficuts bengalensis.The review describes some new bioactive drugs and isolated compounds from plants such as roseoside,epigallocatechin gallate,beta-pyrazol-1-ylalanine,cinchonain Ib,leucocyandin 3-O-beta-d-galactosyl cellobioside,leucopelargonidin-3- O-alpha-L rhamuoside,glycyrrhetinic acid,dehydrotrametenolic acid,strictinin,isostrictinin,pedunculagin, epicatechin and christinin-A showing significant insulinomimetic and antidiabetic activity with more efficacy than conventional hypoglycaemic agents.Thus,from the review majorly,the antidiabetic activity of medicinal plants is attributed to the presence of polyphenols,flavonoida, terpenoids,coumarins and other constituents which show reduction in blood glucose levels.The review also discusses the management aspect of diabetes mellitus using these plants and their active principles.

Targeting cell death signaling in colorectal cancer:Current strategies and future perspectives

The evasion from controlled cell death induction has been considered as one of the hallmarks of cancer cells. Defects in cell death signaling are a fundamental phenomenon in colorectal cancer. Nearly any non-invasive cancer treatment finally aims to induce cell death. However, apoptosis resistance is the major cause for insufficient therapeutic success and disease relapse in gastrointestinal oncology. Various compounds have been developed and evaluated with the aim to meet with this obstacle by triggering cell death in cancer cells. The aim of this review is to illustrate current approaches and future directions in targeting cell death signaling in colorectal cancer. The complex signaling network of apoptosis will be demonstrated and the “druggability” of targets will be identified. In detail, proteins regulating mitochondrial cell death in colorectal cancer, such as Bcl-2 and survivin, will be discussed with respect to potential therapeutic exploitation. Death receptor signaling and targeting in colorectal cancer will be outlined. Encouraging clinical trials including cell death based targeted therapies for colorectal cancer are under way and will be demonstrated. Our conceptual understanding of cell death in cancer is rapidly emerging and new types of controlled cellular death have been identified. To meet this progress in cell death research, the implication of autophagy and necroptosis for colorectal carcinogenesis and therapeutic approaches will also be depicted. The main focus of this topic highlight will be on the revelation of the complex cell death concepts in colorectal cancer and the bridging from basic research to clinical use.

Catalytic Metalloporphyrin Protects Against Paraquat Neurotoxicity in vivo

Objective To examine the neuroprotective effects of a novel manganese porphyrin, manganese （Ill） meso-tetrakis （N,N＇-diethylimidazolium-2-yl） porphyrin （MnTDM）, in the mouse model of Parkinson＇s disease （PD） induced by paraquat （PQ）. Methods Male C57BL / 6 mice were subcutaneously injected with either saline or PQ at 2-day intervals for a total of 10 doses, MnTDM was subcutaneously injected with the PQ 2 h before treatment. Performance on the pole and swim test were measured 7 days after the last injection and animals were sacrificed one day later. Levels of dopamine （DA） and its metabolites in the striatum were measured by high-performance liquid chromatography with an electrochemical detector （HPLC-ECD）. Thiobarbituric acid （TBA） method was used to assay the lipid peroxidation product, malondialdehyde （MDA）, and the number of tyrosine hydroxylase （TH） positive neurons was estimated using immunohistochemistry. Results Pretreatment with MnTI）M significantly attenuated PQ-impaired behavioral performance, depleted dopamine content in striata, increased MDA, and dopaminergic neuron loss in the substantia nigra. Conclusions Oxidative stress plays an important role in PQ-induced neurotoxicity which can be potentially prevented by manganese porphyrin. These findings also propose a possible therapeutical strategy for neurodegenerative disorders associated with oxidative stress such as PD.

Development of therapeutic options on type 2 diabetes in years:Glucagon-like peptide-1 receptor agonist’s role intreatment; from the past to future

Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia.Type 2 diabetes (T2DM) accounting for 90% of cases globally.The worldwide prevalence of DM is rising dramatically over the last decades,from 30 million cases in 1985 to 382 million cases in 2013.It’s estimated that 451 million people had diabetes in 2017.As the pathophysiology was understood over the years,treatment options for diabetes increased.Incretin-based therapy is one of them.Glucagon-like peptide-1 receptor agonist (GLP-1 RA) not only significantly lower glucose level with minimal risk of hypoglycemia but also,they have an important advantage in themanagement of cardiovascular risk and obesity.Thus,we will review here GLP-1 RAsrole in the treatment of diabetes.

MOFzyme: FJU-21 with Intrinsic High Protease-Like Activity for Hydrolysis of Proteins

In this work, metal-organic frameworks (MOFs) FJU-21 was synthesized by solvothermal method. The crystal structure of FJU-21 was characterized by XRD and BET and it was applied to the catalytic hydrolysis of bovine serum albumin. The effects of reaction pH, temperature and reaction time on the catalytic activity of FJU-21 were studied. FJU-21 were found to possess an intrinsic enzyme mimicking activity similar to that found in trypsin. The Michaelis constant (Km) of the artificial protease (0.18 × 10-3 - 0.20 × 10-3 M-1) was about 15-fold lower than that free trypsin (2.7 × 10-3 M-1) and about 3-fold lower than that of soluble Cu(II) oxacyclen (0.54 × 10-3 M-1). The Kcat of FJU-21 is 102 times higher than that of soluble Cu(II) oxacyclen catalysts and, indicating a much higher affinity of BSA for FJU-21 surface. FJU-21 could be reused for eleven times without losing in its activity.

High density lipoprotein as a therapeutic target:Focus on its functionality

Cardiovascular diseases(CVDs)are the leading cause of death globally.CVDs are a group of disorders of the heart and blood vessels and include coronary heart disease,cerebrovascular disease and rheumatic heart disease among other conditions.There are multiple independent risk factors for CVD,including hypertension,age,smoking,insulin resistance,elevated low-density lipoprotein cholesterol(LDL-C)levels,and triglyceride levels.LDL-C levels have traditionally been the target for therapies aimed at reducing CVD risk.High density lipoprotein(HDL)constitutes the only lipoprotein fraction with atheroprotective functions.Early HDL-targeted therapies have focused on increasing HDL-C levels.However,clinical trials have shown that raising HDL-C with niacin failed to achieve CVD reduction.A possible explanation for these findings is that these drugs could interfere with lipid metabolism and cause alterations in HDL structure and composition,leading to loss of functionality.As a result,targeting HDL-C levels would be insufficient to achieve CVD risk reduction,making HDL functionality a more desirable focus for HDL-directed therapies.There are several drugs which show the potential to improve HDL functionality.These drugs include molecules already approved for human use,such as statins and niacin,and particularly,compounds currently undergoing development such as apolipoprotein A-I mimetics and reconstituted HDL preparations.These therapies show promising potential to improve HDL functionality specifically.Future therapeutic strategies should incorporate HDL functionality as a main target of interest.

圆二色谱研究胶原模拟多肽三螺旋结构及其热稳定性

胶原是广泛研究和应用的生物材料,具有独特的三螺旋结构,此结构与其生物学性能密切相关。以胶原模拟多肽(collagen mimetic peptide,CMP)作为胶原的模型分子,通过圆二色谱研究了CMP的三螺旋结构、热稳定性等随序列或长度的改变所发生的规律性变化。根据形成胶原三螺旋结构的重复序列(POG)_n及胶原上α_2β_1整合素识别位点序列GFOGER设计五种不同序列或长度的CMP,采用圆二色谱表征了CMP的三螺旋结构,并通过检测CMP的程序升温变性和程序降温复性过程中圆二色谱的变化,研究了CMP三螺旋结构的热变性过程、解链温度以及复性过程。实验结果显示,五种CMP室温下均以三螺旋结构的形式存在,CMP三螺旋结构的热稳定性随POG的个数增加而增强;不同于胶原,CMP三螺旋结构的热变性是可逆的,升温过程中三螺旋解聚(变性),降温过程又可重新组装(复性),复性过程有明显的'磁滞'现象。研究结果可为进一步研究胶原与CMP分子特征性的三螺旋结构形成规律以及基于CMP的人工类胶原生物材料的研究提供依据。

MOFzyme: Enzyme Mimics of Fe/Fe-MIL-101

In this work, metal-organic frameworks (MOFs) Fe-MIL-101 was synthesized by hydrothermal method, and Fe/Fe-MIL-101 with different loadings was prepared. The crystal structure of the Fe/Fe-MIL-101 sample was characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and specific surface area measurement (BET). Fe/Fe-MIL-101 was found to posses an intrinsic enzyme mimicking activity similar to that found in natural horse-radish peroxidase (HRP). The Michaelis constant (Km) of 5% Fe/Fe-MIL-101 with ABTS as the substrate is about 10-fold smaller than Fe-MIL-101 and about 3-fold smaller than HRP, and about 108 times less than that of CuO NPs (Km = 10.28 mM), indicating a much higher affinity for ABTS than HRP and most of the peroxidase mimetics.

Chronic Dietary Administration of 2-Deoxy-D-Glucose Does Not Compromise Neurobehavioral Functions at Tumor Preventive Doses in Mice

Beneficial effects of dietary energy restriction (DER), including extension of life-span, reduction in cancer risk, anti-cancer effects and decrease in age related neurodegenerative diseases have been well established. Given that DER is difficult to implement in humans due to practical constraints, development of energy restriction mimetics (ERMs) is considered as a suitable alternative. Our recent studies have established the anti-tumor effects of the dietary administration of the glycolytic inhibitor 2-deoxy-D-glucose, a potential ERM, an alternative to DER;without any adverse effects on general physiology. Since functioning of the brain is critically dependent on glucose, we investigated the effects of chronic dietary 2-DG administration on the behavioural outcome in mice. Our findings based on a battery of neuro-behavioural tests clearly suggest that the chronic dietary administration of 2-DG that appreciably impairs the process of tumorigenesis has no adverse effect on the cognitive, affective and sensory-motor functions. Together with the maintenance of normal physiology reported by us earlier, these observations strengthen the potential of dietary 2-DG as a safe cancer preventive strategy.

How the Bcl-2 family of proteins interact to regulate apoptosis

Commitment of cells to apoptosis is governed largely by protein-protein interactions between members of the Bcl-2 protein family. Its three sub-families have distinct roles： the BH3-only proteins trigger apoptosis by binding via their BH3 domain to pro-survival relatives, while the pro-apoptotic Bax and Bak have an essential downstream role involving disruption of organellar membranes and induction of caspase activation. The BH3-only proteins act as damage sensors, held inert until their activation by stress signals. Once activated, they were thought to bind promiscuously to pro-survival protein targets but unexpected selectivity has recently emerged from analysis of their interactions. Some BH3-only proteins also bind to Bax and Bak. Whether Bax and Bak are activated directly by these BH3-only proteins, or indirectly as a consequence of BH3-only proteins neutralizing their pro-survival targets is the subject of intense debate. Regardless of this, a detailed understanding of the interactions between family members, which are often selective, has notable implications for designing anti-cancer drugs to target the Bcl-2 family.