The role of natural flavonoids on neuroinflammation as a therapeutic target for Alzheimer's disease:a narrative review

Alzheimer's disease is a neurodegenerative disease that affects a large proportion of older adult people and is characterized by memory loss,progressive cognitive impairment,and various behavioral disturbances.Although the pathological mechanisms underlying Alzheimer's disease are complex and remain unclear,previous research has identified two widely accepted pathological characteristics:extracellular neuritic plaques containing amyloid beta peptide,and intracellular neurofibrillary tangles containing tau.Furthermore,research has revealed the significant role played by neuroinflammation over recent years.The inflammatory microenvironment mainly consists of microglia,astrocytes,the complement system,chemokines,cytokines,and reactive oxygen intermediates;collectively,these factors can promote the pathological process and aggravate the severity of Alzheimer's disease.Therefore,the development of new drugs that can target neuroinflammation will be a significant step forward for the treatment of Alzheimer's disease.Flavonoids are plant-derived secondary metabolites that possess various bioactivities.Previous research found that multiple natural flavonoids could exert satisfactory treatment effects on the neuroinflammation associated with Alzheimer's disease.In this review,we describe the pathogenesis and neuroinflammatory processes of Alzheimer's disease,and summarize the effects and mechanisms of 13 natural flavonoids(apigenin,luteolin,naringenin,quercetin,morin,kaempferol,fisetin,isoquercitrin,astragalin,rutin,icariin,mangiferin,and anthocyanin)derived from plants or medicinal herbs on neuroinflammation in Alzheimer's disease.As an important resource for the development of novel compounds for the treatment of critical diseases,it is essential that we focus on the exploitation of natural products.In particular,it is vital that we investigate the effects of flavonoids on the neuroinflammation associated with Alzheimer's disease in greater detail.

Numerical simulation for 2D double-diffusive convection(DDC) in rectangular enclosures based on a high resolution upwind compact streamfunction model Ⅰ: numerical method and code validation

A high resolution upwind compact streamfunction numerical algorithm for two-dimensional(2D)double-diffusive convection(DDC)is developed.The unsteady Navier-Stokes(N-S)equations in the streamfunction-velocity form and the scalar temperature and concentration equations are used.An optimized third-order upwind compact(UCD3 opt)scheme with a low dispersion error for the first derivatives is utilized to approximate the third derivatives of the streamfunction in the advection terms of the N-S equations and the first derivatives in the advection terms of the scalar temperature and concentration equations.The remaining first derivatives of the streamfunction(velocity),temperature,and concentration variables used in the governing equations are discretized by the fourth-order compact Pade(SCD4)schemes.With the temperature and concentration variables and their approximate values of the first derivatives obtained by the SCD4 schemes,the explicit fourth-order compact schemes are suggested to approximate the second derivatives of temperature and concentration in the diffusion terms of the energy and concentration equations.The discretization of the temporal term is executed with the second-order Crank-Nicolson(C-N)scheme.To assess the spatial behavior capability of the established numerical algorithm and verify the developed computer code,the DDC flow is numerically solved.The obtained results agree well with the benchmark solutions and some accurate results available in the literature,verifying the accuracy,effectiveness,and robustness of the provided algorithm.Finally,a preliminary application of the proposed method to the DDC is carried out.

Enhanced lysosome escape mediated by 1,2-dicarboxylic-cyclohexene anhydride-modified poly-L-lysine dendrimer as a gene delivery system

Antisense oligodeoxynucleotide(ASODN)can directly interfere a series of biological events of the target RNA derived from tumor cells through Watson-Crick base pairing,in turn,plays antitumor therapeutic roles.In the study,a novel HIF-1αASODN-loaded nanocomposite was formulated to efficiently deliver gene to the target RNA.The physicochemical properties of nanocomposite were characterized using TEM,FTIR,DLS and zeta potentials.The mean diameter of resulting GEL-DGL-FA-ASODN-DCA nanocomposite was about 170–192 nm,and according to the agarose gel retardation assay,the loading amount of ASODN accounted for 166.7 mg/g.The results of cellular uptake showed that the nanocomposite could specifically target to HepG2 and Hela cells.The cytotoxicity assay demonstrated that the toxicity of vectors was greatly reduced by using DCA to reversibly block the cationic DGL.The subcellular distribution images clearly displayed the lysosomal escape ability of the DCA-modified nanocomposite.In vitro exploration of molecular mechanism indicated that the nanocomposite could inhibit m RNA expression and HIF-1αprotein translation at different levels.In vivo optical images and quantitative assay testified that the formulation accumulated preferentially in the tumor tissue.In vivo antitumor efficacy research confirmed that this nanocomposite had significant antitumor activity and the tumor inhibitory rate was 77.99%.These results manifested that the GEL-DGL-FA-ASODNDCA nanocomposite was promising in gene therapeutics for antitumor by interacting directly with target RNA.

Novel Combination Therapy for Triple-Negative Breast Cancer based on an Intelligent Hollow Carbon Sphere

Triple-negative breast cancer(TNBC)is a subtype of breast cancer with high mortality,and the efficacy of monotherapy for TNBC is still disappointing.Here,we developed a novel combination therapy for TNBC based on a multifunctional nanohollow carbon sphere.This intelligent material contains a superadsorbed silicon dioxide sphere,sufficient loading space,a nanoscale hole on its surface,a robust shell,and an outer bilayer,and it could load both programmed cell death protein 1/programmed cell death ligand 1(PD-1/PD-L1)small-molecule immune checkpoints and small-molecule photosensitizers with excellent loading contents,protect these small molecules during the systemic circulation,and achieve accumulation of them in tumor sites after systemic administration followed by the application of laser irradiation,thereby realizing dual attack of photodynamic therapy and immunotherapy on tumors.Importantly,we integrated the fasting-mimicking diet condition that can further enhance the cellular uptake efficiency of nanoparticles in tumor cells and amplify the immune responses,further enhancing the therapeutic effect.Thus,a novel combination therapy“PD-1/PD-L1 immune checkpoint blockade+photodynamic therapy+fasting-mimicking diet”was developed with the aid of our materials,which eventually achieved a marked therapeutic effect in 4T1-tumor-bearing mice.The concept can also be applied to the clinical treatment of human TNBC with guiding significance in the future.

Myelin Oligodendrocyte Glycoprotein-IgG Contributes to Oligodendrocytopathy in the Presence of Complement, Distinct from Astrocytopathy Induced by AQP4-IgG

Immunoglobulin G against myelin oligodendrocyte glycoprotein(MOG-Ig G) is detectable in neuromyelitis optica spectrum disorder(NMOSD) without aquaporin-4 Ig G(AQP4-Ig G), but its pathogenicity remains unclear.In this study, we explored the pathogenic mechanisms of MOG-Ig G in vitro and in vivo and compared them with those of AQP4-Ig G. MOG-Ig G-positive serum induced complement activation and cell death in human embryonic kidney(HEK)-293 T cells transfected with human MOG. In C57 BL/6 mice and Sprague-Dawley rats, MOG-Ig G only caused lesions in the presence of complement. Interestingly, AQP4-Ig G induced astroglial damage, while MOGIg G mainly caused myelin loss. MOG-Ig G also induced astrocyte damage in mouse brains in the presence ofcomplement. Importantly, we also observed ultrastructural changes induced by MOG-Ig G and AQP4-Ig G. These findings suggest that MOG-Ig G directly mediates cell death by activating complement in vitro and producing NMOSDlike lesions in vivo. AQP4-Ig G directly targets astrocytes,while MOG-Ig G mainly damages oligodendrocytes.

Autoantibody to MOG suggests two distinct clinical subtypes of NMOSD

We characterized a unique group of patients with neuromyelitis optica spectrum disorder(NMOSD) who carried autoantibodies of aquaporin-4(AQP4) and myelin-oligodendrocyte glycoprotein(MOG). Among the 125 NMOSD patients, 10(8.0%) were AQP4- and MOG-ab double positive, and 14(11.2%) were MOG-ab single positive. The double-positive patients had a multiphase disease course with a high annual relapse rate(P=0.0431), and severe residual disability(P<0.0001). Of the double-positive patients, 70% had MS-like brain lesions, more severe edematous, multifocal regions on spinal magnetic resonance imaging(MRI), pronounced decreases of retinal nerve fiber layer thickness and atrophy of optic nerves. In contrast, patients with only MOG-ab had a higher ratio of monophasic disease course and mild residual disability. Spinal cord MRI illustrated multifocal cord lesions with mild edema, and brain MRIs showed more lesions around lateral ventricles. NMOSD patients carrying both autoantibodies to AQP4 and MOG existed and exhibited combined features of prototypic NMO and relapsing-remitting form of MS, whereas NMOSD with antibodies to MOG only exhibited an "intermediate" phenotype between NMOSD and MS. Our study suggests that antibodies against MOG might be pathogenic in NMOSD patients and that determination of anti-MOG antibodies maybe instructive for management of NMOSD patients.

Fingolimod alters inflammatory mediators and vascular permeability in intracerebral hemorrhage

Intracerebral hemorrhage （ICH） leads to high rates of death and disability. The pronounced inflammatory reactions that rapidly follow ICH contribute to disease progression. Our recent clinical trial demonstrated that oral administration of an immune modulator fingolimod restrained secondary injury derived from initial hematoma, but the mechanisms remain unknown. In this study, we aim to investigate the effects of fingolimod on inflammatory mediators and vascular permeability in the clinical trial of oral fingolimod for intracerebral hemorrhage （ICH）. The results showed that fingolimod decreased the numbers of circulating CD4~ T, CD8~ T, CD19~ B, NK, and NKT cells and they recovered quickly after the drug＇ was stopped. The plasma ICAM level was decreased and IL-10 was increased by fingolimod. Interestingly, fingolimod protected vascular permeability as indicated by a decreased plasma level of MMP9 and the reduced rT1%. In conclusion, modulation of systemic inflammation by fingolimod demonstrates that it is an effective therapeutic agent for ICH. Fingolimod may prevent perihematomal edema enlargement by protecting vascular permeability.

Neural Stem Cells Transfected with Leukemia Inhibitory Factor Promote Neuroprotection in a Rat Model of Cerebral Ischemia

Leukemia inhibitory factor(LIF) contributes to the neuroprotection by neural stem cells(NSCs) after ischemic stroke. Our aim was to explore whether LIFtransfected NSCs(LIF-NSCs) can ameliorate brain injury and promote neuroprotection in a rat model of cerebral ischemia. To accomplish this goal, we transfected NSCs with a lentivirus carrying the LIF gene to stably overexpress LIF. The LIF-NSCs reduced caspase 3 activation under conditions of oxygen-glucose deprivation in vitro.Transient cerebral ischemia was induced in rats by 2 h of middle cerebral artery occlusion(MCAo), and LIF-NSCs were intravenously injected at 6 h post-ischemia. LIF-NSC treatment reduced the infarction volume and improved neurological recovery. Moreover, LIF-NSCs improved glial cell regeneration and ameliorated white matter injuryin the MCAo rats. The NSCs acted as carriers and increased the expression of LIF in the lesions to protect against cerebral infarction, suggesting that LIF-NSCs could be a potential treatment for cerebral infarction.

Experimental models of neuromyelitis optica: current status, challenges and future directions

Neuromyelitis optica （NMO） is a recurrent inflammatory disease that predominantly attacks the optic nerves and spinal cord. NMO-IgG, the specific autoantibody present in the vast majority of NMO patients, targets the astrocytic water channel protein aquaporin 4 （AQP4）, and differentiates NMO from multiple sclerosis. The growing clinical and research interest in NMO makes it urgent to produce an animal model of NMO. The pathogenic effect of anti-AQP4 antibodies derived from the serum of patients paves the way to generating an experimental model based on the anti-AQP4-mediated astrocyte damage. In this review, we discuss the contribution of experimental models to the understanding of the pathogenesis of the disease and drug development. Key questions raised by the existing models are also discussed.

Alterations of natural killer cells in traumatic brain injury

To investigate the relationship between natural killer（NK） cells and traumatic brain injury（TBI）, we tracked an established phenotype of circulating NK cells at several time points in patients with different grades of TBI. In serial peripheral blood samples, NK cells were prospectively measured by flow cytometry of CD3-CD56＋ lymphocytes. Compared to healthy controls, TBI patients had reductions in both the percentage and the absolute number of NK cells. Furthermore, the magnitude of NK cell reduction correlated with the degree of TBI severity at several time points. That is, NK cell population size was independently associated with lower Glasgow Coma Scale scores. In addition, at some time points, a positive correlation was found between the NK cell counts and Glasgow Outcome Scale scores. Our results indicate that TBI induces a reduction in the number of NK cells, and the magnitude of the reduction appears to parallel the severity of TBI.

Monoclonal Antibody-Based Treatments for Neuromyelitis Optica Spectrum Disorders:From Bench to Bedside

Neuromyelitis optica(NMO)/NMO spectrum disorder(NMOSD)is a chronic,recurrent,antibodymediated,inflammatory demyelinating disease of the central nervous system,characterized by optic neuritis and transverse myelitis.The binding of NMO-IgG with astrocytic aquaporin-4(AQP4)functions directly in the pathogenesis of>60%of NMOSD patients,and causes astrocyte loss,secondary inflammatory infiltration,demyelination,and neuron death,potentially leading to paralysis and blindness.Current treatment options,including immunosuppressive agents,plasma exchange,and B-cell depletion,are based on small retrospective case series and open-label studies.It is noteworthy that monoclonal antibody(mAb)therapy is a better option for autoimmune diseases due to its high efficacy and tolerability.Although the pathophysiological mechanisms of NMOSD remain unknown,increasingly,therapeutic studies have focused on mAbs,which target B cell depletion,complement and inflammation cascade inactivation,bloodbrain-barrier protection,and blockade of NMO-IgG-AQP4 binding.Here,we review the targets,characteristics,mechanisms of action,development,and potential efficacy of mAb trials in NMOSD,including preclinical and experimental investigations.

Unleashing energy storage ability of aqueous battery electrolytes

Electrolytes make up a large portion of the volume of energy storage devices,but they often do not contribute to energy storage.The ability of using electrolytes to store charge would promise a significant increase in energy density to meet the needs of evolving electronic devices.Redox-flow batteries use electrolytes to store energy and show high energy densities,but the same design cannot be applied to portable or microdevices that require static electrolytes.Therefore,implementing electrolyte energy storage in a non-flow design becomes critical.This review summarizes the requirements for a stable and efficient electrolyte and diverse redox-active species dissolved in aqueous solutions.More importantly,we review the pioneering works using static electrolyte energy storage in the hope that it will pave a new way to design compact and energy-dense batteries.