Tangeretin attenuates acute lung injury in septic mice by inhibiting ROS-mediated NLRP3 inflammasome activation via regulating PLK1/AMPK/DRP1 signaling axis.

OBJECTIVE: NLRP3 inflammasome-mediated pyroptosis of macrophage acts essential roles in the progression of sepsis-induced acute lung injury (ALI). Tangeretin (TAN), enriched in citrus fruit peel, presents anti-oxidative and anti-inflammatory effects. Here, we aimed to explore the potentially protective effect of TAN on sepsis-induced ALI, and the underlying mechanism of TAN in regulating NLRP3 inflammasome. MATERIAL AND METHODS: The effect of TAN on sepsis-induced ALI and NLRP3 inflammasome-mediated pyroptosis of macrophage were examined in vivo and in vitro using a LPS-treated mice model and LPS-induced murine macrophages, respectively. The mechanism of TAN regulating the activation of NLRP3 inflammasome in sepsis-induced ALI was investigated with HE staining, Masson staining, immunofluorescent staining, ELISA, molecular docking, transmission electron microscope detection, qRT-PCR, and western blot. RESULTS: TAN could evidently attenuate sepsis-induced ALI in mice, evidenced by reducing pulmonary edema, pulmonary congestion and lung interstitial fibrosis, and inhibiting macrophage infiltration in the lung tissue. Besides, TAN significantly suppressed inflammatory cytokine IL-1ß and IL-18 expression in the serum or bronchoalveolar lavage fluid (BALF) samples of mice with LPS-induced ALI, and inhibited NLRP3 inflammasome-mediated pyroptosis of macrophages. Furthermore, we found TAN inhibited ROS production, preserved mitochondrial morphology, and alleviated excessive mitochondrial fission in LPS-induced ALI in mice. Through bioinformatic analysis and molecular docking, Polo-like kinase 1 (PLK1) was identified as a potential target of TAN for treating sepsis-induced ALI. Moreover, TAN significantly inhibited the reduction of PLK1 expression, AMP-activated protein kinase (AMPK) phosphorylation, and Dynamin related protein 1 (Drp1) phosphorylation (S637) in LPS-induced ALI in mice. In addition, Volasertib, a specific inhibitor of PLK1, abolished the protective effects of TAN against NLRP3 inflammasome-mediated pyroptosis of macrophage and lung injury in the cell and mice septic models. CONCLUSION: TAN attenuates sepsis-induced ALI by inhibiting ROS-mediated NLRP3 inflammasome activation via regulating PLK1/AMPK/DRP1 signaling axis, and TAN is a potentially therapeutic candidate against ALI through inhibiting pyroptosis.

Hypertension as an independent risk factor for severity and mortality in patients with COVID-19: a retrospective study.

PURPOSE OF THE STUDY: Hypertension is one of the most common comorbidities in COVID-19 pneumonia. However, whether it is an independent factor on the severity and mortality of COVID-19 has not been studied. STUDY DESIGN: In this study, 736 patients with a PCR-confirmed diagnosis of COVID-19 were included from 12 January 2020 to 25 March 2020. All patients were divided into two groups according to whether or not they were hypertensive. After propensity score matching (PSM) to remove the interference of mismatches in the baseline data, the clinical characteristics and outcomes of angiotensin II receptor blocker (ARB)/ACE inhibitors application were analysed. RESULTS: A total of 220 (29.9%) patients were hypertensive, and 516 (70.1%) patients were not hypertensive. PSM eliminated demographic and comorbidity differences between the two groups. Of all participants, 32 patients died (4.3% mortality), including 17 out of 220 in the hypertension group (7.7%) and 15 out of 516 in the non-hypertension group (2.9%). The incidence of intensive care unit (ICU) stay in the hypertension group (12.8%) was higher than in the non-hypertension group (5.3%) (p<0.05). Logistic regression analysis showed that hypertension was an independent risk factor for death, not other comorbidities. Kaplan-Meier analysis showed that mortality was higher in the hypertension group than in the non-hypertension group before and after PSM (p<0.05). There was no statistically significant difference in ICU therapy, mortality and hospitalisation time between hypertensive patients with or without ARBs/ACE inhibitors (p>0.05). CONCLUSION: Hypertension was an independent risk factor for the severity and mortality of patients with COVID-19. ARBs/ACE inhibitors should not be discontinued in hypertensive patients with COVID-19.

Response of salinity gradient power generation to inflow mode and temperature difference by reverse electrodialysis.

Sustainable utilization has been becoming the core idea of concentrated seawater disposal, which makes the harvest of salinity gradient power based on reverse electrodialysis (RED) become one of the important ways. As the important factors affecting RED performance, different flow orientations along the membrane and solution temperature have been studied in the previous researches. However, there are still some details that need to be clarified. In this study, the inflow mode was further detailed investigated. The results showed that after eliminating the interference of bubbles in the counter-current, the co-current was still better than the counter-current; when the solution of HCC (high concentration compartment) and LCC (low concentration compartment) was circulated for 3 h, the concentration of concentrated seawater discharge liquid was reduced by 6.93%, which was conducive to reducing the negative impact on the marine ecological environment. Meanwhile, the response of salinity gradient power generation to temperature difference was that high temperature had a positive effect on power density, and the order was both the HCC and LCC (0.44 W m-2) > LCC (0.42 W m-2) > HCC (0.39 W m-2). Although the RED performance was more sensitive to the temperature rise of LCC, the positive temperature difference between HCC and LCC is a more practical advantage because the temperature of concentrated seawater in HCC is usually high. These new observations could provide supports for the industrial development of RED in generating electricity economically and reducing the negative environmental impact of concentrated seawater.

A Novel Immunosuppressant, Luteolin, Modulates Alloimmunity and Suppresses Murine Allograft Rejection.

An allograft is rejected in the absence of any immunosuppressive treatment because of vigorous alloimmunity and thus requires extensive immunosuppression for its survival. Although there are many conventional immunosuppressants for clinical use, it is necessary to seek alternatives to existing drugs, especially in case of transplant patients with complicated conditions. Luteolin, a natural ingredient, exists in many plants. It exhibits multiple biological and pharmacological effects, including anti-inflammatory properties. In particular, luteolin has been shown to upregulate CD4+CD25+ regulatory T cells (Tregs) in the context of airway inflammation. However, it remains unknown whether luteolin regulates alloimmune responses. In this study, we demonstrated that luteolin significantly prolonged murine skin allograft survival, ameliorated cellular infiltration, and downregulated proinflammatory cytokine gene expression in skin allografts. Furthermore, luteolin increased the percentage of CD4+Foxp3+ Tregs while reducing frequency of mature dendritic cells and CD44highCD62Llow effector CD4+/CD8+ T cells posttransplantation. It also suppressed the proliferation of T cells and their production of cytokines IFN-γ and IL-17A in vitro while increasing IL-10 level in the supernatant. Moreover, luteolin promoted CD4+Foxp3+ Treg generation from CD4+CD25- T cells in vitro. Depleting Tregs largely, although not totally, reversed luteolin-mediated extension of allograft survival. More importantly, luteolin inhibited AKT/mTOR signaling in T cells. Thus, for the first time, to our knowledge, we found that luteolin is an emerging immunosuppressant as an mTOR inhibitor in allotransplantation. This finding could be important for the suppression of human allograft rejection, although it remains to be determined whether luteolin has an advantage over other conventional immunosuppressants in suppression of allograft rejection.

Clear cell sarcomas of the kidney are characterised by BCOR gene abnormalities, including exon 15 internal tandem duplications and BCOR-CCNB3 gene fusion.

AIMS: Clear cell sarcoma of the kidney (CCSK) is a rare paediatric renal malignant tumour. The majority of CCSKs have internal tandem duplications (ITDs) of the BCOR gene, whereas a minority have the YWHAE-NUTM2 gene fusion. A third 'double-negative' (DN) category comprises CCSKs with neither BCOR ITDs nor YWHAE-NUTM2 fusion. The aim of this study was to characterise 11 histologically diagnosed CCSKs immunohistochemically (with CCND1, BCOR and CCNB3 stains) and genetically. METHODS AND RESULTS: By next-generation sequencing, 10 cases (90.9%) had BCOR exon 15 ITDs, with positive BCOR immunoreactivity being found in four (36%) or eight (72%) cases, depending on the antibody clone. By reverse transcription polymerase chain reaction, none had the YWHAE-NUTM2 fusion. The DN case had a BCOR-CCNB3 fusion and strong nuclear CCNB3 and BCOR immunoreactivity. Quantitative polymerase chain reaction showed markedly elevated BCOR expression in this case, whereas BCOR ITD cases had lower levels of elevated BCOR expression. CONCLUSIONS: The majority of the CCSKs in our cohort had BCOR ITDs, and none had the YWHAE-NUTM2 fusion. We verified the strong, diffuse cyclin D1 (CCND1) immunoreactivity in CCSKs described in recent reports. BCOR immunoreactivity was not consistently positive in all CCSKs with BCOR ITDs, and therefore cannot be used as a diagnostic immunohistochemical stain to identify BCOR ITD cases. The DN case was a BCOR-CCNB3 fusion sarcoma. BCOR-CCNB3 sarcoma is typically a primary bone sarcoma affecting male adolescents, and this is the first report of it presenting in a kidney of a young child as a CCSK. The full spectrum of DN CCSKs awaits more comprehensive characterisation.

[Recognition of Similarities and Differences--a New Thinking Paradigm of Critically Care Integrative Medicine].

"Wise men could recognize similarities, but the fool only recognizes differences" in Su-wen, which expounded clinical thinking methods of Chinese medicine (CM). "To recognize similarities and differences simultaneously" is of important clinical significance in understanding the laws of diseases. CM pays much attention to recognize similarities, while modern medicine emphasizes the differences observed. In order to develop integrative medicine (IM), similarities recognition and differences identification must be combined together to innovate new thinking methods of IM.

Efficacy and safety of hyperbaric oxygen therapy for long COVID: a protocol for systematic review and meta-analysis.

INTRODUCTION: There is still a lack of therapeutic options for long COVID. Several studies have shown the benefit of hyperbaric oxygen therapy (HBOT) on long COVID. However, the efficacy and safety of HBOT for long COVID remain unclear. Therefore, we will conduct this systematic review to assess the feasibility of HBOT as a primary or complemental therapy for long COVID. METHODS AND ANALYSIS: Databases such as Web of Science, PubMed, Embase, Cochrane Database of Systematic Reviews, ClinicalTrials.gov, International Clinical Trials Registry Platform, Wanfang Database, China National Knowledge Infrastructure, SINOMED, VIP Database and the Chinese Clinical Trial Registry will be searched systematically from the establishment to 9 December 2023. All articles will be reviewed by two independent reviewers. Cochrane risk of bias tool will be used to assess the risk of bias in the study. We will evaluate heterogeneity using a visual inspection of the funnel plot. If an available number of studies are identified, we will perform a meta-analysis. ETHICS AND DISSEMINATION: No ethical approval is required since this study is based on published articles. The findings will be published in a peer-reviewed journal or disseminated through conference presentations. PROSPERO REGISTRATION NUMBER: CRD42023482523.

Eosinophilic gastroenteritis in an elderly men associated with antibiotic use post maxillofacial space infection: a case report.

A 79-year-old man underwent operative drainage and 2-week cephalosporin treatment due to a maxillofacial space infection (bilateral submaxillaris, submentum, and left face). However, he experienced anorexia, nausea, vomiting, and emaciation in the following 2 months. It was initially considered that a malignancy might be present, thus a series of examinations were performed. Laboratory investigations showed increases in inflammatory markers and a significant eosinophilia, which seemed to be a hematological system disease. Combined with the gastrointestinal endoscopes and histology examination, the patient was diagnosed with eosinophilic gastroenteritis (EGE). After cessation of antibiotic treatment and administration of corticosteroid, our patient experienced a rapid progress in his clinical condition. Despite the low incidence, EGE should be considered in patients with unknown cause of gastrointestinal disorder, elevated eosinophilia, and so on.

Fuzhengjiedu formula exerts protective effect against LPS-induced acute lung injury via gut-lung axis.

BACKGROUND: Acute lung injury (ALI) is distinguished by rapid and severe respiratory distress and prolonged hypoxemia. A traditional Chinese medicine (TCM), known as the Fuzhengjiedu formula (FZJDF), has been shown to have anti-inflammatory benefits in both clinical and experimental studies. The precise underlying processes, nevertheless, are yet unclear. PURPOSE: This study sought to enlighten the protective mechanism of FZJDF in ALI through the standpoint of the gut-lung crosstalk. METHODS: The impact of FZJDF on lipopolysaccharide (LPS)-induced ALI murine model were investigated, and the lung injury score, serum interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) expression were measured to confirm its anti-inflammatory effects. Additionally, gut microbiota analysis and serum and fecal samples metabolomics were performed using metagenomic sequencing and high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry, respectively. RESULTS: FZJDF significantly induced histopathological changes caused by LPS-induced ALI as well as downregulated the serum concentration of IL-1ß and TNF-α. Furthermore, FZJDF had an effect in gut microbiota disturbances, and linear discriminant effect size analysis identified signal transduction, cell motility, and amino acid metabolism as the potential mechanisms of action in the FZJDF-treated group. Several metabolites in the LPS and FZJDF groups were distinguished by untargeted metabolomic analysis. Correlations were observed between the relative abundance of microbiota and metabolic products. Comprehensive network analysis revealed connections among lung damage, gut microbes, and metabolites. The expression of glycine, serine, glutamate, cysteine, and methionine in the lung and colon tissues was dysregulated in LPS-induced ALI, and FZJDF reversed these trends. CONCLUSION: This study revealed that FZJDF considerably protected against LPS-induced ALI in mice by regulating amino acid metabolism via the gut-microbiota-lung axis and offered thorough and in-depth knowledge of the multi-system linkages of systemic illnesses.

Mendelian randomization and Bayesian model averaging of autoimmune diseases and Long COVID.

Background: Following COVID-19, reports suggest Long COVID and autoimmune diseases (AIDs) in infected individuals. However, bidirectional causal effects between Long COVID and AIDs, which may help to prevent diseases, have not been fully investigated. Methods: Summary-level data from genome-wide association studies (GWAS) of Long COVID (N = 52615) and AIDs including inflammatory bowel disease (IBD) (N = 377277), Crohn's disease (CD) (N = 361508), ulcerative colitis (UC) (N = 376564), etc. were employed. Bidirectional causal effects were gauged between AIDs and Long COVID by exploiting Mendelian randomization (MR) and Bayesian model averaging (BMA). Results: The evidence of causal effects of IBD (OR = 1.06, 95% CI = 1.00-1.11, p = 3.13E-02), CD (OR = 1.10, 95% CI = 1.01-1.19, p = 2.21E-02) and UC (OR = 1.08, 95% CI = 1.03-1.13, p = 2.35E-03) on Long COVID was found. In MR-BMA, UC was estimated as the highest-ranked causal factor (MIP = 0.488, MACE = 0.035), followed by IBD and CD. Conclusion: This MR study found that IBD, CD and UC had causal effects on Long COVID, which suggests a necessity to screen high-risk populations.

Research progress on the effect of traditional Chinese medicine on the activation of PRRs-mediated NF-κB signaling pathway to inhibit influenza pneumonia.

Influenza pneumonia has challenged public health and social development. One of the hallmarks of severe influenza pneumonia is overproduction of pro-inflammatory cytokines and chemokines, which result from the continuous activation of intracellular signaling pathways, such as the NF-κB pathway, mediated by the interplay between viruses and host pattern recognition receptors (PRRs). It has been reported that traditional Chinese medicines (TCMs) can not only inhibit viral replication and inflammatory responses but also affect the expression of key components of PRRs and NF-κB signaling pathways. However, whether the antiviral and anti-inflammatory roles of TCM are related with its effects on NF-κB signaling pathway activated by PRRs remains unclear. Here, we reviewed the mechanism of PRRs-mediated activation of NF-κB signaling pathway following influenza virus infection and summarized the influence of anti-influenza TCMs on inflammatory responses and the PRRs/NF-κB signaling pathway, so as to provide better understanding of the mode of action of TCMs in the treatment of influenza pneumonia.

Simultaneous determination of twenty-nine active compounds in fuzhengjiedu granules by HPLC-QQQ-MS/MS.

As an empirical medicine of traditional Chinese medicine, Fuzhengjiedu Granules have shown an effect against COVID-19 in clinical and inflammatory animal models. It is formulated with eight herbs, including Aconiti Lateralis Radix Praeparata, Zingiberis Rhizoma, Glycyrrhizae Radix Et Rhizoma, Lonicerae Japonicae Flos, Gleditsiae Spina, Fici Radix, Pogostemonis Herba, and Citri Reticulatae Pericarpium. This study established a high-performance liquid chromatography-triple quadrupole mass spectrometry (HPLC-QQQ-MS/MS) method by simultaneously determining 29 active compounds in the granules with significant content differences. Separation by gradient elution using acetonitrile and water (0.1% formic acid) as mobile phases was performed on a Waters Acquilty UPLC T3 column (2.1 mm × 100 mm, 1.7 µm). A triple quadrupole mass spectrometer, operating in positive and negative ionization modes, was used for multiple reaction monitoring to detect the 29 compounds. All calibration curves showed good linear regression (r2 > 0.998). RSDs of precision, reproducibility, and stability of active compounds were all lower than 5.0%. The recovery rates were 95.4-104.9%, with RSDs< 5.0%. This method was successfully used to analyze the samples, and the results showed that 26 representative active components from 8 herbs were detected in the granules. While aconitine, mesaconitine, and hypaconitine were not detected, indicating that the existing samples were safe. The granules had the maximum and minimum content of hesperidin (27.3 ± 0.375 mg/g) and benzoylaconine (38.2 ± 0.759 ng/g). To conclude, a fast, accurate, sensitive, and reliable HPLC-QQQ-MS/MS method was established, which can simultaneously detect 29 active compounds that have a considerable difference in the content of Fuzhengjiedu Granules. This study can be used to control the quality and safety of Fuzhengjiedu Granules and provide a basis and guarantee for further experimental research and clinical application.

Effectiveness of kumquat decoction for the improvement of cough caused by SARS-CoV-2 Omicron variants, a multicentre, prospective observational study.

BACKGROUND: Kumquat decoction is a traditional Chinese medicine formula and has been widely used to alleviate the coronavirus disease 2019 (COVID-19)-related cough in China. However, the effectiveness and safety of kumquat decoction remain unclear. PURPOSE: To assess the effectiveness and safety of kumquat decoction for COVID-19-related cough. STUDY DESIGN: A multicentre, prospective observational study. METHODS: We enrolled consecutive patients with mild-to-moderate COVID-19 from December 31, 2022, to January 3, 2023, during the Omicron phase in Yangshuo County, China. The primary outcome was the time from study baseline to sustained cough resolution by the last follow-up day on January 31, 2023. The effectiveness was evaluated by Cox proportional hazards models based on propensity score analyses. The secondary outcomes were the resolution of cough and other COVID-19-related symptoms by Days 3, 5, and 7. RESULTS: Of 1434 patients, 671 patients were excluded from the analysis of cough resolution. Among the remaining 763 patients, 481 (63.04%) received kumquat decoction, and 282 (36.96%) received usual care. The median age was 38.0 (interquartile range [IQR] 29.0, 50.0) years, and 55.7% were women. During a median follow-up of 7.000 days, 68.2% of patients in the kumquat group achieved sustained cough resolution (93.77 per 1000 person-days) compared to 39.7% in the usual care group (72.94 per 1000 person-days). The differences in restricted mean survival time (RMST) (kumquat decoction minus usual care group) for cough resolution were -0.742 days (95% CI, -1.235 to -0.250, P = 0.003) on Day 7. In the main analysis using propensity-score matching, the adjusted hazard ratio (HR) for cough resolution (kumquat decoction vs. usual care group) was 1.94 (95% CI, 1.48 to 2.53, P < 0.001). Similar findings were found in multiple sensitivity analyses. In addition, the use of kumquat decoction was associated with the resolution of cough, and a stuffy nose on Days 5 and 7, as well as the resolution of sore throat on Day 7 following medication. CONCLUSION: In this study among patients with COVID-19-related cough, receiving kumquat decoction was associated with an earlier resolution of cough symptoms.

Post-hospitalization rehabilitation alleviates long-term immune repertoire alteration in COVID-19 convalescent patients.

The global pandemic of Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an once-in-a-lifetime public health crisis. Among hundreds of millions of people who have contracted with or are being infected with COVID-19, the question of whether COVID-19 infection may cause long-term health concern, even being completely recovered from the disease clinically, especially immune system damage, needs to be addressed. Here, we performed seven-chain adaptome immune repertoire analyses on convalescent COVID-19 patients who have been discharged from hospitals for at least 6 months. Surprisingly, we discovered lymphopenia, reduced number of unique CDR3s, and reduced diversity of the TCR/BCR immune repertoire in convalescent COVID-19 patients. In addition, the BCR repertoire appears to be activated, which is consistent with the protective antibody titres, but serological experiments reveal significantly lower IL-4 and IL-7 levels in convalescent patients compared to those in healthy controls. Finally, in comparison with convalescent patients who did not receive post-hospitalization rehabilitation, the convalescent patients who received post-hospitalization rehabilitation had attenuated immune repertoire abnormality, almost back to the level of healthy control, despite no detectable clinic demographic difference. Overall, we report the potential long-term immunological impairment for COVID-19 infection, and correction of this impairment via post-hospitalization rehabilitation may offer a new prospect for COVID-19 recovery strategy.

[Atypical teratoid/rhabdoid tumors of central nervous system in childhood: a clinical and histopathologic study of 6 cases].

OBJECTIVE: To study the clinicopathologic features, immunohistochemical findings, diagnosis and differential diagnosis of atypical teratoid/rhabdoid tumors (AT/RT) of central nervous system in childhood. METHODS: The clinicopathologic data, morphologic features and immunophenotypes were reviewed in 6 cases of AT/RT. EnVision method was applied. Antibodies include cytokeratin (CK), epithelial membrane antigen (EMA), vimentin, smooth muscle actin (SMA), muscle specific actin (MSA), glial fibrinary acid protein (GFAP), desmin, placental alkaline phosphatase (PLAP) and INI1. RESULTS: Five of the six cases of AT/RT occurred in infancy and early childhood. Histologically, the predominant component was rhabdoid cells. Cytoplasmic inclusions were present in all cases. Primitive neuroectodermal tumor (PNET) component was also identified in 5 of the 6 cases studied. Immunohistochemically, the tumor cells were positive for cytokeratin, epithelial membrane antigen and vimentin. The staining for INI1, desmin and PLAP was negative. Smooth muscle actin was expressed in 2 cases and glial fibrillary acidic protein in 5 cases. The proliferative index as demonstrated by Ki-67 staining was high. CONCLUSIONS: AT/RT is not a particularly uncommon malignancy in childhood. The histologic hallmark is the presence of rhabdoid cells with cytoplasmic inclusions. The tumor cells are positive for cytokeratin, epithelial membrane antigen and vimentin, and negative for INI1. Differential diagnosis includes PNET, medulloblastoma and medullomyoblastoma.