Brain Pathology in COVID-19:Clinical Manifestations and Potential Mechanisms

Neurological manifestations of coronavirus disease 2019(COVID-19)are less noticeable than the respiratory symptoms,but they may be associated with disability and mortality in COVID-19.Even though Omicron caused less severe disease than Delta,the incidence of neurological manifestations is similar.More than 30%of patients experienced“brain fog”,delirium,stroke,and cognitive impairment,and over half of these patients presented abnormal neuroimaging outcomes.In this review,we summarize current advances in the clinical findings of neurological manifestations in COVID-19 patients and compare them with those in patients with influenza infection.We also illustrate the structure and cellular invasion mechanisms of SARS-CoV-2 and describe the pathway for central SARS-CoV-2 invasion.In addition,we discuss direct damage and other pathological conditions caused by SARS-CoV-2,such as an aberrant interferon response,cytokine storm,lymphopenia,and hypercoagulation,to provide treatment ideas.This review may offer new insights into preventing or treating brain damage in COVID-19.

Neddylation is a novel therapeutic target for lupus by regulating double negative T cell homeostasis

Systemic lupus erythematosus(SLE),a severe autoimmune disorder,is characterized by systemic inflammatory response,autoantibody accumulation and damage to organs.The dysregulation of double-negative(DN)T cells is considered as a crucial commander during SLE.Neddylation,a significant type of protein post-translational modification(PTM),has been well-proved to regulate T cell-mediated immune response.However,the function of neddylation in SLE is still unknown.Here,we reported that neddylation inactivation with MLN4924,a specific inhibitor of NEDD8-activating enzyme E1(NAE1),or genetic abrogation of Ube2m in T cells decreased DN T cell accumulation and attenuated murine lupus development.Further investigations revealed that inactivation of neddylation blocked Bim ubiquitination degradation and maintained Bim level in DN T cells,contributing to the apoptosis of the accumulated DN T cells in lupus mice.Then double knockout(KO)lupus-prone mice(Ube2m-/-Bim-/-lpr)were generated and results showed that loss of Bim reduced Ube2m deficiency-induced apoptosis in DN T cells and reversed the alleviated lupus progression.Our findings identified that neddylation inactivation promoted Bim-mediated DN T cell apoptosis and attenuated lupus progression.Clinically,we also found that in SLE patients,the proportion of DN T cells was raised and their apoptosis was reduced.Moreover,compared to healthy groups,SLE patients exhibited decreased Bim levels and elevated Cullin1 neddylation levels.Meantime,the inhibition of neddylation induced Bim-dependent apoptosis of DN T cells isolated from SLE patients.Altogether,our findings provide the direct evidence about the function of neddylation during lupus,suggesting a promising therapeutic approach for this disease.

B1-cell-produced anti-phosphatidylserine antibodies contribute to lupus nephritis development via TLR-mediated Syk activation

Autoantibodies produced by B cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). However, both the cellular source of antiphospholipid antibodies and their contributions to the development of lupus nephritis (LN) remain largely unclear. Here, we report a pathogenic role of anti-phosphatidylserine (PS) autoantibodies in the development of LN. Elevated serum PS-specific IgG levels were measured in model mice and SLE patients, especially in those with LN. PS-specific IgG accumulation was found in the kidney biopsies of LN patients. Both transfer of SLE PS-specific IgG and PS immunization triggered lupus-like glomerular immune complex deposition in recipient mice. ELISPOT analysis identified B1a cells as the main cell type that secretes PS-specific IgG in both lupus model mice and patients. Adoptive transfer of PS-specific B1a cells accelerated the PS-specific autoimmune response and renal damage in recipient lupus model mice, whereas depletion of B1a cells attenuated lupus progression. In culture, PS-specific B1a cells were significantly expanded upon treatment with chromatin components, while blockade of TLR signal cascades by DNase I digestion and inhibitory ODN 2088 or R406 treatment profoundly abrogated chromatin-induced PS-specific IgG secretion by lupus B1a cells. Thus, our study has demonstrated that the anti-PS autoantibodies produced by B1 cells contribute to lupus nephritis development. Our findings that blockade of the TLR/Syk signaling cascade inhibits PS-specific B1-cell expansion provide new insights into lupus pathogenesis and may facilitate the development of novel therapeutic targets for the treatment of LN in SLE.

Adding Fuel to the Fire by Increased GABAergic Inhibition:A Seizure-Amplifying Nigra-Parafascicular Pathway

Epilepsy is a common neurological disorder characterized by recurrent seizures.Most anti epileptic drugs (AEDs)work by regulating the balance of the excitatory glutamatergic and inhibitory GABAergic transmission.However,the current AEDs cannot successfully control seizures in most (>70%) patients with temporal lobe epilepsy (TLE)[1],in whom seizures typically begin in the hippocampus.This may be caused by changes in the synaptic efficacy and remodeling of neural circuits,such as alterations in the distribution/expression of GABA_A receptor subunits and mossy-fiber sprouting.Since Dr.Karen Gale and colleagues originally described the seizure-modulating effects of nigral GABAergic transmission in the early 1980s [2]。

An Environmentally Benign Catalytic Method for Versatile Synthesis of 1,4-Dihydropyridines via Multicomponent Reactions

The synthesis of diverse 1,4-dihydropyridines have been achieved via the multicomponent reactions of aldehydes,enaminones and amines.The reactions have been smoothly performed in water to provide all products with moderate to excellent yields by using lactic acid as a green catalyst.

Multicomponent Reactions for Diverse Synthesis of N-Substituted and NH 1,4-Dihydropyridines

The multicomponent reactions of aldehydes,electron deficient alkynes and amines have been successfully per-formed to yield a number of symmetrical 2,6-unsubstituted 1,4-dihydropyridines(1,4-DHPs).This method has been found generally applicable for the synthesis of both N-substituted and N-unsubstituted 1,4-DHPs by employing secondary amine to activate the alkyne component via enaminoester intermediates.The present method runs through an enamine type activation,which is different from the known approach employing AcOH as solvent.

Treatment Effects of Integrated TCM and Western Medicine Treatment Scheme on COVID-19: A Single-armed Clinical Trial

Backgroud:The outbreak of COVID-19 has brought unprecedented perils to human health and raised public health concerns in more than two hundred countries.Safe and effective treatment scheme is needed urgently.Objective:To evaluate the effects of integratedTCM and western medicine treatment scheme on COVID-19.Methods:A single-armed clinical trial was carried out in Hangzhou Xixi Hospital,an affiliated hospital with Zhejiang Chinese Medical University.102 confirmed cases were screened out from 725 suspected cases and 93 of them were treated with integrated TCM and western medicine treatment scheme.Results:83 cases were cured,5 cases deteriorated,and 5 cases withdrew from the study.No deaths were reported.The mean relief time of fever,cough,diarrhea,and fatigue were(4.78±4.61)days,(7.22±4.99)days,(5.28±3.39)days,and(5.28±3.39)days,respectively.It took(14.84±5.50)days for SARS-CoV-2 by nucleic acid amplification-based testing to turn negative.Multivariable cox regression analysis revealed that age,BMI,PISCT,BPC,AST,CK,BS,and UPRO were independent risk factors for COVID-19 treatment.Conclusion:Our study suggested that integrated TCM and western medicine treatment scheme was effective for COVID-19.