The Dual Role of Non-coding RNAs in the Development of Periodontitis

This review aims to sum up how Non-coding RNAs(ncRNAs)regulate the development of periodontitis and provides a new perspective for understanding the pathogenesis of periodontitis.We explored the ncRNA's dual role in the development of periodontitis by summarizing evidence from previous in vivo and in vitro studies as well as clinical samples.In our review,the downregulation of 18 miRNAs,22 lncRNAs and 10 circRNAs demonstrates protective roles in periodontitis.In contrast,the expression of other 11 miRNAs,7 lncRNAs and 6 circRNAs are upregulated in periodontitis,which promote the progression of periodontitis.These dysregulated ncRNAs exert their protective or destructive roles by mainly influencing cell proliferation,differentiation and apoptosis via cross-talking with various molecules or signaling pathways.Our findings suggested which and how ncRNAs promote or delay the progression of periodontitis,which may greatly contribute to diagnose and therapy development of periodontitis based on ncRNAs in the future.

Accurate Assessment and Tracking the Process of Liver-Specific Injury by the Residual Tissue Activity of Carboxylesterase 1 and Dipeptidyl Peptidase 4

Accurately assessing and tracking the progression of liver-specific injury remains a major challenge in the field of biomarker research.Here,we took a retrospective validation approach built on the mutuality between serum and tissue biomarkers to characterize the liver-specific damage of bile duct cells caused by a-naphthyl isothiocyanate(ANIT).We found that carboxylesterase 1(CES1),as an intrahepatic marker,and dipeptidyl peptidase 4(DPP-IV),as an extrahepatic marker,can reflect the different pathophysiologies of liver injury.Levels of CES1 and DPP-IV can be used to identify liver damage itself and the inflammatory state,respectively.While the levels of the conventional serological biomarkers alkaline phosphatase(ALP),alanine aminotransferase(ALT),and aspartate aminotransferase(AST)were all concomitantly elevated in serum and tissues after ANIT-induced injury,the levels of bile acids decreased in bile,increased in serum,and ascended in intrahepatic tissue.Although the level of γ-glutamyl transpeptidase(γ-GT)changed in an opposite direction,the duration was much shorter than that of CES1 and was quickly restored to normal levels.Therefore,among the abovementioned biomarkers,only CES1 made it possible to specifically determine whether the liver cells were destroyed or damaged without interference from inflammation.CES1 also enabled accurate assessment of the anti-cholestasis effects of ursodeoxycholic acid(UDCA;single component)and Qing Fei Pai Du Decoction(QFPDD;multicomponent).We found that both QFPDD and UDCA attenuated ANIT-induced liver damage.UDCA was more potent in promoting bile excretion but showed relatively weaker anti-injury and antiinflammatory effects than QFPDD,whereas QFPDD was more effective in blocking liver inflammation and repairing liver damage.Our data highlights the potential of the combined use of CES1(as an intrahepatic marker of liver damage)and DPP-IV(as an extrahepatic marker of inflammation)for the accurate evaluation and tracking of liver-specific injury—an application that allows for the differentiation of liver damage and inflammatory liver injury.

Xiaochaihutang attenuates liver fibrosis in rats through activation of Nrf2 pathway

OBJECTIVE Oxidative sress is one of the key factor responsible for occurrence and development of hepatic fibrosis,a common consequence of chronic liver injury of multiple etiology.Nuclear factor erythroid 2-related factor 2(Nrf2)serves as a major regulator of a celular defense system against oxidative stress.Xiaochaihutang(XCHT),a compound of seven botanical extracts used for liver diseases traditionally in East Asia.However,few studies have investigated its anti-hepatic fibrosis effects and pathophysiological mechanism of action.The present study was designed to confirm the anti-hepatic fibrosis effects and explore its potential mechanism of action by investigating the intervention of Nrf2 pathway.METHODS Liver fibrosis was induced by repeated injection of Carbon tetrachloride(CCl4) over a period of 9 weeks.Starting from the 6 th week,the animals in treatment groups were given the appropriate dose of XCHT granules and silybin.Biochemical parameters,histological changes of the liver and alpha-smooth muscle actin(α-SMA) were determined.The expressions of Nrf2,Keap1,Nqo1,HO-1,Gclc and Gclm were assessed by RT-PCR and Western blot.RESULTS CCl4 caused a significant fibrosis damage in the rat liver and the liver functions and fibrosis degree were significantly improved by XCHT(5 g·kg^(-1) and 10 g·kg^(-1)).XCHT(5 g·kg^(-1) and 10 g·kg^(-1)) treatment significantly decreased the number of cells labeled with α-SMA antibodies.Moreover,XCHT(5 g·kg^(-1) and 10 g·kg^(-1))significantly increase Nqo1,HO-1,Gclc and Gclm expressions in the liver.CONCLUSION T hese studies establish XCHT is a potentially useful therapeutic agent for treatment of hepatic fibrosis and it might be via regulation of Nrf2 pathway in rats against oxidative stress,making further efforts to inhibiting the activated HSCs.Activation or up-regulation of Nrf2 pathway may be an alternative treatment strategy for liver fibrosis.

Strengthening pharmacotherapy research for COVID-19-induced pulmonary fibrosis

The global spread of severe acute respiratory syndrome coronavirus 2 has resulted in a significant number of individuals developing pulmonary fibrosis(PF),an irreversible lung injury.This condition can manifest within a short inter-val following the onset of pneumonia symptoms,sometimes even within a few days.While lung transplantation is a potentially lifesaving procedure,its limited availability,high costs,intricate surgeries,and risk of immunological rejection present significant drawbacks.The optimal timing of medication administration for coronavirus disease 2019(COVID-19)-induced PF remains controversial.Despite this,it is crucial to explore pharmacotherapy interventions,involving early and preventative treatment as well as pharmacotherapy options for advanced-stage PF.Additionally,studies have demonstrated disparities in anti-fibrotic treatment based on race and gender factors.Genetic mutations may also impact therapeutic efficacy.Enhancing research efforts on pharmacotherapy interventions,while considering relevant pharmacological factors and optimizing the timing and dosage of medication administration,will lead to enhanced,personalized,and fair treatment for individuals impacted by COVID-19-related PF.These measures are crucial in lessening the burden of the disease on healthcare systems and improving patients'quality of life.

Pharmacological effects of icariin and icariinriside on central nervous system

Epimedium Brevicornum is a traditional Chinese medicinal plant possessing properties of sweet, warm, tonifying kidney, strong bones and rheumatism. Icariin, a flavonoid compound, is one of the main active ingredients of Epimedium. Icariinriside(ICS) is the main metabolite of icariin. Icariinand ICS have multiple pharmacological effects such as anti-tumor, anti-oxidative stress, improvement of cardiovascular and cerebrovascular, and regulation of endocrine. We have conducted a series of studies on the neuroprotection and mechanisms of action of icariin and ICS for many years. The main findings are reported as follows.(1) Effect on Alzheimer disease(AD) model animals: Icariin significantly attenuated learning and memory loss, hippocampal neuron loss and senile plaque formation in APP/PS1 transgenic AD model mice, which may be related to inhibition of Aβ production and reduction of PDE5(phosphodiesterase 5).In addition, icariin significantly attenuated Aβ25-35-induced learning and memory decline and hippocampal neuronal apoptosis in rats, which may be related to lowering PDE5 content and up-regulating BDNF/Trkb/CREB signaling pathway, inhibiting MAPK and NF-κB signaling pathways, and increasing expression of acetylcholinesterase(ACHE) and choline acetyltransferase(CHAT) in the hippocampus. At the same time, icariin can significantly improve the learning and memory dysfunction induced by amanita proline in rats, which may be related to the inhibition of hippocampal neuronal apoptosis, antiexcitatory amino acid toxicity and regulation of MAPK and NF-κB signaling pathways.(2) Effects on Parkinson disease(PD) model animals: The study found that in LPS-induced dopaminergic neuron injury animal models and cell models, icariin can inhibit microglia by inhibiting the expression of inflammatory factors such as TNF-α, IL-1β, NO and COX-2. Activation of glial cells increases the expression of neurotrophic factors such as BDNF and GDNF, increases the content of dopamine(DA) and its metabolites 3, 4-dihydroxyphenylacetic acid(DOPAC) and homovanillic acid(HVA), inhibits MAPK and the NF-κB signaling pathway, protecting dopaminergic neurons. In addition, icariin significantly attenuated6-OHDA-induced dopaminergic neuronal damage. In Nrf2 knockout mice, the neuroprotective effect of icariin disappeared, suggesting that Nrf2 may be one of the targets of icariin to play neuroprotective effects.(3) Effects on vascular dementia(VD) model animals: Icarin can improve the learning and memory ability and memory function of chronic hypoperfusion rats, and its mechanism may be related to increase the level of VEGF/VEGFR2 protein in the brain and activate multiple downstream signaling pathways to promote angiogenesis to play an indirect protective effect on neurons;The level of BDNF/Trk B protein in the brain increases the phosphorylation level of CREB and exerts direct neuroprotective effects.(4)Effect on cerebral ischemia: In a model of ischemic brain injury, icariin acts to up-regulate Sirt1 by activating p38, thereby exerting an anti-ischemic injury and protecting neuronal cells. In addition, icariin has neuroprotective effects on cerebral ischemia-reperfusion injury in rats, which may increase GSH-Px,SOD activity, decrease MDA content, inhibit free radical damage, reduce NO content, NOS activity,and inhibit neurotoxic damage. Reduction of MPO activity, TNF-α, IL-1β content is associated with inhibition of inflammatory response.(5) Cell protection: Icariin has a protective effect on 6-OHDA-induced oxidative damage in PC12 cells, which may be related to inhibition of apoptosis and regulation of Keap1/Nrf2/ARE signaling pathway, while ICS can attenuate oxygen-glucose deprivation/reoxygenation-induced cellular damage in PC12 cells. The mechanism of cellular oxidative damage may be related to inhibition of apoptosis and regulation of Nrf2/SIRT3 signaling pathway.Icariin and ICS have good preventive and therapeutic effects on central nervous system diseases such as AD, PD, VD, etc. However, due to the complexity of the molecular mechanisms of icariin and ICS, the molecular mechanisms of the central nervous system are still worthy of further study.

Protective effect of icarisideⅡ on oxygen-glucose deprivation and reoxygenation-induced injury incerebral cortical neurons

OBJECTIVE To explore the effect of icariside Ⅱ(ICS Ⅱ) on oxygen-glucose deprivation and reoxygenation(OGD/R)-induced injury in cerebral cortical neuronal cels.METHODS Primary cerebral cortical neuronal cells were deprived of oxygen and glucose for 2 h to simulate ischemic stroke injury in vitro.The experiment was divided into 8 groups,which were control,control+ICSⅡ 25 μmol·L^(-1),OGD/R,OGD/R+ICSⅡ(6.25,12.5,25 μmol·L^(-1)),OGD/R+3-methyladenine(3-MA) and OGD/R+Rapamycin(Rap).The protective effect of ICS Ⅱ were detected by MTT assay and lactate dehydrogenase(LDH),respectively.Autophagic flux and autophagy related proteins expressions were detected by using adenovirus harboring tf-LC3 and Western blotting,respectively.RESULTS Compared with OGD/R group,the cell viability treated with ICSⅡwas elevated in a concentration-dependent manner,and the leakage rate of LDH was lowed.Moreover,ICSⅡ not only suppressed OGD/R-induced autophagic flux,but also inhibited the increase of LC3-Ⅱ/LC3-Ⅰ ratio and Beclin 1 after OGD/R insulted.CONCLUSION ICS Ⅱ exerts protective effects on OGD/R-induced cerebral cortical neuronal cells through inhibiting excessive autophagy.

Effect of icariin on microglia-mediated neuro-inflammation through Nrf2 signaling pathway

OBJECTIVE To investigate the protective effect of icariin(ICA) on lipopolysaccharide(LPS)-induced BV2 microglia injury,and to clarify the role of nuclear factor erythroid 2-related factor 2(Nrf2) signaling pathway in BV2 microglia-mediated neuroinflammation.METHODS BV2 microglia were randomly divided into control,ICA(0.1 μmol·L^(-1)),LPS(1 mg·L^(-1)),LPS + ICA(0.01 μmol·L^(-1)),and LPS + ICA(0.1 μmol·L^(-1))groups.BV2 microglia were treated with ICA for 30 min and then treated with LPS for 24 h.MTT assay was used to determine the cells survival rate,Griess kit and ELISA kits were used to detect the contents of NO,IL-1β and IL-18 in the culture supernatant,Western blotting was used to detect the expression of Nrf2,HO-1 and NQO1.Real time RT-PCR was used to detect the expression of Nrf2,HO-1 and NQO1 after ICA addition for 2,6 and 24 h.And immunofluorescence was used to observe the activation of Nrf2.RESULTS ICA reduced LPS-induced NO,IL-1β and IL-18 production in the culture supernatant,and ICA increase LPS-induced mRNA and protein expression of Nrf2 signaling pathway.CONCLUSION ICA protects LPS induced neuroinflammation by regulating Nrf2 signaling pathway.

Protective effect of sodium ferulate on cardiac hypertrophy in spontaneously hypertensive rats

OBJECTIVE To investigate the inhibitory effect and mechanism of sodium ferulate(SF)on myocardial hypertrophy in spontaneously hypertensive(SHR).METHODS Forty 14-week-old SHR male rats were randomly divided into model group(SHR,receive distilled water)and SF treatment groups(SF 20,40 and 80 mg·kg^-1 per day,respectively).Age-matched male Wistar-Kyoto(WKY)rats gavaged with distilled water served as controls.After 12 weeks of treatment,the effects of SF on cardiac hypertrophy were evaluated using echocardiographic measurement,pathological analysis and the expression of atrial natriuretic peptide(ANP),myosin heavy chainβ(β-MHC)-a gene related to myocardial hypertrophy.In order to explore the mechanism of SF on myocardial hypertrophy,the calcium-sensing receptor(CaSR),calcineurin(CaN),nuclear factor of activated T cell 3(NFAT3),phosphorylation NFAT3(p-NFAT3),zinc finger transcription factor(GATA4),phosphorylation GATA4(p-GATA4),protein kinase Cβ(PKC-β),Raf-1,extracellular regulated protein kinase 1/2(ERK 1/2),phosphorylation ERK1/2(p-ERK 1/2)and mitogen-activated protein kinase phosphatase-1(MKP-1)were detected.RESULTS The myocardial hypertrophy parameters,myocardial cell cross section area,left ventricular wall thickness and expression of ANP and β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 were significantly increased,while the left ventricular cavity was significantly smaller,expression of p-NFAT3 and MKP-1 were significantly decreased,meanwhile,the ultra⁃structure of cardiomyocytes was significantly damaged in 26-week-old SHR rats.Notably,SF significantly ameliorated myocardial hyper⁃trophy in 26-week-old SHR rats;suppressed the overexpression of ANP,β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 and increased the expression of p-NFAT3 and MKP-1.CONCLUSION SF can inhibit cardiac hypertrophy in SHR rats,and the mechanism may be related to the inhibition of CaSR mediated signaling pathway.

A network pharmacology approach combined with animal experiment to investigate the blood enriching effect of Gei herba

Background:To explore active components of Lanbuzheng(Gei herba)and its underlying complex mechanism in treating blood deficiency induced by chemotherapy drug based on network pharmacology and mice experimental validation.Methods:Active components of Lanbuzheng(Gei herba)were screened by Lipinski’s rule of five.Targets acted with active components were predicted by PharmMapper database,and targets whose function associated with blood deficiency were screened by Therapeutic Target Database and UniProt.The networks of component-target and target-pathway were constructed by Cytoscape.The levels of peripheral blood and organ indexes were detected in the animal experiments.Results:One hundred and seventy-three components of Lanbuzheng(Gei herba)were collected,and 60 active components were screened according to the rule of five.According to the degree value of compounds,the top 5 compounds were docosyl trans ferulate,C32 decursin,agrimonolide 6-O-β-D-glucoside,degree=11,173-ethoxyphaeophorbide,and eugenol.Finally,59 targets associated with blood deficiency were obtained and the top 5 targets were MAPK14,TTR,CDK2,AKR1B1 and AR.Based on the interaction network of componenttarget and target-pathway,it’s found that 60 active components could act with 59 targets and 44 pathways for treating blood deficiency.And then,the mice experiments showed that Lanbuzheng(Gei herba)could enrich blood by increasing the levels of red blood cell,white blood cell,hemoglobin,red blood cell specific volume and platelet,and the indexes of liver,thymus and spleen,which validated the treating effect of Lanbuzheng(Gei herba).Conclusion:In this study,a network pharmacology approach and animal experiments were established to explore the nourishing blood effect of Lanbuzheng(Gei herba).The results demonstrated that Lanbuzheng(Gei herba)could improve blood deficiency and provide a theoretical basis for the further research on the in-depth mechanism of Lanbuzheng(Gei herba).

Analysis of the metabolic mechanism in Cantharidin-induced hepatotoxicity in LO2 cells using lipidomics analysis

Background:Cantharidin is a major active compound from Banmao(Mylabris).Cantharidin has obvious anticancer activity.However,its clinical application is limited due to serious hepatotoxicity.Methods:To evaluate the toxicity of human liver LO2 cells exposed to cantharidin by lipidomics.After exposing LO2 cells to different doses of cantharidin,the metabolites in LO2 cells were analyzed by nontargeted lipidomics based on liquid chromatography-mass spectrometry.Partial least-squares discriminant analysis and orthogonal partial least-squares discriminant analysis were used to screen differentially expressed metabolites,and then the main metabolic pathways were analyzed.Results:Pattern recognition analysis showed that the lipid metabolite profiles were changed significantly after cantharidin treatment,and 39 differential lipid metabolites were found.Additional analysis showed that these metabolites could mainly involve the metabolic pathways of triglyceride and acylcarnitine for cantharidin toxicity to LO2 cells.Conclusion:Cantharidin has obvious toxic effects on LO2 cells from the perspective of lipid metabolism.Moreover,the LO2 cytotoxicity induced by cantharidin is mainly related to the disorder of triglyceride and acylcarnitine metabolism.It can provide a scientific basis for cantharidin-induced hepatotoxicity.

Biocatalytic stereoselective synthesis of methyl mandelates by engineering a cytochrome P450 hydroxylase

Chiral methyl mandelates are useful synthons in organic transformation and pharmaceutical synthesis.Green synthesis of these valuable compounds by direct C–H activating oxidative hydroxylation has attracted keen interest.Described herein is achieving the stereoselective and efficient bio-hydroxylation of methyl 2-phenylacetates to the chiral methyl mandelates by directed evolution of the cytochrome P450DA hydroxylase.In the present study,a new colorimetric high-throughput screening assay was successfully developed based on a dualenzyme cascade for the engineering of the P450DA's hydroxylation activity.Several beneficial variants with enhanced bio-hydroxylation activity were created by combining random mutagenesis and site-saturated/directed mutagenesis strategies.Whole-cell bio-hydroxylation of various methyl 2-phenylacetates using the best septupletmutant P450DA-11 yielded the corresponding chiral methyl mandelates in up to 92%isolated yields and>99%ee.

Elafibranor:A promising treatment for alcoholic liver disease,metabolic-associated fatty liver disease,and cholestatic liver disease

Liver diseases pose a significant threat to human health.Although effective therapeutic agents exist for some liver diseases,there remains a critical need for advancements in research to address the gaps in treatment options and improve patient outcomes.This article reviews the assessment of Elafibranor's effects on liver fibrosis and intestinal barrier function in a mouse model of alcoholic liver disease(ALD),as reported by Koizumi et al in the World Journal of Gastroenterology.We summarize the impact and mechanisms of Elafibranor on ALD,metabolic-associated fatty liver disease,and cholestatic liver disease based on current research.We also explore its potential as a dual agonist of PPARα/δ,which is undergoing Phase III clinical trials for metabolic-associated steatohepatitis.Our goal is to stimulate further investigation into Elafibranor's use for preventing and treating these liver diseases and to provide insights for its clinical application.

Helicobacter pylori,esophageal precancerous lesions,and proton pump inhibitor overuse

This article reviews the cohort study published in the World Journal of Gastroenterology,which reported low rates of Helicobacter pylori(H.pylori)infection among esophageal cancer(EC)patients,coupled with proton pump inhibitor(PPI)overuse.These findings suggest a potential protective role of H.pylori against EC and indicate a possible association between PPI use and increased cancer risk.In light of these findings,our article examines the complex relationship between H.pylori and esophageal precancerous lesions,exploring the potential underlying mechanisms.We also address growing concerns regarding PPI overuse,including its potential effects on cancer therapy efficacy and the risk of drug interactions.Ultimately,this article highlights the urgent need for further research to evaluate the safety and efficacy of PPIs in cancer patients and to better understand their broader implications.

Icariin ameliorates memory deficits through regulating brain insulin signaling and glucose transporters in 3×Tg-AD mice

Icariin,a major prenylated flavonoid found in Epimedium spp.,is a bioactive constituent of Herba Epimedii and has been shown to exert neuroprotective effects in experimental models of Alzheimer’s disease.In this study,we investigated the neuroprotective mechanism of icariin in an APP/PS1/Tau triple-transgenic mouse model of Alzheimer’s disease.We performed behavioral tests,pathological examination,and western blot assay,and found that memory deficits of the model mice were obviously improved,neuronal and synaptic damage in the cerebral cortex was substantially mitigated,and amyloid-βaccumulation and tau hyperphosphorylation were considerably reduced after 5 months of intragastric administration of icariin at a dose of 60 mg/kg body weight per day.Furthermore,deficits of proteins in the insulin signaling pathway and their phosphorylation levels were significantly reversed,including the insulin receptor,insulin receptor substrate 1,phosphatidylinositol-3-kinase,protein kinase B,and glycogen synthase kinase 3β,and the levels of glucose transporter 1 and 3 were markedly increased.These findings suggest that icariin can improve learning and memory impairments in the mouse model of Alzheimer’s disease by regulating brain insulin signaling and glucose transporters,which lays the foundation for potential clinical application of icariin in the prevention and treatment of Alzheimer’s disease.

Lithocarpus polystachyus(Sweet Tea)water extract promotes human hepatocytes HL7702 proliferation through activation of HGF/AKT/ERK signaling pathway

Objective:Sweet Tea(ST),derived from the leaves of Lithocarpus polystachyus,is a Chinese folk medicine with wide pharmacological activities.However,the promotive effects of ST water extract on hepatocytes proliferation and its underlying mechanism remains still unknown.In the present study,the beneficial effects of ST water extract on human hepatocytes and its possible mechanism were investigated.Methods:MTT assay was used to detect the safety range of ST;HL7702 cells were divided into four groups:control group,ST low-(50μg/m L),medium-(200μg/m L)and high-concentration(800μg/m L)groups;Brd U ELISA and EDU staining were used to observe DNA content and cell proliferation;Moreover,flow cytometry was applied to analyze the distribution of cell cycle.Furthermore,the expression of cyclin D1,CDK4,HGF/c-Met,Akt,Erk1/2 were detected by Western blot.Results:It was found that ST water extract concentration-dependent promoted human hepatocytes HL7702 cell proliferation within 72 h through accumulating the cells in S phase and G2/M phase.Furthermore,ST water extract up-regulated expression of Cyclin D1 and CDK4 proteins.Moreover,ST water extract not only increased HGF expression and phosphorylation of c-Met level,but also activated the phosphorylation levels of AKT,ERK1/2.Interestingly,both of AKT inhibitor A6730 and ERK1/2 inhibitor U0126 reversed the promotive effects of ST water extract,which further confirmed that activation of AKT and ERK1/2 were involved.Conclusion:The findings reveal that ST water extract promoted HL7702 cells proliferation through the stimulation of cell cycle mediated by activating the AKT-and ERK1/2-related pathway.

The Chinese Society of Clinical Oncology(CSCO)clinical guidelines for the diagnosis and treatment of nasopharyngeal carcinoma

Nasopharyngeal carcinoma(NPC)is a malignant epithelial tumor originating in the nasopharynx and has a high incidence in Southeast Asia and North Africa.To develop these comprehensive guidelines for the diagnosis and management of NPC,the Chinese Society of Clinical Oncology(CSCO)arranged a multi-disciplinary team comprising of experts from all sub-specialties of NPC to write,discuss,and revise the guidelines.Based on the findings of evidencebased medicine in China and abroad,domestic experts have iteratively developed these guidelines to provide proper management of NPC.Overall,the guidelines describe the screening,clinical and pathological diagnosis,staging and risk assessment,therapies,and follow-up of NPC,which aim to improve the management of NPC.

Hypervalent iodine-mediated gem-difluorination of vinyl halides enabled by exclusive 1,2-halo migration

β-Difluorinated alkyl halides are of significant value in the modular synthesis of gem-difluorinated molecules.An exclusive 1,2-halo migratory gem-difluorination of vinyl halides with in situ-generated PhIF_(2)·HF is described.This protocol provides a general and practical approach towards a wide variety ofβ-difluorinated alkyl bromides.Bothα-andβ-bromoalkyl alkenes are suitable substrates,leading to two distinct types of products.The extension of this protocol to vinyl chloride and iodide are also feasible.The synthetic versatility of this method has been highlighted by the late-stage modification of complex small molecules and further transformations of theβ-difluorinated alkyl halides to valuable CF_(2)-containing compounds.

Rutin pretreatment promotes microglial M1 to M2 phenotype polarization

Microglial cells are important resident innate immune components in the central nervous system that are often activated during neuroinflammation.Activated microglia can display one of two phenotypes,M1 or M2,which each play distinct roles in neuroinflammation.Rutin,a dietary flavonoid,exhibits protective effects against neuroinflammation.However,whether rutin is able to influence the M1/M2 polarization of microglia remains unclear.In this study,in vitro BV-2 cell models of neuroinflammation were established using 100 ng/mL lipopolysaccharide to investigate the effects of 1-hour rutin pretreatment on microglial polarization.The results revealed that rutin pretreatment reduced the expression of the proinflammatory cytokines tumor necrosis factor-α,interleukin-1β,and interleukin-6 and increased the secretion of interleukin-10.Rutin pretreatment also downregulated the expression of the M1 microglial markers CD86 and inducible nitric oxide synthase and upregulated the expression of the M2 microglial markers arginase 1 and CD206.Rutin pretreatment inhibited the expression of Toll-like receptor 4 and myeloid differentiation factor 88 and blocked the phosphorylation of I kappa B kinase and nuclear factor-kappa B.These results showed that rutin pretreatment may promote the phenotypic switch of microglia M1 to M2 by inhibiting the Toll-like receptor 4/nuclear factor-kappa B signaling pathway to alleviate lipopolysaccharide-induced neuroinflammation.

Targeting MAPK pathways by naringenin modulates microglia M1 / M2 polarization in lipopolysaccharide-stimulated cultures

OBJECTIVE Neuroinflammation is considered to be an important and inevitable pathological process associated with all types of damages to the central nervous system.The hallmark of neuroinflammation is the microglia activation.In response to different micro-environmental disturbances,microglia could polarize into either an M1 pro-inflammatory phenotype,exacerbating neurotoxicity,or an M2 anti-inflammatory phenotype,exerting neuroprotection.Therefore,shifting the polarization of microglia toward the M2 phenotype could possess a more viable strategy for the neuroinflammatory disorders treatment.Naringenin(NAR) is natural y a grapefruit flavonoid and possesses various kinds of pharmacological activities,such as anti-inflammatory and neuroprotective activities.In the present study,we aimed to investigate the potential effects of NAR on microglial M1/M2 polarization and further reveal the underlying mechanisms of actions.METHODS BV-2 cells were pretreated with NAR(100 μmol·L^(-1)) for 1 h and then incubated with LPS(1 mg·L^(-1)) for 24 h.The effects of NAR on LPS-induced microglia activation,microglial M1/M2 polarization and MAPK pathways were detected.In addition,BV-2 cells were incubated with or without anisomycin(ANI,a selective agonist of JNK) to evaluate the role of JNK on microglia activation and microglia M1/M2 polarization.RESULTS First,NAR inhibited LPS-induced microglial activation.Then,NAR shifted the M1 pro-inflammatory microglia phenotype to the M2 anti-inflammatory M2 microglia state as demonstrated by the decreased expression of M1 markers,ie,inducible tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β)and the elevated expression of M2 markers(ie,arginase 1,IL-4 and IL-10).In addition,the effects of NAR on microglial polarization was dependent on MAPK signaling,particularly JNK inactivation,as evidenced by the fact that the selective activator of JNK abolished NAR-promoted M2 polarization and further NAR-inhibited microglial activation.CONCLUSION NAR promotes microglia M1/M2 polarization,thus conferring anti-neuroinflammatory effects via the inhibition of MAPK signaling activation.These findings might provide new alternative avenues for neuroinflammation-related disorders treatment.

Hippocampal neurogenesis and pro-neurogenic therapies for Alzheimer's disease

Adult hippocampal neurogenesis(AHN)facilitates hippocampal circuits plasticity and regulates hippocampus-dependent cognition and emotion.However,AHN malfunction has been widely reported in both human and animal models of Alzheimer's disease(AD),the most common form of dementia in the elderly.Proneurogenic therapies including rescuing innate AHN,cell engraftment and glianeuron reprogramming hold great potential for compensating the neuronal loss and rewiring the degenerated neuronal network in AD,but there are still great challenges to be overcome.This review covers recent advances in unraveling the involvement of AHN in AD and highlights the prospect of emerging proneurogenic remedies.