Ixekizumab-induced urticaria is associated with the short duration of remission in psoriasis by activation of mast cells.

BACKGROUND: Mast cell degranulation plays a pivotal role in urticaria and is also an early histologic characteristic of psoriasis. However, whether the activation of mast cells contributes to psoriasis recurrence after discontinuation of interleukin (IL)-17A blockers remains unclear. OBJECTIVE: To investigate the role of mast cells in ixekizumab treatment-associated urticaria (ITAUR) and assess the effect of urticaria eruption on psoriasis relapse. METHODS: A retrospective analysis was performed on biopsies of patients who experienced psoriasis relapse after discontinuation of ixekizumab. Transcriptomic and histopathologic features were assessed. Patterns were compared between patients with ITAUR and nonurticaria (NUR) as well as psoriasis-like mice with mast cell activation or inactivation. RESULTS: Patients with ITAUR experienced early relapse compared with NUR group after treatment withdrawal. Transcriptomic and histopathologic analyses revealed that patients with ITAUR had an elevated proportion of mast cells in resolved skin. Especially, the proportion of IL-17A+ mast cells was inversely correlated with the duration of remission. LIMITATIONS: The mechanism of mast cell activation in ITAUR has not been precisely elucidated. CONCLUSION: Ixekizumab treatment increases IL-17A+ mast cells in lesions of ITAUR, which is associated with early psoriasis relapse after ixekizumab withdrawal.

Culprit Plaques of Large Parent Arteries, Rather than Cerebral Small Vessel Disease, Contribute to Early Neurological Deterioration in Stroke Patients with Intracranial Branch Atheromatous Disease.

INTRODUCTION: Intracranial branch atheromatous disease (BAD) has been applied to occlusions that occur at the origin of large caliber penetrating arteries due to the microatheromas or large parent artery plaques. This study aimed to explore the association between culprit plaques of large parent arteries, neuroimaging markers of cerebral small vessel disease (CSVD), and the risk of early neurological deterioration (END) in stroke patients with BAD. METHODS: A total of 97 stroke patients with BAD in the vascular territories of the lenticulostriate arteries or paramedian pontine arteries, diagnosed using high-resolution magnetic resonance imaging, were prospectively recruited in this observational study. A culprit plaque in the middle cerebral artery was defined as the only arterial plaque on the ipsilateral side of an infarction visible on diffusion-weighted imaging. A culprit plaque in the basilar artery (BA) was identified when it was observed within the same axial slices of an infarction or on the adjacent upper or lower slice, whereas a plaque within the BA located in the ventral region was considered non-culprit. If more than one plaque was present in the same vascular territory, the most stenotic plaque was chosen for the analysis. Four CSVD neuroimaging markers, including white matter hyperintensity, lacunes, microbleeds, and enlarged perivascular spaces, were evaluated in accordance with the total CSVD score. The associations between neuroimaging features of lesions within large parent arteries, neuroimaging markers of CSVD, and the risk of END in stroke patients with BAD were investigated using logistic regression analysis. RESULTS: END occurred in 41 stroke patients (42.27%) with BAD. The degree of large parent artery stenosis (p < 0.001), culprit plaques of large parent arteries (p < 0.001), and plaque burden (p < 0.001) were significantly different between the END and non-END groups in stroke patients with BAD. In logistic regression analysis, culprit plaques of large parent arteries (odds ratio, 32.258; 95% confidence interval, 4.140-251.346) were independently associated with the risk of END in stroke patients with BAD. CONCLUSIONS: Culprit plaques of large parent arteries could predict the risk of END in stroke patients with BAD. These results suggest that lesions in the large parent arteries, rather than damage to the cerebral small vessels, contribute to END in stroke patients with BAD.

Macrophage lineage cells-derived migrasomes activate complement-dependent blood-brain barrier damage in cerebral amyloid angiopathy mouse model.

Accumulation of amyloid beta protein (Aß) in brain vessels damages blood brain barrier (BBB) integrity in cerebral amyloid angiopathy (CAA). Macrophage lineage cells scavenge Aß and produce disease-modifying mediators. Herein, we report that Aß40-induced macrophage-derived migrasomes are sticky to blood vessels in skin biopsy samples from CAA patients and brain tissue from CAA mouse models (Tg-SwDI/B and 5xFAD mice). We show that CD5L is packed in migrasomes and docked to blood vessels, and that enrichment of CD5L impairs the resistance to complement activation. Increased migrasome-producing capacity of macrophages and membrane attack complex (MAC) in blood are associated with disease severity in both patients and Tg-SwDI/B mice. Of note, complement inhibitory treatment protects against migrasomes-mediated blood-brain barrier injury in Tg-SwDI/B mice. We thus propose that macrophage-derived migrasomes and the consequent complement activation are potential biomarkers and therapeutic targets in CAA.

Bone Marrow Mesenchymal Stem Cell-Derived Dermcidin-Containing Migrasomes enhance LC3-Associated Phagocytosis of Pulmonary Macrophages and Protect against Post-Stroke Pneumonia.

Pneumonia is one of the leading causes of death in patients with acute ischemic stroke (AIS). Antibiotics fail to improve prognosis of patients with post-stroke pneumonia, albeit suppressing infection, due to adverse impacts on the immune system. The current study reports that bone marrow mesenchymal stem cells (BM-MSC) downregulate bacterial load in the lungs of stroke mice models. RNA-sequencing of the lung from BM-MSC-treated stroke models indicates that BM-MSC modulates pulmonary macrophage activities after cerebral ischemia. Mechanistically, BM-MSC promotes the bacterial phagocytosis of pulmonary macrophages through releasing migrasomes, which are migration-dependent extracellular vesicles. With liquid chromatography-tandem mass spectrometry (LC-MS/MS), the result shows that BM-MSC are found to load the antibacterial peptide dermcidin (DCD) in migrasomes upon bacterial stimulation. Besides the antibiotic effect, DCD enhances LC3-associated phagocytosis (LAP) of macrophages, facilitating their bacterial clearance. The data demonstrate that BM-MSC is a promising therapeutic candidate against post-stroke pneumonia, with dual functions of anti-infection and immunol modulation, which is more than a match for antibiotics treatment.

Combined healthy lifestyle in early pregnancy and risk of gestational diabetes mellitus: A prospective cohort study.

OBJECTIVE: To examine the association of a combined healthy lifestyle in early pregnancy with gestational diabetes mellitus (GDM) risk. DESIGN, SETTING AND POPULATION: A Chinese prospective cohort study with 6980 pregnant women. METHODS: Individual modifiable lifestyle factors were assessed in early pregnancy and a combined lifestyle score was derived from the sum of the lifestyle factors, with a higher score indicating a healthier lifestyle. The association of a combined healthy lifestyle with GDM risk was examined. MAIN OUTCOME MEASURES: Gestational diabetes mellitus was diagnosed in middle pregnancy according to the International Association of Diabetes and Pregnancy Study Group criteria or diagnoses in medical records. RESULTS: Overall, 501 (7.2%) pregnant women were diagnosed with GDM. Being physically active (total energy expenditure in upper three quintiles, i.e. ≥100.1 metabolic equivalent of task [MET]-hours/week; odds ratio [OR] 0.76, 95% confidence interval [CI] 0.63-0.92), healthy diet (total intake of vegetables and fruits ≥5 times/day; OR 0.74, 95% CI 0.59-0.94), sufficient sleep (night-time sleep duration ≥7 hours/night; OR 0.66, 95% CI 0.48-0.90) and healthy weight (early-pregnancy BMI <24.0 kg/m2 ; OR 0.57, 95% CI 0.46-0.71) were associated with lower GDM risk. The GDM risk decreased linearly across the combined lifestyle score (Ptrend <0.001): women with 2, 3 and 4 lifestyle factors compared with those with 0-1 factor had 38% (OR 0.62, 95% CI 0.46-0.84), 57% (OR 0.43, 95% CI 0.31-0.58) and 66% (OR 0.34, 95% CI 0.22-0.52) lower risks of GDM, respectively. CONCLUSION: A healthy lifestyle in early pregnancy was associated with a substantially lower GDM risk.

Topical emollient prevents the development of atopic dermatitis and atopic march in mice.

To investigate the effect of emollient on atopic march in a murine model of atopic dermatitis (AD). Following induction of AD with topical calcipotriol (MC903) and ovalbumin (OVA), one group of mice was treated topically with a linoleic acid-ceramide-containing emollient, while mice without emollient treatment served as disease controls. After 28 days, clinical, histological and transcriptomic analyses were performed in the skin lesions and the lung as well as serum cytokine levels. Treatments of mice with MC903 and OVA induced a typical phenotype of AD, accompanied by increased expression levels of Th2 and basophil-related genes in the lung. Topical emollients markedly decreased the severity of skin lesions and inflammatory cell infiltration. Moreover, emollient treatments significantly downregulated expression levels of AD-related genes (286 of 1450 differentially expressed genes), including those related to innate inflammation (S100a8/a9, Il1b, Defb3/6, Mmp12), chemokines (Cxcl1/3, Ccl3/4) and epidermal permeability barrier (Krt2/6b/80, Serpinb12, Lce3e, Sprr2), etc. Downregulated genes were enriched in mitochondrial OXPHOS-related pathways, while upregulated genes were mainly enriched in axon guidance and tight junctions. Moreover, topical emollient treatments decreased total serum levels of IL-4, along with substantial reductions in IgE and thymic stromal lymphopoietin (TSLP) levels. Furthermore, 187 of 275 upregulated genes in lung tissue were also significantly downregulated, including those involved in leucocyte chemotaxis (Ccl9, Ccr2, Retnlg, Ccl3, Cxcl10, Il1r2, etc.) and basophil activation (Mcpt8, Cd200r3, Fcer1a, Ms4a2). In conclusion, topical emollient not only reduces skin inflammation, but also mitigates systemic inflammation by decreasing TSLP and IgE levels. Moreover, topical emollient reduces chemokine production and basophil infiltration and activation in the lung.

Inhibition of interaction between ROCK1 and Rubicon restores autophagy in endothelial cells and attenuates brain injury after prolonged ischemia.

Acute ischemic stroke (AIS) induces cerebral endothelial cell death resulting in the breakdown of the blood-brain barrier (BBB). Endothelial cell autophagy acts as a protective mechanism against cell death. Autophagy is activated in the very early stages of ischemic stroke and declines after prolonged ischemia. Previous studies have shown that Rubicon can inhibit autophagy. The current study aimed to investigate whether continuous long-term ischemia can inhibit autophagy in endothelial cells after ischemic stroke by regulating the function of Rubicon and its underlying mechanism. Wild-type male C57BL/6J mice were subjected to transient middle cerebral artery occlusion (tMCAO). ROCK1, ROCK2, and NOX2 inhibitors were injected into male mice 1 h before the onset of tMCAO. Disease severity and BBB permeability were evaluated. bEnd.3 cells were cultured in vitro and subjected to oxygen-glucose deprivation (OGD). bEnd.3 cells were pretreated with or without ROCK1, ROCK2, or NOX2 inhibitors overnight and then subjected to OGD. Cell viability and permeability were also evaluated. The expression of Rubicon, ROCK1, and autophagy-related proteins were analyzed. Increased BBB permeability was correlated with Rubicon expression in tMCAO mice and Rubicon was upregulated in endothelial cells subjected to OGD. Autophagy was inhibited in endothelial cells after long-term OGD treatment and knockdown of Rubicon expression restored autophagy and viability in endothelial cells subjected to 6-h OGD. ROCK1 inhibition decreased the interaction between Beclin1 and Rubicon and restored cell viability and autophagy suppressed by 6-h OGD treatment in endothelial cells. Additionally, ROCK1 inhibition suppressed Rubicon, attenuated BBB disruption, and brain injury induced by prolonged ischemia in 6-h tMCAO mice. Prolonged ischemia induced the death of brain endothelial cells and the breakdown of the BBB, thus aggravating brain injury by increasing the interaction of ROCK1 and Rubicon with Beclin1 while inhibiting canonical autophagy. Inhibition of ROCK1 signaling in endothelial cells could be a promising therapeutic strategy to prolong the therapeutic time window in AIS.

Melatonin Offers Dual-Phase Protection to Brain Vessel Endothelial Cells in Prolonged Cerebral Ischemia-Recanalization Through Ameliorating ER Stress and Resolving Refractory Stress Granule.

Ischemic-reperfusion injury limits the time window of recanalization therapy in cerebral acute ischemic stroke (AIS). Brain vessel endothelial cells (BVECs) form the first layer of the blood-brain barrier (BBB) and are thus the first sufferer of ischemic-reperfusion disorder. The current study demonstrates that melatonin can reduce infarct volume, alleviate brain edema, ameliorate neurological deficits, and protect BBB integrity in prolonged-stroke mice. Here, we demonstrate that endoplasmic reticulum (ER)-associated injury contributes to BVEC death in the dural phase of reperfusion after prolonged ischemia. When encountering ischemia, ER stress arises, specifically activating PERK-EIF2α signaling and the subsequent programmed cell death. Prolonged ischemia leads stress granules (SGs) to be refractory, which remain unresolved and accumulate in ER during recanalization. During reperfusion, refractory SGs activate PKR-EIF2α and further exacerbate BVEC injury. We report that melatonin treatment downregulates ER stress in the ischemic period and enhances dissociation of the refractory SGs during reperfusion, thus offering dual-phase protection to BVECs in prolonged cerebral stroke. Mechanistically, melatonin enhances autophagy in BVECs, which preserves ER function and resolves refractory SGs. We, therefore, propose that melatonin is a potential treatment to extend the time window of delayed recanalization therapy in AIS.

Natural Killer Cells Disrupt Nerve Fibers by Granzyme H in Atheriosclerotic Cerebral Small Vessel Disease.

Natural killer (NK) cells are enriched in the central nervous system in aging-related atheriosclerotic cerebral small vessel disease (aCSVD), but their roles and underlying mechanism remain to be elucidated. To identify potential cytotoxic molecules released by NK cells in aCSVD lesions, proteomic analysis of cerebrospinal fluid (CSF), plasma, and peripheral NK cells from patients with aCSVD were performed. We found that integrin ß2 (ITGB2), cathepsin D (CTSD), and granzyme H (GZMH) were highly expressed in NK cells. ITGB2 interacted with intercellular adhesion molecule 1 in vascular endothelial cells. As assessed by immunofluorescence and scanning electron microscopy of the blood-brain barrier model, transwell membranes covered with primary human brain microvascular endothelial cells and astrocytes, we demonstrated that the CTSD-mediated degradation of collagen in the blood-brain barrier depended on the cytotoxicity of NK cells in aCSVD. With the immunostaining in vitro and in vivo, GZMH disruption of demyelinated nerve fibers was reversed by cotreatment with the inhibitor 3,4-DCIC during white matter hyperintensity (WMH) in aCSVD. Our results indicate that NK cells contribute to CTSD-induced damage to the blood-brain barrier and GZMH-induced disruption of nerve fibers during WMH in aCSVD.

FOXP3+ macrophage represses acute ischemic stroke-induced neural inflammation.

Proper termination of cell-death-induced neural inflammation is the premise of tissue repair in acute ischemic stroke (AIS). Macrophages scavenge cell corpses/debris and produce inflammatory mediators that orchestrate immune responses. Here, we report that FOXP3, the key immune-repressive transcription factor of Tregs, is conditionally expressed in macrophages in stroke lesion. FOXP3 ablation in macrophages results in detrimental stroke outcomes, emphasizing the beneficial role of FOXP3+ macrophages. FOXP3+ macrophages are distinct from the M1 or M2 subsets and display superactive efferocytic capacity. With scRNAseq and analysis of FOXP3-bound-DNA isolated with CUT & RUN, we show that FOXP3 facilitates macrophage phagocytosis through enhancing cargo metabolism. FOXP3 expression is controlled by macroautophagic/autophagic protein degradation in resting macrophages, while initiation of LC3-associated phagocytosis (LAP) competitively occupies the autophagic machineries, and thus permits FOXP3 activation. Our data demonstrate a distinct set of FOXP3+ macrophages with enhanced scavenging capability, which could be a target in immunomodulatory therapy against AIS.Abbreviations: ADGRE1/F4/80: adhesion G protein-coupled receptor E1; AIF1/Iba1: allograft inflammatory factor 1; AIS: acute ischemic stroke; ARG1: arginase 1; ATP: adenosine triphosphate; BECN1/Beclin1: Beclin 1, autophagy related; BMDM: bone marrow-derived macrophages; CKO: conditional knockout; CSF1/M-CSF: colony stimulating factor 1 (macrophage); CSF2/GM-CSF: colony stimulating factor 2; CSF3/G-CSF: colony stimulating factor 3; CUT & RUN: cleavage under targets and release using nuclease; CyD: cytochalasin D; DAMP: danger/damage-associated molecular pattern; DIL: dioctadecyl-3,3,3,3-tetramethylin docarbocyanine; ELISA: enzyme linked immunosorbent assay; GO: Gene Ontology; FCGR3/CD16: Fc receptor, IgG, low affinity III; HMGB1: high mobility group box 1; IFNG/IFNγ: interferon gamma; IP: immunoprecipitation; KEGG: Kyoto Encyclopedia of Genes and Genomes; ITGAM/CD11b: integrin subunit alpha M; ITGAX/CD11c: integrin subunit alpha X; LAP: LC3-associated phagocytosis; LC-MS: liquid chromatography-mass spectrometry; LPS: lipopolysaccharide; MRC1/CD206: mannose receptor, C type 1; O4: oligodendrocyte marker O4; PBMC: peripheral blood mononuclear cells; RBC: red blood cells; PTPRC/CD45: protein tyrosine phosphatase, receptor type, C; RBFOX3/NeuN: RNA binding protein, fox 1 homolog (C. elegans) 3; RUBCN/Rubicon: RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; scRNAseq: single cell RNA sequencing; SQSTM1/p62 (sequestosome 1); TGFB/TGFß: transforming growth factor, beta; tMCAO: transient middle cerebral artery occlusion; TNF/TNFα: tumor necrosis factor; Treg: regulatory T cell.

Long-term glycemic variability and risk of adverse health outcomes in patients with diabetes: A systematic review and meta-analysis of cohort studies.

AIMS: To quantify associations of different metrics of long-term glycemic variability (GV) with multiple adverse diabetes-related outcomes. METHODS: We searched PubMed and Embase from database inception to 23 August 2021. GV was based on measurements of HbA1c or fasting plasma glucose (FPG) and calculated by standard deviation (SD), coefficient of variance (CV) or other metrics. Outcomes included mortality, cardiovascular disease (CVD), renal disease, peripheral neuropathy, retinopathy, dementia and cancer. Random-effects meta-analyses were adopted to pool the relative risks (RRs). RESULTS: Seventy-five articles with 2,051,701 participants were included. When comparing top with bottom quartiles, HbA1c variabilities were associated with all-cause mortality (RRCV = 1.63, 95 % CI 1.37-1.92; RRSD = 1.87, 1.55-2.26), CVD (RRCV = 1.38, 1.07-1.78; RRSD = 1.34, 1.12-1.59), renal disease (RRCV = 1.43, 1.18-1.74; RRSD = 1.44, 1.24-1.67), and peripheral neuropathy (RRCV = 1.84, 1.40-2.43; RRSD = 1.98, 1.51-2.61), but not retinopathy. FPG variabilities were associated with all-cause mortality (RRCV = 1.59, 1.43-1.78; RRSD = 1.67, 1.26-2.20), renal disease (RRCV = 1.77, 1.32-2.38), and retinopathy (RRCV = 1.92, 1.10-3.35), but not CVD and peripheral neuropathy. Associations of GV with Alzheimer's disease (RRHbA1c-CV = 1.38, 1.13-1.70; RRFPG-CV = 1.32, 1.07-1.63) and cancer (RRHbA1c-SD = 2.19, 1.52-3.17; RRFPG-CV = 3.64, 2.21-5.98) were each found significant in one study. CONCLUSIONS: Long-term GV was associated with multiple adverse diabetes-related outcomes, while the strength of associations varied. The findings support the use of long-term GV for diabetes management in clinical practice.

Brain Activity in Different Brain Areas of Patients With Dry Eye During the Female Climacteric Period According to Voxel-Based Morphometry.

We aim to investigate potential morphological alterations of the brain in female climacteric patients with dry eye (DE) and their relationship to behavioral performances. Twenty-five female patients with DE disease during the female climacteric period and 25 age and education-matched healthy controls (HCs) underwent magnetic resonance imaging. Imaging data were analyzed using voxel-based morphometry (VBM) to identify group differences in DE patients and HCs. Compared with HCs, patients with DE during the female climacteric period had significantly decreased VBM in the Putamen_L, Thalamus_R, Precuneus_L, Frontal_Sup_R, Cingulum_Mid_L, and Frontal_Mid_L. There was increased VBM in the Temporal_Pole_Sup_R, Precentral_R and Insula_L. Receiver operating characteristic curve analysis indicated that the VBM method has clear potential for diagnosis of DE patients during the climacteric period. Correlation analysis found a negative correlation between the VBM values of the Putamen_L and the anxiety score (AS) and depression score (DS), a positive correlation was found between VBM values of the Temporal_Pole_Sup_R and AS. Moreover, VBM values in the Cingulum_Mid_L were positively correlated with AS and DS. These results revealed abnormal spontaneous activity in the brain regions of patients with DE during the climacteric period, which may indicate underlying pathological mechanisms. These results may help to advance clinical treatments.

Application of kNN and SVM to predict the prognosis of advanced schistosomiasis.

Predictive models for prognosis of small sample advanced schistosomiasis patients have not been well studied. We aimed to construct prognostic predictive models of small sample advanced schistosomiasis patients using two machine learning algorithms, k nearest neighbour (kNN) and support vector machine (SVM) utilising routinely available data under the government medical assistance programme. The predictive models were derived from 229 patients from Xiantao and externally validated by 77 patients of Jiayu, two county-level cities in Hubei province, China. Candidate predictors were selected according to expert opinions and literature reports, including clinical features, sociodemographic characteristics, and medical examinations results. An area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were used to evaluate the models' predictive performances. The AUC values were 0.879 for the kNN model and 0.890 for the SVM model in the training set, 0.852 for the kNN model, and 0.785 for the SVM model in the external validation set. The kNN and SVM models can be used to improve the health services provided by healthcare planners, clinicians, and policymakers.

Altered Brain Activity in Patients With Comitant Strabismus Detected by Analysis of the Fractional Amplitude of Low-Frequency Fluctuation: A Resting-State Functional MRI Study.

More and more studies showed that strabismus is not simply an ocular disease, but a neuro-ophthalmology disease. To analyze potential changes in brain activity and their relationship to behavioral performance in comitant strabismus patients and healthy controls. Our study recruited 28 patients with comitant strabismus and 28 people with matched weight, age range, and sex ratio as healthy controls. Using resting-state functional magnetic resonance imaging, we evaluated fALFF to compare spontaneous brain activity between comitant strabismus and healthy controls. We did hospital anxiety and depression scale questionnaires for these patients. We found significantly lower fALFF value in comitant strabismus patients compared with controls in the left frontal superior medial gyrus and the right middle cingulum. In the latter region, fALFF was significantly negatively correlated with the hospital anxiety and depression scale, as well as the duration of disease. Receiver operating characteristic curve analysis indicated that the fALFF method has clear potential for the diagnosis of comitant strabismus patients. These results revealed abnormal spontaneous activity in two brain regions of comitant strabismus patients, which may indicate underlying pathologic mechanisms and may help to advance clinical treatment.

SARS-CoV-2 might transmit through the skin while the skin barrier function could be the mediator.

During the coronavirus disease 2019 (COVID-19) pandemic, it were reported that COVID-19 patients could have cutaneous symptoms, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was observed on the skin of COVID-19 patients, which indicated that the skin is one target of SARS-CoV-2. Meanwhile, reports about SARS-CoV-2 transmission through food cold-chain overpacks emerged. With the fact that SARS-CoV-2 could survive on the skin for more than 9 h, the skin could be implicated in SARS CoV-2 transmission. Angiotensin-converting enzyme 2 (ACE2), a critical membrane protein for SARS-CoV-2 that enters a host cell, was recognized to be associated with the risk of SARS-CoV-2 infection. Therefore, tissues that express ACE2 might have the potential to be infected by and transmit SARS-CoV-2. The skin is one such tissue that expresses ACE2. However, unlike the lung that expresses ACE2 on the upper-most epithelial layer, the skin is composed of different layers of cells that function as a barrier, and cells under the top epidermal layer express ACE2. Since the skin barrier is the first line of protection, the typical position of ACE2-expressing cells in the skin implies that the skin barrier function could be the mediator of SARS-CoV-2. In our study, we found that ACE2 could be expressed in the skin, and its expression level is increased in psoriasis, an inflammatory disease of the skin with barrier dysfunction. Additionally, by applying the SARS-CoV-2 pseudovirus on mouse models with or without deteriorated skin barrier, we found that the SARS-CoV-2 pseudovirus could infect the skin and lungs of mouse models, and when the skin barrier was impaired, more SARS-CoV-2-infected cells could be found. Thus, we hypothesized that a deteriorated condition of the skin barrier might increase the risk of SARS-CoV-2 infection through the skin.

Myocardial protective effect and transcriptome profiling of Naoxintong on cardiomyopathy in zebrafish.

BACKGROUND: Cardiomyopathy is a kind of cardiovascular diseases, which makes it more difficult for the heart to pump blood to other parts of the body, eventually leading to heart failure. Naoxintong (NXT), as a traditional Chinese Medicine (TCM) preparation, is widely used in the treatment of cardiovascular diseases, including cardiomyopathy, while its underlying mechanism has not been fully elucidated. The purpose of this study is to investigate the therapeutic effect of NXT on cardiomyopathy and its molecular mechanism in zebrafish model. METHODS: The zebrafish cardiomyopathy model was established using terfenadine (TFD) and treated with NXT. The therapeutic effect of NXT on cardiomyopathy was evaluated by measuring the heart rate, the distance between the sinus venosus and bulbus arteriosus (SV-BA), the pericardial area, and the blood flow velocity of zebrafish. Then, the zebrafish hearts were isolated and collected; transcriptome analysis of NXT on cardiomyopathy was investigated. Moreover, the heg1 mutant of zebrafish congenital cardiomyopathy model was used to further validate the therapeutic effect of NXT on cardiomyopathy. Additionally, UPLC analysis combined with the zebrafish model investigation was performed to identify the bioactive components of NXT. RESULTS: In the TFD-induced zebrafish cardiomyopathy model, NXT treatment could significantly restore the cardiovascular malformations caused by cardiac dysfunction. Transcriptome and bioinformatics analyses of the TFD and TFD + NXT treated zebrafish developing hearts revealed that the differentially expressed genes were highly enriched in biological processes such as cardiac muscle contraction and heart development. As a cardiac development protein associated with cardiomyopathy, HEG1 had been identified as one of the important targets of NXT in the treatment of cardiomyopathy. The cardiovascular abnormalities of zebrafish heg1 mutant could be recovered significantly from NXT treatment, including the expanded atrial cavity and blood stagnation. qRT-PCR analysis further showed that NXT could restore cardiomyopathy phenotype in zebrafish through HEG1-CCM signaling. Among the seven components identified in NXT, paeoniflorin (PF) and salvianolic acid B (Sal B) were considered to be the main bioactive ones with myocardial protection. CONCLUSION: NXT presented myocardial protective effect and could restore myocardial injury and cardiac dysfunction in zebrafish; the action mechanism was involved in HEG1-CCM signaling.

Temporal and Spatial Dynamics of Inflammasome Activation After Ischemic Stroke.

Background: The inflammasome represents a highly pro-inflammatory mechanism. It has been identified that inflammasome was activated after ischemic stroke. However, the impact of inflammasomes on stroke outcomes remains contradictory. The participating molecules and the functioning arena of post-stroke inflammasome activation are still elusive. Methods: In the present study, blood samples from stroke patients were collected and analyzed with flow cytometry to evaluate the correlation of inflammasome activation and stroke outcomes. A stroke model was established using male C57/Bl6 mice with transient middle cerebral artery occlusion (tMCAO, 1 h). The dynamics of inflammasome components, cell type, and location of inflammasome activation and the therapeutic effects of inhibiting post-stroke inflammasome executors were evaluated. Results: We found that a high level of inflammasome activation might indicate detrimental stroke outcomes in patients and mice models. Post-stroke inflammasome activation, especially NLRP3, cleaved Caspase-1, cleaved Caspase-11, IL-1ß, IL-18, and GSDMD, peaked at 3-5 days and declined at 7 days with the participation of multiple components in mice. Macrophage that infiltrated into the ischemic lesion was the main arena for post-stroke inflammasome activation among myeloid cells according to the data of mice. Among all the members of the Caspase family, Caspase-1 and -11 served as the main executing enzymes. Inhibiting Caspase-1/-11 signaling efficiently suppressed DAMPs-induced macrophage inflammasome activation and displayed neuroprotection to stroke models including infarct size (Control: 48.05 ± 14.98; Cas1.i: 19.34 ± 12.21; Cas11.i: 21.43 ± 14.67, P < 0.001) and neurological deficit score (0 d-Control: 2.20 ± 0.63; 0 d-Cas1.i: 2.20 ± 0.63; 0 d-Cas11.i: 2.20 ± 0.63; 1 d-Control: 2.50 ± 0.53; 1 d-Cas1.i: 1.50 ± 0.71; 1 d-Cas11.i: 2.00 ± 0.67; 2 d-Control: 2.30 ± 0.48; 2 d-Cas1.i: 1.30 ± 0.48; 2 d-Cas11.i: 1.50 ± 0.53; 3 d-Control: 2.00 ± 0.67; 3 d-Cas1.i: 1.20 ± 0.42; 3 d-Cas11.i: 1.30 ± 0.48, P < 0.001). Conclusions: Taken together, inflammasome activation played a detrimental role in stroke pathology. Targeting post-stroke inflammasome executing enzymes fitting in the dynamics of macrophages might obtain potential and efficient therapeutic effects.

Case Report: Central Nervous System Immune Reconstitution Inflammatory Syndrome Related to Bacterial Meningitis.

Central nervous system immune reconstitution inflammatory syndrome (CNS-IRIS) describes clinical characteristics that may be observed in previously immunocompromised patients during rapid restoration of immunity function in the presence of a pathogen. There have been no reports about CNS-IRIS related to bacterial meningitis so far. Here, we report a 24-year-old pregnant female patient with bacterial meningitis. Her clinical and neuroradiological condition worsened after induced labor despite great effective anti-infective therapy. CNS-IRIS was considered. Corticosteroids were administered, and the patient gradually recovered. We present the first case of CNS-IRIS associated with bacterial meningitis.

High-salt diet downregulates TREM2 expression and blunts efferocytosis of macrophages after acute ischemic stroke.

BACKGROUND: A high-salt diet (HSD) is one of the major risk factors for acute ischemic stroke (AIS). As a potential mechanism, surplus salt intake primes macrophages towards a proinflammatory phenotype. In this study, whether HSD could blunt the efferocytic capability of macrophages after ischemic stroke, thus exacerbating post-stroke neural inflammation, was investigated. METHODS: Wild-type male C57BL/6 mice were fed with fodder containing 8% sodium chloride for 4 weeks and subjected to transient middle cerebral occlusion (tMCAO). Disease severity, macrophage polarization as well as efferocytic capability were evaluated. Bone marrow-derived macrophages were cultured in vitro, and the impact of high salinity on their efferocytic activity, as well as their expression of phagocytic molecules, were analyzed. The relationships among sodium concentration, macrophage phenotype, and disease severity in AIS patients were explored. RESULTS: HSD-fed mice displayed increased infarct volume and aggravated neurological deficiency. Mice fed with HSD suffered exacerbated neural inflammation as shown by higher inflammatory mediator expression and immune cell infiltration levels. Infiltrated macrophages within stroke lesions in HSD-fed mice exhibited a shift towards proinflammatory phenotype and impaired efferocytic capability. As assessed with a PCR array, the expression of triggering receptor expressed on myeloid cells 2 (TREM2), a receptor relevant to phagocytosis, was downregulated in high-salt-treated bone marrow-derived macrophages. Enhancement of TREM2 signaling restored the efferocytic capacity and cellular inflammation resolution of macrophages in a high salinity environment in vitro and in vivo. A high concentration of urine sodium in AIS patients was found to be correlated with lower TREM2 expression and detrimental stroke outcomes. CONCLUSIONS: HSD inhibited the efferocytic capacity of macrophages by downregulating TREM2 expression, thus impeding inflammation resolution after ischemic stroke. Enhancing TREM2 signaling in monocytes/macrophages could be a promising therapeutic strategy to enhance efferocytosis and promote post-stroke inflammation resolution.