MicroRNA-3061 downregulates the expression of PAX7/Wnt/Ca2+ signalling axis genes to induce premature ovarian failure in mice.

The in-depth mechanisms of microRNA regulation of premature ovarian failure (POF) remain unclear. Crispr-cas9 technology was used to construct transgenic mice. The qPCR and Western blot was used to detect the expression level of genes. H&E staining were used to detect ovarian pathological phenotypes. We found that the expression levels of microRNA-3061 were significantly higher in ovarian granulosa cells (OGCs) of POF mouse models than in controls. The miR-3061+/-/AMH-Cre+/- transgenic mice manifested symptoms of POF. RNA-Seq and luciferase reporter assay confirmed that the PAX7 was one of the target genes negatively regulated by microRNA-3061 (miR-3061-5p). Moreover, PAX7 mediated the expression of non-canonical Wnt/Ca2+ signalling pathway by binding to the motifs of promoters to stimulate the transcriptional activation of Wnt5a and CamK2a. In contrast, specific knock-in of microRNA-3061 in OGCs significantly downregulated the expression levels of PAX7 and inhibited the expression of downstream Wnt/Ca2+ signalling pathway. We also discerned a correlation between the expression levels of mRNAs of the Wnt/Ca2+ signalling pathway and the levels of E2 and FSH in POF patients by examining gene expression in the follicular fluid-derived exosomes of women. We confirmed that overexpression of microRNA-3061 induced proliferative inhibition of OGCs and ultimately induced POF in mice by suppressing the transcription factor PAX7 and downregulating expression levels of its downstream Wnt/Ca2+ signalling pathway genes.

Potential mechanisms underlying inhibition of xenograft lung cancer models by kaempferol: modulation of gut microbiota in activating immune cell function.

Context: As a flavonoid compound, kaempferol has great potential in anti-lung cancer therapy, but the mechanism of its therapeutic effect needs further exploration. Objective: To explore the therapeutic effect of kaempferol on lung cancer, as well as its capability to regulate the gut microbiota and stimulate immune function. Materials & methods: Twenty-four BALB/c mice were divided into four groups. The first two groups, consisting of 12 normal mice, were administered either PBS or Kaempferol (Kaem) via gavage. The remaining 12 mice, which were subcutaneously inoculated with Lewis Lung Carcinoma (LLC) cells, were similarly divided and subjected to the same treatments respectively. The inhibitory effect of kaempferol on xenograft lung cancer models was explored with in vivo experiments, the diversity of gut microbiota was investigated by 16S rDNA sequencing, and the treatment effect on immune cells was quantified using flow cytometry. Results: Kaempferol exerted a significant inhibitory effect on xenograft lung cancer models in vivo. It effectively inhibited the proliferation of LLC cells and significantly activated cytotoxic T cells, natural killer cells, and other immune cells in mice. 16S rRNA sequencing of fecal samples from tumor-bearing mice treated with kaempferol showed a significant increase in the abundances of potentially advantageous microbial species such as c_Bacilli, o_Lactobacillales, f_Lachnospiraceae, s_uncultured_bacterium_g_Lactobacillus, g_Lactobacillus, f_Bacteroidaceae, g_Bacteroides, and s_uncultured_bacterium_g_Bacteroides, s_Bacteroides_acidifaciens. An increase in the proportions of three types of immune cells might associated with the above dominant bacterial species. Conclusion: Kaempferol can inhibit xenograft lung cancer models. Such inhibition effect might come from the activation of T cells, NK cells, and other immune cells which are modulated by the gut microbiota.

Phospholipid Bilayer Inspired Sandwich Structural Nanofibrous Membrane for Atmospheric Water Harvesting and Selective Release.

Atmospheric water harvesting (AWH) has been broadly exploited to meet the challenge of water shortage. Despite the significant achievements of AWH, the leakage of hydroscopic salt during the AWH process hinders its practical applications. Herein, inspired by the unique selective permeability of the phospholipid bilayer, a sandwich structural (hydrophobic-hydrophilic-hydrophobic) polyacrylonitrile nanofibrous membrane (San-PAN) was fabricated for AWH. The hydrophilic inner layer loaded with LiCl could capture water from the air. The hydrophobic microchannels in the outer layer could selectively allow the free transmission of gaseous water molecules but confine the hydroscopic salt solution in the hydrophilic layer, achieving continuous and recyclable water sorption/desorption. As demonstrated, the as-prepared AWH devices presented high-efficient adsorption kinetics from 1.66 to 4.08 g g-1 at 30% to 90% relative humidity. Thus, this work strengthens the understanding of the water transmission process along microchannels and provides insight into the practical applications of AWH.

Codonopsis pilosula polysaccharide alleviates rotenone-induced murine brain organoids death through downregulation of gene body DNA methylation modification in the ZIC4/PGM5/CAMTA1 axis.

Here, the protective mechanism of Codonopsis pilosula polysaccharide (CpP) against mouse brain organoids (mBO) damage was analyzed, and the rotenone affected the genomic epigenetic modifications and physiological activity of mouse brain organoids was examined. Pathological experiments have shown that rotenone significantly damaged the subcellular organelles of mouse brain organoids. According to RRBS-Seq, rotenone significantly promoted gene body hypermethylation modifications in mouse brain organoids. Molecular biology experiments have confirmed that rotenone significantly promoted the hypermethylation modification of Zic4, Pgm5, and Camta1 gene bodies in mouse brain organoids, and their expression levels were significantly lower than those of the control group. Bioinformatic analysis suggested that multiple binding motif of transcription factors ZIC4 (Zinc finger protein of the cerebellum 4) were present at the promoters of both the Pgm5 (Phosphoglucomutase 5) and Camta1 (Calmodulin binding transcription activator 1) genes. When the expression of Zic4 was silenced, the proliferation of mouse brain organoids was significantly reduced and the expression level of PGM5 was also significantly decreased. In addition, Codonopsis pilosula polysaccharide treatment of mouse brain organoids significantly reduced the cytotoxicity of rotenone, promoted cell cycle progression, increased intracellular glutathione activity, significantly induced the demethylation modification of the Zic4, Pgm5, and Camta1 gene bodies, and promoted the high expression of ZIC4 and PGM5. Therefore, the study confirmed that Codonopsis pilosula polysaccharide alleviated rotenone-induced mouse brain organoids death by downregulating DNA gene bodies methylation modification of the Zic4/Pgm5/Camta1 axis.

Capsaicin inhibits A7r5 cell senescence via the mitochondrial carrier protein Slc25a12.

Aging of vascular smooth muscle cells (VSMCs) is the principal factor responsible for the loss of vascular function, and continuous exposure to high glucose is one of the key factors contributing to the aging of VSMCs. This study established a high glucose-induced senescence model of the A7r5 cell line and used transcriptome sequencing to screen the regulatory target genes of high glucose-induced cellular senescence. The study revealed that the expression of the Slc25a12 gene, which belongs to the solute carrier family 25 member 12, was notably reduced following damage caused by high glucose levels. This inhibition was shown to cause mitochondrial malfunction and cellular senescence. The encoded product of the Slc25a12 gene is a mitochondrial carrier protein that binds to calcium and aids in transporting aspartate for glutamate exchange within the inner mitochondrial membrane. Mitochondrial dysfunction compromises the cell's capacity to resist oxidation and repair damage, and is an inherent element in hastening cellular aging. Moreover, our findings validated that the transient receptor potential vanilloid 1 (TRPV1) agonist capsaicin hindered the decrease in Slc25a12 expression, prevented mitochondrial dysfunction, and blocked cellular senescence. Could the regulation of Slc25a12 expression by capsaicin restore cellular mitochondrial function and restrict senescence? In vitro tests have verified that interference with A7r5 Slc25a12 noticeably diminishes capsaicin's effectiveness in repairing mitochondrial function and inhibiting senescence. The findings indicate that capsaicin delays mitochondrial dysfunction and therefore hinders cellular senescence by regulating the mitochondrial membrane protein Slc25a12 in the A7r5 cell line.

Nanopolyphenol rejuvenates microglial surveillance of multiple misfolded proteins through metabolic reprogramming.

Microglial surveillance plays an essential role in clearing misfolded proteins such as amyloid-beta, tau, and α-synuclein aggregates in neurodegenerative diseases. However, due to the complex structure and ambiguous pathogenic species of the misfolded proteins, a universal approach to remove the misfolded proteins remains unavailable. Here, we found that a polyphenol, α-mangostin, reprogrammed metabolism in the disease-associated microglia through shifting glycolysis to oxidative phosphorylation, which holistically rejuvenated microglial surveillance capacity to enhance microglial phagocytosis and autophagy-mediated degradation of multiple misfolded proteins. Nanoformulation of α-mangostin efficiently delivered α-mangostin to microglia, relieved the reactive status and rejuvenated the misfolded-proteins clearance capacity of microglia, which thus impressively relieved the neuropathological changes in both Alzheimer's disease and Parkinson's disease model mice. These findings provide direct evidences for the concept of rejuvenating microglial surveillance of multiple misfolded proteins through metabolic reprogramming, and demonstrate nanoformulated α-mangostin as a potential and universal therapy against neurodegenerative diseases.

The Potential Diagnostic Biomarkers for the IgG Subclass in Coal Workers' Pneumoconiosis.

Evidence suggests that exposure to coal dust increases immunoglobulin concentration. However, there is a paucity of data reporting immunoglobulin G (IgG) subclass in coal workers' pneumoconiosis (CWP). Therefore, this study intended to evaluate potential diagnostic biomarkers for the disease. CWP patients, dust-exposed workers without pneumoconiosis (DEW), and matched healthy controls (HCs) presented to the General Hospital of Datong Coal Mining Group and Occupational Disease Prevention and Treatment Hospital of Datong Coal Mining Group between May 2019 and September 2019 were recruited. The serum immunoglobulin concentration was determined by the multiplex immunoassay technique. Totally, 104 CWP patients, 109 DEWs, and 74 HCs were enrolled. Serum levels of IgG1, IgG2, IgM, and IgA were elevated in CWPs compared with those in DEWs and HCs (P < 0.05). The order of diagnostic accuracy between CWPs and DEWs depicted by the receiver operating characteristic (ROC) curve was IgG2, IgM, IgG1, IgG3, and IgA. Significantly higher IgG1/IgG3 and IgG2/IgG3 ratios were observed in the CWP group than in DEW and HC groups. Based on the IgG2/IgG3 ratio, the area under the ROC curve between CWP and DEW was 0.785 (95% CI 0.723-0.838), with a sensitivity of 73.1% and a specificity of 73.4%. Our findings suggest that IgG1, IgG2, IgM, and IgA are higher in the CWPs than DEWs and HCs. The IgG2/IgG3 ratio provides a viable alternative for the diagnosis of CWP.

p85S6K sustains synaptic GluA1 to ameliorate cognitive deficits in Alzheimer's disease.

BACKGROUND: Ribosomal protein S6 kinase 1 (S6K1) is a serine-threonine kinase that has two main isoforms: p70S6K (70-kDa isoform) and p85S6K (85-kDa isoform). p70S6K, with its upstream mammalian target of rapamycin (mTOR), has been shown to be involved in learning and memory and participate in the pathophysiology of Alzheimer's disease (AD). However, the function of p85S6K has long been neglected due to its high similarity to p70S6k. The role of p85S6K in learning and memory is still largely unknown. METHODS: We fractionated the postsynaptic densities to illustrate the differential distribution of p85S6K and p70S6K. Coimmunoprecipitation was performed to unveil interactions between p85S6K and the GluA1 subunit of AMPA receptor. The roles of p85S6K in synaptic targeting of GluA1 and learning and memory were evaluated by specific knockdown or overexpression of p85S6K followed by a broad range of methodologies including immunofluorescence, Western blot, in situ proximity ligation assay, morphological staining and behavioral examination. Further, the expression level of p85S6K was measured in brains from AD patients and AD model mice. RESULTS: p85S6K, but not p70S6K, was enriched in the postsynaptic densities. Moreover, knockdown of p85S6K resulted in defective spatial and recognition memory. In addition, p85S6K could interact with the GluA1 subunit of AMPA receptor through synapse-associated protein 97 and A-kinase anchoring protein 79/150. Mechanistic studies demonstrated that p85S6K could directly phosphorylate GluA1 at Ser845 and increase the amount of GluA1 in synapses, thus sustaining synaptic function and spine densities. Moreover, p85S6K was found to be specifically decreased in the synaptosomal compartment in the brains of AD patients and AD mice. Overexpression of p85S6K ameliorated the synaptic deficits and cognitive impairment in transgenic AD model mice. CONCLUSIONS: These results strongly imply a significant role for p85S6K in maintaining synaptic and cognitive function by interacting with GluA1. The findings provide an insight into the rational targeting of p85S6K as a therapeutic potential for AD.

TRPV1 regulates ApoE4-disrupted intracellular lipid homeostasis and decreases synaptic phagocytosis by microglia.

Although the ε4 allele of the apolipoprotein E (ApoE4) gene has been established as a genetic risk factor for many neurodegenerative diseases, including Alzheimer's disease, the mechanism of action remains poorly understood. Transient receptor potential vanilloid 1 (TRPV1) was reported to regulate autophagy to protect against foam cell formation in atherosclerosis. Here, we show that ApoE4 leads to lipid metabolism dysregulation in microglia, resulting in enhanced MHC-II-dependent antigen presentation and T-cell activation. Lipid accumulation and inflammatory reactions were accelerated in microglia isolated from TRPV1flox/flox; Cx3cr1cre-ApoE4 mice. We showed that metabolic boosting by treatment with the TRPV1 agonist capsaicin rescued lipid metabolic impairments in ApoE4 neurons and defects in autophagy caused by disruption of the AKT-mTOR pathway. TRPV1 activation with capsaicin reversed ApoE4-induced microglial immune dysfunction and neuronal autophagy impairment. Capsaicin rescued memory impairment, tau pathology, and neuronal autophagy in ApoE4 mice. Activation of TRPV1 decreased microglial phagocytosis of synapses in ApoE4 mice. TRPV1 gene deficiency exacerbated recognition memory impairment and tau pathology in ApoE4 mice. Our study suggests that TRPV1 regulation of lipid metabolism could be a therapeutic approach to alleviate the consequences of the ApoE4 allele.

Cordycepin improved neuronal synaptic plasticity through CREB-induced NGF upregulation driven by MG-M2 polarization: a microglia-neuron symphony in AD.

PURPOSE: Microglia-neuron crosstalk is critically involved in synaptic plasticity and degeneration by releasing diverse mediators in Alzheimer's disease (AD). Therefore, determining contributors that modulate the systemic microenvironment is essential. Cordycepin (CCS) is a novel neuroprotective compound obtained from Cordyceps militaris. However, the anti-AD efficacy and potential mechanism of CCS treatment remain unclear. This study aimed to elucidate the microglia-neuron symphony in AD after CCS treatment and to explore the possible mechanisms of its neuroprotective efficacy. METHODS AND RESULTS: CCS treatment improved learning and memory impairment in 9-month-old APP/PS1 mice by behavioral tests. CCS polarized the microglia from M1 to M2, inhibited neuronal apoptosis and promoted synaptic remodeling accompanied by in vivo and in vitro upregulation of NGF. The cAMP-response element-binding protein (CREB) was also activated after MG-M2 polarization. Further, we verified that the sg3 promoter region of NGF (-1018 to -1011) is the key binding site for CREB-induced NGF transcription, which increased NGF expression and secretion. Finally, microglia-derived NGF was confirmed as an important mediator in microglia-neuron symphony to improve the neuronal microenvironment after CCS treatment. CONCLUSIONS: CCS improved the neuronal synaptic plasticity and senescence by promoting MG-M2 activation driven by CREB-induced NGF upregulation and facilitated symphony communication between the microglia and neuron in AD. This study provides a new perspective on the development of a novel strategy for anti-AD therapy and offers new targets for anti-AD drug development.

The aberrant levels of decorin induce damages of human salivary gland epithelial cells and polarization of macrophages.

OBJECTIVES: This study aimed to preliminarily address the levels of decorin (DCN, a critical component of extracellular matrix) and its potential roles in primary Sjögren's syndrome (pSS). METHODS: DCN levels were determined in the salivary glands of experimental SS (ESS) mice and pSS patients by RNA sequencing, bioinformatics analysis, or immunohistochemical staining. Its correlation with interested genes and co-localization with a putative receptor was studied in pSS patients. In addition, its potential roles on salivary gland epithelium and macrophages were tested by exogenous administration to corresponding cell lines, followed by the evaluation of apoptosis using flow cytometry or cytokine expression using quantitative real-time polymerase chain reaction. RESULTS: Our data revealed a significant elevation of DCN in the salivary glands of the ESS mice model and pSS patients. In addition, the bioinformatics analysis of DCN in the GSE40611 (RNA-seq, parotid glands) dataset displayed an elevation of the DCN level in the parotid glands of pSS patients that positively correlated with several chemokines (CXCL13, CXCL9, and CCL20), Interleukin -1 ß (IL1 -ß), and caspase3 but negatively correlated with the proliferation relative gene MKI67. The stimulatory effects of DCN on the salivary gland epithelial cells (A253 cell line) and macrophages have been determined as they are considered active participants in the progression of SS. The data showed that DCN induced the apoptosis of A253 cells and polarization of macrophages towards the M1 phenotype, characterized by the expression of pro-inflammatory cytokines. CONCLUSIONS: Our study provided preliminary evidence to understand the clinical significance of DCN in pSS and broadened our horizons in understanding the mechanism of pSS.

Development of a Machine Learning Model to Discriminate Mild Cognitive Impairment Subjects from Normal Controls in Community Screening.

Background: Mild cognitive impairment (MCI) is a transitional stage between normal aging and probable Alzheimer's disease. It is of great value to screen for MCI in the community. A novel machine learning (ML) model is composed of electroencephalography (EEG), eye tracking (ET), and neuropsychological assessments. This study has been proposed to identify MCI subjects from normal controls (NC). Methods: Two cohorts were used in this study. Cohort 1 as the training and validation group, includes184 MCI patients and 152 NC subjects. Cohort 2 as an independent test group, includes 44 MCI and 48 NC individuals. EEG, ET, Neuropsychological Tests Battery (NTB), and clinical variables with age, gender, educational level, MoCA-B, and ACE-R were selected for all subjects. Receiver operating characteristic (ROC) curves were adopted to evaluate the capabilities of this tool to classify MCI from NC. The clinical model, the EEG and ET model, and the neuropsychological model were compared. Results: We found that the classification accuracy of the proposed model achieved 84.5 ± 4.43% and 88.8 ± 3.59% in Cohort 1 and Cohort 2, respectively. The area under curve (AUC) of the proposed tool achieved 0.941 (0.893-0.982) in Cohort 1 and 0.966 (0.921-0.988) in Cohort 2, respectively. Conclusions: The proposed model incorporation of EEG, ET, and neuropsychological assessments yielded excellent classification performances, suggesting its potential for future application in cognitive decline prediction.

Nitric oxide-soluble guanylyl cyclase pathway as a contributor to age-related memory impairment in Drosophila.

Age-related changes in the transcriptome lead to memory impairment. Several genes have been identified to cause age-dependent memory impairment (AMI) by changes in their expression, but genetic screens to identify genes critical for AMI have not been performed. The fruit fly is a useful model for studying AMI due to its short lifespan and the availability of consistent techniques and environments to assess its memory ability. We generated a list of candidate genes that act as AMI regulators by performing a comprehensive analysis of RNAsequencing data from young and aged fly heads and genome-wide RNAi screening data to identify memory-regulating genes. A candidate screen using temporal and panneuronal RNAi expression was performed to identify genes critical for AMI. We identified the guanylyl cyclase ß-subunit at 100B (gycß) gene, which encodes a subunit of soluble guanylyl cyclase (sGC), the only intracellular nitric oxide (NO) receptor in fruit flies, as a negative regulator of AMI. RNAi knockdown of gycß in neurons and NO synthase (NOS) in glia or neurons enhanced the performance of intermediate-term memory (ITM) without apparent effects on memory acquisition. We also showed that pharmacological inhibition of sGC and NOS enhanced ITM in aged individuals, suggesting the possibility that age-related enhancement of the NO-sGC pathway causes memory impairment.

Possible Neuropathology of Sleep Disturbance Linking to Alzheimer's Disease: Astrocytic and Microglial Roles.

Sleep disturbances not only deteriorate Alzheimer's disease (AD) progress by affecting cognitive states but also accelerate the neuropathological changes of AD. Astrocytes and microglia are the principal players in the regulation of both sleep and AD. We proposed that possible astrocyte-mediated and microglia-mediated neuropathological changes of sleep disturbances linked to AD, such as astrocytic adenosinergic A1, A2, and A3 regulation; astrocytic dopamine and serotonin; astrocyte-mediated proinflammatory status (TNFα); sleep disturbance-attenuated microglial CX3CR1 and P2Y12; microglial Iba-1 and astrocytic glial fibrillary acidic protein (GFAP); and microglia-mediated proinflammatory status (IL-1b, IL-6, IL-10, and TNFα). Furthermore, astrocytic and microglial amyloid beta (Aß) and tau in AD were reviewed, such as astrocytic Aß interaction in AD; astrocyte-mediated proinflammation in AD; astrocytic interaction with Aß in the central nervous system (CNS); astrocytic apolipoprotein E (ApoE)-induced Aß clearance in AD, as well as microglial Aß clearance and aggregation in AD; proinflammation-induced microglial Aß aggregation in AD; microglial-accumulated tau in AD; and microglial ApoE and TREM2 in AD. We reviewed astrocytic and microglial roles in AD and sleep, such as astrocyte/microglial-mediated proinflammation in AD and sleep; astrocytic ApoE in sleep and AD; and accumulated Aß-triggered synaptic abnormalities in sleep disturbance. This review will provide a possible astrocytic and microglial mechanism of sleep disturbance linked to AD.

Effectiveness and Safety of Idarucizumab for Periprocedural Cardiac Tamponade After Catheter Ablation of Atrial Fibrillation in Dabigatran Recipients: A Retrospective Controlled Study.

OBJECTIVE: This study aimed to investigate the effectiveness and safety of idarucizumab for periprocedural cardiac tamponade after catheter ablation of atrial fibrillation (AF) in patients treated with dabigatran. METHODS: We retrospectively studied 28 patients who received catheter ablation of AF and developed periprocedural cardiac tamponade. Patients were divided into two groups: control group (14 cases) and the study group (14 cases). Patients in the control group were administered warfarin bridged with low molecular weight heparin, while patients in the study group were given dabigatran for anticoagulation. Heparin was used for anticoagulation during surgery in both groups. Patients with cardiac tamponade in control group was reversed with protamine and the ones in study group were given protamine and idarucizumab. In the two groups, operative time, time to resume anticoagulation, bleeding time, length of hospital stay, hemodynamic parameters, coagulation function parameters, number of patients undergoing thoracotomy for hemostasis, pericardiocentesis drainage volume, and pericardial drainage retention time were recorded. RESULTS: There was no statistical difference in operative time and length of hospital stay between the two groups (p > 0.05); however, time to resume anticoagulation and bleeding time were significantly lower in the study group than in the control group, with a statistical difference (p < 0.05). After anticoagulation therapy, there was no apparent change and no statistical difference in the hemodynamic parameters and SaO2 between the two groups (p > 0.05). The pericardial drainage volume retention time was significantly shorter in the study group than in the control group, with a statistical difference (p < 0.05). CONCLUSION: Idarucizumab can rapidly and effectively reverse the anticoagulant effect of dabigatran in patients with AF who have periprocedural cardiac tamponade after catheter ablation.

A breakdown in microglial metabolic reprogramming causes internalization dysfunction of α-synuclein in a mouse model of Parkinson's disease.

BACKGROUND: The α-synuclein released by neurons activates microglia, which then engulfs α-synuclein for degradation via autophagy. Reactive microglia are a major pathological feature of Parkinson's disease (PD), although the exact role of microglia in the pathogenesis of PD remains unclear. Transient receptor potential vanilloid type 1 (TRPV1) channels are nonselective cation channel protein that have been proposed as neuroprotective targets in neurodegenerative diseases. METHODS: Using metabolic profiling, microglia energy metabolism was measured including oxidative phosphorylation and aerobic glycolysis. The mRFP-GFP-tagged LC3 reporter was introduced to characterize the role of TRPV1 in microglial autophagy. α-synuclein preformed fibril (PFF) TRPV1flox/flox; Cx3cr1Cre mouse model of sporadic PD were employed to study the capacity of TRPV1 activation to attenuate neurodegeneration process. RESULTS: We found that acute exposure to PFF caused microglial activation as a result of metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis via the AKT-mTOR-HIF-1α pathway. Activated microglia eventually reached a state of chronic PFF-tolerance, accompanied by broad defects in energy metabolism. We showed that metabolic boosting by treatment with the TRPV1 agonist capsaicin rescued metabolic impairments in PFF-tolerant microglia and also defects in mitophagy caused by disruption of the AKT-mTOR-HIF-1α pathway. Capsaicin attenuated phosphorylation of α-synuclein in primary neurons by boosting phagocytosis in PFF-tolerant microglia in vitro. Finally, we found that behavioral deficits and loss of dopaminergic neurons were accelerated in the PFF TRPV1flox/flox; Cx3cr1Cre mouse model of sporadic PD. We identified defects in energy metabolism, mitophagy and phagocytosis of PFF in microglia from the substantia nigra pars compacta of TRPV1flox/flox; Cx3cr1Cre mice. CONCLUSION: The findings suggest that modulating microglial metabolism might be a new therapeutic strategy for PD.

Clinical value of 18F-FDG PET/CT in IgG4-related disease.

OBJECTIVE: To investigate the clinical value of 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) in IgG4-related disease (IgG4-RD). METHODS: Seventy two patients diagnosed with IgG4-RD who underwent PET/CT were included. Correlations between clinical variables and PET/CT findings were analyzed by Spearman's correlation test. Conventional radiology was compared to PET/CT to evaluate detection discrepancies. The detection ability of insidious organ involvement by PET/CT at disease onset was investigated. The utility value of PET/CT for the 2019 ACR/EULAR classification criteria was analyzed with the multivariate logistic analysis and ROC curve. RESULTS: SUVmax of main involved organ was positively correlated with IgG4-RD Responder Index (IgG4-RD RI), serum and tissue IgG4 levels and IgG4/IgG ratio, serum eosinophils counts and number of involved organs, while negatively correlated with serum IgM levels. PET/CT was superior in detecting organ/tissue involvements including prostate, gastrointestinal tract and lung compared with conventional imaging. For patients with pancreato-hepato-biliary or head-neck involvements at onset, PET/CT showed superiority in detecting insidious lesions. Multivariate analysis showed that disease duration, multiple-organ involvement, SUVmax of main involved organ and mean SUVmax of all involved organs were significantly associated with the fulfillment of the 2019 ACR/EULAR classification criteria. ROC curves indicated that the cut-off value for SUVmax of main involved organ and mean SUVmax of all involved organs for fulfillment of the 2019 ACR/EULAR classification criteria for IgG4-RD were 4.1 and 3.5, respectively. CONCLUSION: 18F-FDG PET/CT has potential capacity to monitor disease activity, evaluate organ involvements and assist in the classification criteria in IgG4-RD.

Research on natural products from traditional Chinese medicine in the treatment of myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion injury (MIRI) is a complicated pathologic process that involves multiple factors including oxidative stress (free radical damage), inflammatory response, calcium overloading, and apoptosis in cardiomyocytes. According to Traditional Chinese Medicine (TCM), MIRI belongs to the categories of "chest numbness", "palpitations" and "angina pectoris". Present data indicate that the application of TCM in myocardial ischemia-reperfusion injury is promising and continues to attract research attention. While the efficacy of Chinese herbal medicine has been well-proven, the underlying molecular mechanisms remain elusive. The common proven mechanisms of Chinese herbal medicine in the treatment of MIRI include regulating lipid metabolism, protecting mitochondria, and improving energy metabolism, attenuating calcium (Ca2+) overload, scavenging oxygen free radicals, inhibiting apoptosis, and reducing autophagy. Others are the regulation of inflammatory cytokine expressions and healing of inflammatory lesions, modulation of cell signaling pathways, improvement of endothelial cell function, and protection of myocardial cells. In this review, we highlight recent studies that focus on elucidating these molecular mechanisms and the therapeutic effects of natural compounds deriving from TCM in MIRI, to ascertain the research progress made and the prospects in this field.

The Traditional Chinese Medicine Hua Tuo Zai Zao Wan Alleviates Atherosclerosis by Deactivation of Inflammatory Macrophages.

Introduction: Positive effects have been observed when the traditional Chinese medicine Hua Tuo Zai Zao Wan (HTZZW) has been used for the treatment of atherosclerosis (AS), although with an unclear mechanism. Methods: ApoE-/- C57/BALB mice were used to determine the efficacy of HTZZW by blood lipid biochemical analysis and histopathology H&E staining. qPCR and western blot were used to determine the expression of METTL3/14 and NF-κB. Results: High-fat diet-fed ApoE-/- mice that consumed HTZZW exhibited significantly smaller plaque areas and significantly decreased unstable collagen areas in the aortic arch as well as significantly lower blood levels of total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol compared with the control group. Consumption of HTZZW significantly decreased the proportion of Mφ1 in the peripheral blood. HTZZW not only inhibited the expression of m6A methyltransferases METTL14, METTL3, and overall RNA methylation level, but it also decreased the m6A modification level on specific sites of NF-κB mRNA. Conclusion: HTZZW significantly alleviated the progression of AS by regulating the expression of the m6A methyltransferases METTL14 and METTL3 in macrophages, eliminating m6A modifications of NF-κB mRNA, influencing the stability of NF-κB mRNA, and ultimately resulting in the deactivation of inflammatory macrophages.

RS-5645 attenuates inflammatory cytokine storm induced by SARS-CoV-2 spike protein and LPS by modulating pulmonary microbiota.

An inflammatory cytokine storm is considered an important cause of death in severely and critically ill COVID-19 patients, however, the relationship between the SARS-CoV-2 spike (S) protein and the host's inflammatory cytokine storm is not clear. Here, the qPCR results indicated that S protein induced a significantly elevated expression of multiple inflammatory factor mRNAs in peripheral blood mononuclear cells (PBMCs), whereas RS-5645 ((4-(thiophen-3-yl)-1-(p-tolyl)-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl)methanone) attenuated the expression of the most inflammatory factor mRNAs. RS-5645 also significantly reduced the cellular ratios of CD45+/IFNγ+, CD3+/IFNγ+, CD11b+/IFNγ+, and CD56+/IFNγ+ in human PBMCs. In addition, RS-5645 effectively inhibited the activation of inflammatory cells and reduced inflammatory damage to lung tissue in mice. Sequencing results of 16S rRNA v3+v4 in mouse alveolar lavage fluid showed that there were 494 OTUs overlapping between the alveolar lavage fluid of mice that underwent S protein+ LPS-combined intervention (M) and RS-5645-treated mice (R), while R manifested 64 unique OTUs and M exhibited 610 unique OTUs. In the alveoli of group R mice, the relative abundances of microorganisms belonging to Porphyromonas, Rothia, Streptococcus, and Neisseria increased significantly, while the relative abundances of microorganisms belonging to Psychrobacter, Shimia, and Sporosarcina were significantly diminished. The results of KEGG analysis indicated that the alveolar microbiota of mice in the R group can increase translation and reduce the activity of amino acid metabolism pathways. COG analysis results indicated that the abundance of proteins involved in ribosomal structure and biogenesis related to metabolism was augmented in the alveolar microbiota of the mice in the R group, while the abundance of proteins involved in secondary metabolite biosynthesis was significantly reduced. Therefore, our research results showed that RS-5645 attenuated pulmonary inflammatory cell infiltration and the inflammatory storm induced by the S protein and LPS by modulating the pulmonary microbiota.