Compound 3k治疗骨关节炎:调控氧化应激通路改善软骨细胞糖酵解的作用机制

背景:骨关节炎现已被认为是一种代谢性疾病,既往研究表明糖酵解在骨关节炎的发生发展中起重要作用。Compound 3k作为一种新型糖酵解小分子抑制剂,具有抗炎及抗肿瘤等功效,因此可靶向糖酵解,有望为骨关节炎治疗提供新的思路。目的:基于缺氧诱导因子1α/活性氧的氧化应激通路探究Compound 3k在糖酵解过度活跃所导致的骨关节炎中的作用机制。方法:取对数生长期的ATDC5成软骨细胞,用10 ng/mL白细胞介素1β作用24 h诱导骨关节炎体外细胞模型,以CCK-8法检测不同浓度(0.25,0.5,1,2.5,5,10,15μmol/L)Compound 3k的细胞毒性,选出合适浓度进行后续实验。将软骨细胞随机分为对照组、模型组、治疗组,模型组以10 ng/mL的白细胞介素1β诱导,治疗组以Compound 3k预刺激2 h后与白细胞介素1β共培养,用CCK-8法检测各组细胞增殖情况;用ELISA试剂盒检测各组细胞炎症水平;用试剂盒检测各组细胞活性氧、细胞外乳酸脱氢酶及葡萄糖含量;qRT-PCR及Western blot检测相关炎症因子白细胞介素6、肿瘤坏死因子α及糖酵解相关基因葡萄糖转运蛋白1、甘油醛3-磷酸脱氢酶、单羧酸转运蛋白1和缺氧诱导因子1α的表达水平。结果与结论:①与对照组相比,模型组细胞增殖活性下降、糖酵解水平活跃,表现为细胞外乳酸脱氢酶含量增加(P<0.001),葡萄糖含量减少(P<0.001),相关炎症因子白细胞介素6(P<0.0001)及肿瘤坏死因子α(P<0.001),糖酵解相关基因葡萄糖转运蛋白1(P<0.001)、甘油醛3-磷酸脱氢酶(P<0.001)、单羧酸转运蛋白1(P<0.001)及缺氧诱导因子1α(P<0.001)的表达水平均上调,并伴随氧化应激,活性氧过量产生。②与模型组相比,Compound 3k的治疗有效提高细胞增殖活性,抑制过度活跃的糖酵解水平的同时,抑制了骨关节炎软骨细胞炎症(P<0.001)及糖酵解相关基因的表达(P<0.001),且抑制氧化应激,缺氧诱导因子1α的表达水平下调(P<0.0001),活性氧水平下降。③上述结果证实,Compound 3k抑制了白细胞介素1β诱导的软骨细胞炎症,其机制可能与糖酵解及缺氧诱导因子1α/活性氧介导的氧化应激有关。

Surface/interface engineering of noble-metals and transition metal-based compounds for electrocatalytic applications

Surface/interface engineering plays an important role in improving the performance and economizing the cost and usage of electrocatalysts.In recent years,substantial progress has been achieved in designing and developing highly active electrocatalysts with the deepening understanding of surface and interface enhanced mechanism.In this review,recent development about optimizing the surface and interfacial structure in promoting the electrocatalytic activity of noble-metals and transition metal compounds is presented and the chemical enhancements are also described in detail.The relationship between the surface/interface structures(both atomic and electronic configuration)and the electrochemical behaviors has been discussed.Finally,personal perspectives have been proposed,highlighting the challenges and opportunities for future development in tuning the surface/interface active sites of electrocatalysts.We believe that this timely review will be beneficial to the construction of highly active and durable electrode materials through optimizing surface atomic arrangement and interfacial interaction,which can largely promote the development of next-generation clean energy conversion technologies.

Recent Advances in Transition Metal-Based Catalysts for Electrocatalytic Nitrate Reduction Reaction

The accumulation of excessive nitrate in the atmosphere not only jeopardizes human health but also disrupts the balance of the nitrogen cycle in the ecosystem.Among various nitrate removal technologies,electrocatalytic nitrate reduction reaction(eNO_(3)RR)has been widely studied for its advantages of being eco-friendly,easy to operate,and controllable under environmental conditions with renewable energy as the driving force.Transition metal-based catalysts(TMCs)have been widely used in electrocatalysis due to their abundant reserves,low costs,easy-to-regulate electronic structure and considerable electrochemical activity.In addition,TMCs have been extensively studied in terms of the kinetics of the nitrate reduction reaction,the moderate adsorption energy of nitrogen-containing species and the active hydrogen supply capacity.Based on this,this review firstly discusses the mechanism as well as analyzes the two main reduction products(N_(2)and NH_(3))of eNO_(3)RR,and reveals the basic guidelines for the design of efficient nitrate catalysts from the perspective of the reaction mechanism.Secondly,this review mainly focuses on the recent advances in the direction of eNO_(3RR)with four types of TMCs,Fe,Co,Ni and Cu,and unveils the interfacial modulation strategies of Fe,Co,Ni and Cu catalysts for the activity,reaction pathway and stability.Finally,reasonable suggestions and opportunities are proposed for the challenges and future development of eNO_(3)RR.This review provides far-reaching implications for exploring cost-effective TMCs to replace high-cost noble metal catalysts(NMCs)for eNO_(3)RR.

CO_(2)-assisted oxidation dehydrogenation of light alkanes over metal-based heterogeneous catalysts

Light olefins are important platform feedstocks in the petrochemical industry,and the ongoing global economic development has driven sustained growth in demand for these compounds.The dehydrogenation of alkanes,derived from shale gas,serves as an alternative olefins production route.Concurrently,the target of realizing carbon neutrality promotes the comprehensive utilization of greenhouse gas.The integrated process of light alkanes dehydrogenation and carbon dioxide reduction(CO_(2)-ODH)can produce light olefins and realize resource utilization of CO_(2),which has gained wide popularity.With the introduction of CO_(2),coke deposition and metal reduction encountered in alkanes dehydrogenation reactions can be effectively suppressed.CO_(2)-assisted alkanes dehydrogenation can also reduce the risk of potential explosion hazard associated with O_(2)-oxidative dehydrogenation reactions.Recent investigations into various metal-based catalysts including mono-and bi-metallic alloys and oxides have displayed promising performances due to their unique properties.This paper provides the comprehensive review and critical analysis of advancements in the CO_(2)-assisted oxidative dehydrogenation of light alkanes(C2-C4)on metal-based catalysts developed in recent years.Moreover,it offers a comparative summary of the structural properties,catalytic activities,and reaction mechanisms over various active sites,providing valuable insights for the future design of dehydrogenation catalysts.

Electrodeposition:Synthesis of advanced transition metal-based catalyst for hydrogen production via electrolysis of water

Developing lower-cost and higher-effective catalyst to support hydrogen(H_(2))production by electrochemical water-splitting has been recognized as a preferred strategy to drive the clean energy utilization.As a credible technology for the synthesis of functional materials,electrodeposition has attracted widespread attention,especially suitable for non-noble transition metal-based catalysts(TMCs).Recently,lots of researchers have been devoted to this hot research direction with plentiful achievements,however,a comprehensive review towards this area is still missing.Hence,we summarize the past research progress,presents the technical characteristics of electrodeposition from the viewpoint of fundamental theory and influence factors for the electrochemical deposition behavior,and introduce its application in various of TMCs with versatile nanostructures and compositions.Except a deeper and more comprehensive cognition of electrodeposition,we further discuss the catalyst’s optimized hydrogen evolution reaction(HER),oxygen evolution reaction(OER)performance as well as overall water splitting that combined with the synthetic process.Finally,we conclude the technical advantages towards electrodeposition,propose challenge and future research directions in this promising field.This timely review aims to promote a deeper understanding of effective catalysts obtained via electrodeposition strategy,and provide new guidance for the design and synthesis of future catalysts for hydrogen production.

Hydrogen Production via Hydrolysis and Alcoholysis of Light Metal-Based Materials:A Review

As an environmentally friendly and high-density energy carrier,hydrogen has been recognized as one of the ideal alternatives for fossil fuels.One of the major challenges faced by“hydrogen economy”is the development of efficient,low-cost,safe and selective hydrogen generation from chemical storage materials.In this review,we summarize the recent advances in hydrogen production via hydrolysis and alcoholysis of light-metal-based materials,such as borohydrides,Mg-based and Al-based materials,and the highly efficient regeneration of borohydrides.Unfortunately,most of these hydrolysable materials are still plagued by sluggish kinetics and low hydrogen yield.While a number of strategies including catalysis,alloying,solution modification,and ball milling have been developed to overcome these drawbacks,the high costs required for the“one-pass”utilization of hydrolysis/alcoholysis systems have ultimately made these techniques almost impossible for practical large-scale applications.Therefore,it is imperative to develop low-cost material systems based on abundant resources and effective recycling technologies of spent fuels for efficient transport,production and storage of hydrogen in a fuel cell-based hydrogen economy.

Development of Metal and Metal-Based Composites Anode Materials for Potassium-Ion Batteries

Potassium-ion batteries(KIBs)are considered the next powerful potential generation energy storage system because of substantial potassium resource availability and similar characteristics with lithium.Unfortunately,the actual application of KIBs is inferior to that of lithium-ion batteries(LIBs),in which the fi nite energy density,ordinary circular life,and underdeveloped fabrication technique dominate the key constraints.Various works have recently been directed to growing novel anode electrodes with superior electrochemical capability.Noticeably,metals/metal oxides materials(e.g.,Sb,Sn,Zn,SnO_(2),and MoO_(2))have been widely investigated as KIBs anodes because of high theoretical capacity,suggesting outstanding promise for high-energy KIBs.In this review,the latest research of metals/metal oxides electrodes for potassium storage is summarized.The major strategies to control the electrochemical property of metals/metal oxides electrodes are discussed.Finally,the future investigation foreground for these anode electrodes has been proposed.

Effects of Heavy Metal Pollution of Apple Orchard Surface Soils Associated with Past Use of Metal-Based Pesticides on Soil Microbial Biomass and Microbial Communities

Apple orchard surface soils in Japan are polluted with copper (Cu), lead (Pb), and arsenic (As) due to long-term use of metal-based pesticides. We investigated the effects of heavy metals accumulated in the surface soils in apple orchards on the microbial biomass and the microbial communities. Soil samples were taken from a chestnut orchard (unpolluted control) and five apple orchards with different degrees of heavy metal pollution. Total concentrations of Cu, Pb, and As in soil ranged from 29 to 931 mg/kg, 35 to 771 mg/kg, and 11 to 198 mg/kg, respectively. The amount of microbial biomass carbon expressed on a soil organic carbon basis decreased with increasing concentrations of heavy metals. Thus, the heavy metals that accumulated in apple orchard surface soils had adverse effects on the soil microbial biomass. The analysis of phospholipid fatty acid (PLFA) composition indicated that the microbial community structure had changed because of the pesticide-derived heavy metals in soil. The relative abundance of gram-positive bacterial marker PLFAs increased and that of fungal marker PLFA decreased with increasing concentrations of heavy metals in soil. Denaturing gradient gel electrophoreses targeting the 16S ribosomal RNA gene of bacteria and the 18S ribosomal RNA gene of fungi also showed shifts in the composition of bacterial and fungal communities induced by soil pollution with heavy metals. However, the diversity of microbial communities was not significantly affected by the heavy metal pollution. This was attributable to the adaptation of the microbial communities in apple orchard surface soils to heavy metals derived from previously used pesticides.

Comparative evaluation of commercial Douchi by different molds:biogenic amines,non-volatile and volatile compounds

To provide new insights into the development and utilization of Douchi artificial starters,three common strains(Aspergillus oryzae,Mucor racemosus,and Rhizopus oligosporus)were used to study their influence on the fermentation of Douchi.The results showed that the biogenic amine contents of the three types of Douchi were all within the safe range and far lower than those of traditional fermented Douchi.Aspergillus-type Douchi produced more free amino acids than the other two types of Douchi,and its umami taste was more prominent in sensory evaluation(P<0.01),while Mucor-type and Rhizopus-type Douchi produced more esters and pyrazines,making the aroma,sauce,and Douchi flavor more abundant.According to the Pearson and PLS analyses results,sweetness was significantly negatively correlated with phenylalanine,cysteine,and acetic acid(P<0.05),bitterness was significantly negatively correlated with malic acid(P<0.05),the sour taste was significantly positively correlated with citric acid and most free amino acids(P<0.05),while astringency was significantly negatively correlated with glucose(P<0.001).Thirteen volatile compounds such as furfuryl alcohol,phenethyl alcohol,and benzaldehyde caused the flavor difference of three types of Douchi.This study provides theoretical basis for the selection of starting strains for commercial Douchi production.

Effect of different drying methods on the amino acids,α-dicarbonyls and volatile compounds of rape bee pollen

The significant demand for high quality food has motivated us to adopt appropriate processing methods to improve the food nutritional quality and flavors.In this study,the effects of five drying methods,namely,pulsed vacuum drying(PVD),freeze drying(FD),infrared drying(IRD),hot-air drying(HAD)and sun drying(SD)on free amino acids(FAAs),α-dicarbonyl compounds(α-DCs)and volatile compounds(VOCs)in rape bee pollen(RBP)were determined.The results showed that FD significantly released the essential amino acids(EAAs)compared with fresh samples while SD caused the highest loss.Glucosone was the dominantα-DCs in RBP and the highest loss was observed after PVD.Aldehydes were the dominant volatiles of RBP and SD samples contained more new volatile substances(especially aldehydes)than the other four drying methods.Comprehensively,FD and PVD would be potential methods to effectively reduce the quality deterioration of RBP in the drying process.

Understanding the growth mechanisms of metal-based core–shell nanostructures revealed by in situ liquid cell transmission electron microscopy

Metal-based core-shell nanostructures have garnered enduring interest due to their unique properties and functionalities.However,their growth and transformation mechanisms in liquid media remain largely unknown because they lack direct observation of the dynamic growth process with high spatial and temporal resolution.Developing the in situ liquid cell transmission electron microscopy(TEM)technique offers unprecedented real-time imaging and spectroscopy capabilities to directly track the evolution of structural and chemical transformation of metal-based core–shell nanostructures in liquid media under their working condition.Here,this review highlights recent progress in utilizing in situ liquid cell TEM characterization technique in investigating the dynamic evolution of material structure and morphology of metal-based core–shell nanostructures at the nano/atomic scale in real-time.A brief introduction of the development of liquid cells for in situ TEM is first given.Subsequently,recent advances in in situ liquid cell TEM for the fundamental study of growth mechanisms of metal based core–shell nanostructures are discussed.Finally,the challenge and future developments of metalbased core–shell nanostructures for in situ liquid cell TEM are proposed.Our review is anticipated to inspire ongoing interest in revealing unseen growth dynamics of core–shell nanostructures by in situ liquid cell TEM technique.

Numerical modeling of fracture propagation of supercritical CO_(2)compound fracturing

The exploitation of shale gas is promising due to depletion of the conventional energy and intensification of the greenhouse effect.In this paper,we proposed a heat-fluid-solid coupling damage model of supercritical CO_(2)(SC-CO_(2))compound fracturing which is expected to be an efficient and environmentally friendly way to develop shale gas.The coupling model is solved by the finite element method,and the results are in good agreement with the analytical solutions and fracturing experiments.Based on this model,the fracture propagation characteristics at the two stages of compound fracturing are studied and the influence of pressurization rate,in situ stress,bedding angle,and other factors are considered.The results show that at the SC-CO_(2)fracturing stage,a lower pressurization rate is conducive to formation of the branches around main fractures,while a higher pressurization rate inhibits formation of the branches around main fractures and promotes formation of the main fractures.Both bedding and in situ stress play a dominant role in the fracture propagation.When the in situ stress ratio(δ_(x)/δ_(y))is 1,the presence of bedding can reduce the initiation pressure and failure pressure.Nevertheless,it will cause the fracture to propagate along the bedding direction,reducing the fracture complexity.In rocks without bedding,hydraulic fracturing has the lengthening and widening effects for SC-CO_(2)induced fracture.In shale,fractures induced at the hydraulic fracturing stage are more likely to be dominated by in situ stresses and have a shorter reorientation radius.Therefore,fracture branches propagating along the maximum principal stress direction may be generated around the main fractures induced by SC-CO_(2)at the hydraulic fracturing stage.When the branches converge with the main fractures,fracture zones are easily formed,and thus the fracture complexity and damage area can be significantly increased.The results are instructive for the design and application of SC-CO_(2)compound fracturing.

Recent progress and challenges in structural construction strategy of metal-based catalysts for nitrate electroreduction to ammonia

Ammonia plays an essential role in human production and life as a raw material for chemical fertilizers.The nitrate electroreduction to ammonia reaction(NO_(3)RR)has garnered attention due to its advantages over the Haber-Bosch process and electrochemical nitrogen reduction reaction.Therefore,it represents a promising approach to safeguard the ecological environment by enabling the cycling of nitrogen species.This review begins by discussing the theoretical insights of the NO_(3)RR.It then summarizes recent advances in catalyst design and construction strategies,including alloying,structure engineering,surface engineering,and heterostructure engineering.Finally,the challenges and prospects in this field are presented.This review aims to guide for enhancing the efficiency of electrocatalysts in the NO_(3)RR,and offers insights for converting NO_(3)-to NH_(3).

Role of methoxy and C_(α)-based substituents in electrochemical oxidation mechanisms and bond cleavage selectivity of β-O-4 lignin model compounds

In order to better understand the specific substituent effects on the electrochemical oxidation process of β-O-4 bond, a series of methoxyphenyl type β-O-4 dimer model compounds with different localized methoxyl groups, including 2-(2-methoxyphenoxy)-1-phenylethanone, 2-(2-methoxyphenoxy)-1-phenylethanol, 2-(2-methoxyphenoxy)-1-(4-methoxyphenyl)ethanone, 2-(2-methoxyphenoxy)-1-(4-methoxyphenyl)ethanol, 2-(2,6-dimethoxyphenoxy)-1-(4-methoxyphenyl)ethanone, 2-(2,6-dimethoxyphenoxy)-1-(4-methoxyphenyl)ethanol have been selected and their electrochemical properties have been studied experimentally by cyclic voltammetry, and FT-IR spectroelectrochemistry. Combining with electrolysis products distribution analysis and density functional theory calculations, oxidation mechanisms of all six model dimers have been explored. In particular, a total effect from substituents of both para-methoxy(on the aryl ring closing to Cα) and Cα-OH on the oxidation mechanisms has been clearly observed, showing a significant selectivity on the Cα-Cβbond cleavage induced by electrochemical oxidations.

Preparation of lactic acid bacteria compound starter cultures based on pasting properties and its improvement of glutinous rice flour and dough

The effects of 5 lactic acid bacteria(LAB)fermentation on the pasting properties of glutinous rice flour were compared,and suitable fermentation strains were selected based on the changes of viscosity,setback value,and breakdown value to prepare LAB compound starter cultures.The results revealed that Latilactobacillus sakei HSD004 and Lacticaseibacillus rhamnosus HSD005 had apparent advantages in increasing the viscosity and reducing the setback and breakdown values of glutinous rice flour.In particular,the compound starter created using the two abovementioned LAB in the ratio of 3:1 had better performance than that using a single LAB in improving the pasting properties and increasing the water and oil absorption capacity of glutinous rice flour.Moreover,the gelatinization enthalpy of the fermented samples increased significantly.For frozen glutinous rice dough stored for 28 days,the viscoelasticity of frozen dough prepared by compound starter was better than that of control dough,and the freezable water content was lower than that of control dough.These results indicate that compound LAB fermentation is a promising technology in the glutinous rice-based food processing industry,which has significance for its application.

Modern approaches for detection of volatile organic compounds in metabolic studies focusing on pathogenic bacteria:Current state of the art

Pathogenic microorganisms produce numerous metabolites,including volatile organic compounds(VOCs).Monitoring these metabolites in biological matrices(e.g.,urine,blood,or breath)can reveal the presence of specific microorganisms,enabling the early diagnosis of infections and the timely implementation of tar-geted therapy.However,complex matrices only contain trace levels of VOCs,and their constituent com-ponents can hinder determination of these compounds.Therefore,modern analytical techniques enabling the non-invasive identification and precise quantification of microbial VOCs are needed.In this paper,we discuss bacterial VOC analysis under in vitro conditions,in animal models and disease diagnosis in humans,including techniques for offline and online analysis in clinical settings.We also consider the advantages and limitations of novel microextraction techniques used to prepare biological samples for VOC analysis,in addition to reviewing current clinical studies on bacterial volatilomes that address inter-species in-teractions,the kinetics of VOC metabolism,and species-and drug-resistance specificity.

Assessment of electrostatic discharge sensitivity of nitrogen-rich heterocyclic energetic compounds and their salts as high energy-density dangerous compounds:A study of structural variables

Nitrogen-rich heterocyclic energetic compounds(NRHECs)and their salts have witnessed widespread synthesis in recent years.The substantial energy-density content within these compounds can lead to potentially dangerous explosive reactions when subjected to external stimuli such as electrical discharge.Therefore,developing a reliable model for predicting their electrostatic discharge sensitivity(ESD)becomes imperative.This study proposes a novel and straightforward model based on the presence of specific groups(-NH_(2) or-NH-,-N=N^(+)-O^(-)and-NNO_(2),-ONO_(2) or-NO_(2))under certain conditions to assess the ESD of NRHECs and their salts,employing interpretable structural parameters.Utilizing a comprehensive dataset comprising 54 ESD measurements of NRHECs and their salts,divided into 49/5 training/test sets,the model achieves promising results.The Root Mean Square Error(RMSE),Mean Absolute Error(MAE),and Maximum Error for the training set are reported as 0.16 J,0.12 J,and 0.5 J,respectively.Notably,the ratios RMSE(training)/RMSE(test),MAE(training)/MAE(test),and Max Error(training)/Max Error(test)are all greater than 1.0,indicating the robust predictive capabilities of the model.The presented model demonstrates its efficacy in providing a reliable assessment of ESD for the targeted NRHECs and their salts,without the need for intricate computer codes or expert involvement.

Organic Compounds Possessing the Plastic Crystalline Phase: Calculation of Their Fusion Enthalpies

For the first time, for different organic and inorganic compounds possessing the plastic crystalline phase, a new semiempirical equation describing dependence of their fusion enthalpies on such physico-chemical quantities as normal melting temperature, surface tension, molar volume and critical molar volume is received on the base of the principle of corresponding states and the energy equipartition theorem. Moreover, the proposed equation allows one to take into account the particularities of one-particle molecular rotation in the plastic crystalline phase.

Nutritional values,bioactive compounds and health benefits of purslane(Portulaca oleracea L.):a comprehensive review

Portulaca oleracea L.,commonly known as purslane,is a worldwide weed species belonging to the family Portulacaceae and has been known as“Global Panacea”.As one of the most widely consumed green vegetables and medicinal plants around the world,it has recently been re-evaluated as a potential“new crop”due to the properties that differentiate it as one of the best vegetable sources of omega-3 fatty acid(α-linolenic acid),as well as a variety of nutrients and phytochemicals.Accordingly,emerging research has found that purslane exhibits health-promoting properties like anti-inflammatory,anti-hyperglycemic,antioxidant,neuroprotective,and immunomodulatory.These findings suggest that this species possesses a potential using as a dietary supplement beyond potherb and traditional medicine.This review systematically summarizes the up-to-date research carried out on purslane,including the nutritional compositions,bioactive compounds,and health benefits it exerts as well as limitations,challenges,and future directions of research.Finally,we hope that this review would provide purslane with a comprehensive reference and future scope as functional and health-promoting food for disease prevention and treatment.

Antidiabetic Properties of Bidens pilosa and Its Polyacetylenic Compounds for Management of Diabetes: Systematic Review

Bidens pilosa is a member of the Asteraceae family that is widely distributed across the tropics. It has been utilized by different communities both as food and medicinal herb. This plant and its polyacetylenic compounds hold potential as a natural antidiabetic intervention that can be used to combat this global public health problem. Bioactive compounds found in this plant constitute promising interventions for combating obesity which is a major risk factor for the development of type 2 diabetes. These phytocompounds can work independently or synergistically to modulate appetite, lipase activity, adipogenesis and adipocyte apoptosis. However, the efficacy, mode of action and scope of management of diabetes by these compounds remains elusive. The current review aims to summarize data on efficacy in the management of diabetes, an antidiabetic candidate polyacetylenic compound and possible biological activities as an antidiabetic agent from the available literature. Much emphasis has been directed to cytopiloyne as a representative of polyacetylenic compounds extracted from Bidens pilosa and its activity on diabetic animal models. The majority of the studies conducted on animal models described antidiabetic mechanisms that range from hypoglycemic to secretagogue activity of cytopiloyne in a dose-dependent manner. A clinical trial pilot indicated improved glycemic control of Bidens pilosa formulation among diabetic patients in the study. Bidens pilosa and its compounds are highly potent antidiabetic agent(s) that should be graduated to an intervention for management of diabetes through pre-clinical and clinical trials to elucidate its efficacy and safety.