Expression of cytochrome p450 and other biotransformation genes in fetal and adult human nasal mucosa.

Despite recent progress in the identification and characterization of numerous nasal biotransformation enzymes in laboratory animals, the expression of biotransformation genes in human nasal mucosa remains difficult to study. Given the potential role of nasal biotransformation enzymes in the metabolism of airborne chemicals, including fragrance compounds and therapeutic agents, as well as the potential interspecies differences between laboratory animals and humans, it would be highly desirable to identify those biotransformation genes that are expressed in human nasal mucosa. In this study, a global gene expression analysis was performed to compare biotransformation enzymes expressed in human fetal and adult nasal mucosa to those expressed in liver. The identities of a list of biotransformation genes with apparently nasal mucosa-selective expression were subsequently confirmed by RNA-polymerase chain reaction (PCR) and DNA sequencing of the PCR products. Further quantitative RNA-PCR experiments indicated that, in the fetus, aldehyde dehydrogenase 6 (ALDH6), CYP1B1, CYP2F1, CYP4B1, and UDP glucuronosyltransferase 2A1 are expressed preferentially in the nasal mucosa and that ALDH7, flavin-containing monooxygenase 1, and glutathione S-transferase P1 are at least as abundant in the nasal mucosa as in the liver. The nasal mucosal expression of CYP2E1 was also detected. These findings provide a basis for further explorations of the metabolic capacity of the human nasal mucosa for xenobiotic compounds.     

抗炎-中药治疗动脉粥样硬化的有效途径

动脉粥样硬化发病机制的“炎症-损伤-反应”学说得到广泛支持和认可。炎性反应贯穿于动脉粥样硬化发生、发展的整个过程，并与急性心脑血管事件的发生密切相关；干预AS炎症反应可能是中药治疗动脉粥样硬化的有效途径。本文从动脉粥样硬化发生、发展过程的病理基础角度，总结了炎性反应在动脉粥样硬化形成早期、进展期、成熟期、破裂期的重要作用，并提出了从抗炎角度研究、筛选、治疗动脉粥样硬化中药的思路和方法。     

Antioxidative and in vitro hepatoprotective activity of Bupleurum kaoi leaf infusion

The roots of Bupleurus spp. have been used in traditional Chinese herbal medicine for curing liver diseases. Although bioactive saikosaponins have been detected in the leaves as well as in the roots, the aerial parts of the plants are discarded as waste. In the present study, a leaf infusion of B. kaoi Liu, Chao et Chuang, an indigenous Bupleurus species in Taiwan, was prepared and the antioxidant properties and in vitro hepatoprotective activity were demonstrated. The results show that the leaf infusion exerted DPPH free radical scavenging activity, inhibitory capacity on superoxide anion formation and superoxide anion scavenging activity. The hepatotoxicity of acetaminophen (APAP) and carbon tetrachloride (CCl4) on the rat liver cells were also decreased by the leaf infusion.     

IL-1 receptor-associated kinase 1 participates in the modulation of the NLRP3 inflammasome by tumor-associated macrophages in hepatocellular carcinoma

BackgroundHepatocellular carcinomas (HCCs) occur frequently in the digestive system and are associated with high mortality. This current study examined the regulatory relationship between interleukin (IL)-1 receptor-associated kinase 1 (IRAK1), NLR family pyrin domain-containing 3 (NLRP3) inflammasomes, and tumor-associated macrophages (TAMs) in the growth and metastasis of HCC.MethodsThe expression of IRAK1 and NLRP3 was assessed in tissues and cells via quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. Immunohistology was performed to detect the macrophage markers CD68, CD163, and CD168 in tumor tissues. Small interfering (si)RNA targeting IRAK1 (si-IRAK1) was designed to silence IRAK1 expression. Following si-IRAK1 transfection and/or co-culture with TAMs, HCC cell viability, proliferation, migration, and invasion, as well as the expression of NLRP3 and pro-inflammatory cytokines IL-1 β, IL-18, and monocyte chemotactic protein 1 (MCP-1) were assessed.ResultsHCC tissues showed elevated expression of IRAK1 and NLRP3, as well as increased expression of the macrophage markers CD68, CD163, and CD168, compared to adjacent healthy tissues. Silencing of IRAK1 expression in HepG2 and Huh7 cells resulted in suppression of cell proliferation, migration, and invasion, and also reduced expression of NLRP3 and the pro-inflammatory cytokines IL-1β, IL-18, and MCP-1. Moreover, TAMs promoted HepG2 and Huh7 cell proliferation, migration, and invasion, and elevated the expression of NLRP3, IL-1β, IL-18, and MCP-1. Furthermore, IRAK1 silencing reversed the effects of TAMs on HepG2 and Huh7 cells.ConclusionsThe expression of IRAK1 was associated with HCC growth and metastasis, as well as NLRP3 inflammasome activation. The ability of TAMs to promote HCC growth and metastasis may be activated by NLRP3 inflammasomes and regulated by IRAK1.     

Decreased expression of claudin-18.2 in alpha-fetoprotein-producing gastric cancer compared to conventional gastric cancer

BackgroundAlpha-fetoprotein-producing gastric cancer (AFPGC) is a subtype of gastric cancer (GC) with more aggressive biological behavior. As a highly specific tight junction component exclusively present in gastric mucosa and gastric adenocarcinomas, claudin-18.2 (CLDN18.2) has become an emerging target in GC. In this study, we aimed to provide insight into AFPGC and investigate the expression and the clinical implications of CLDN18.2 in AFPGC.MethodsWe retrospectively collected 98 cases of AFPGC and reviewed their clinical, morphological, and immunohistochemical features. Another 356 patients with stage-matched conventional GC (cGC) were enrolled as a control group. We further surveyed CLDN18.2 expression by immunohistochemistry (IHC) in 51 AFPGC tissues and explained its association with the clinicopathological parameters of AFPGC.ResultsOur results showed that AFPGC was a unique GC type with elevated serum alpha-fetoprotein (AFP), which was a predictor of a worse prognosis. AFPGC showed typical morphological features and positive staining of at least 1 hepatocytic or enteroblastic marker. The expression rate of CLDN18.2 was low, with a positivity rate of 21.6%, which was much lower than that observed in cGC tissues (38.5%). A significant correlation was found between CLDN18.2 expression and the differentiation of AFPGC. CLDN18.2 expression was negatively correlated with the serum AFP level of AFPGC. We also found that AFPGC with a hepatoid type (HPT) component showed a significantly lower CLDN18.2 expression than those without.ConclusionsThis study demonstrated that CLDN18.2 was significantly decreased in AFPGC and was negatively correlated with the patient’s preoperative serum AFP level. The negative correlation between AFP and CLDN18.2 could be explained by retro-differentiation of AFPGC. Special treatment strategies might be needed for this unique tumor type.     

Development and evaluation of time‐resolved fluorescent immunochromatographic assay for quantitative detection of SARS‐CoV‐2 spike antigen

BackgroundThe spread of COVID‐19 worldwide caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has necessitated efficient, sensitive diagnostic methods to identify infected people. We report on the development of a rapid 15‐minute time‐resolved fluorescent (TRF) lateral flow immunochromatographic assay for the quantitative detection of the SARS‐CoV‐2 spike protein receptor‐binding domain (S1‐RBD).ObjectivesOur objective was to develop an efficient method of detecting SARS‐CoV‐2 within 15 min of sample collection.MethodsWe constructed and evaluated a portable, disposable lateral flow device, which detected the S1‐RBD protein directly in nasopharyngeal swab samples. The device emits a fluorescent signal in the presence of S1‐RBD, which can be captured by an automated TRF instrument.ResultsThe TRF lateral flow assay signal was linear from 0 to 20 ng/ml and demonstrated high accuracy and reproducibility. When evaluated with clinical nasopharyngeal swabs, the assay was performed at >80% sensitivity, >84% specificity, and > 82% accuracy for detection of the S1‐RBD antigen.ConclusionThe new S1‐RBD antigen test is a rapid (15 min), sensitive, and specific assay that requires minimal sample preparation. Critically, the assay correlated closely with PCR‐based methodology in nasopharyngeal swab samples, showing that the detected S1‐RBD antigen levels correlate with SARS‐CoV‐2 virus load. Therefore, the new TRF lateral flow test for S1‐RBD has potential application in point‐of‐care settings.     

Increasing nodal vulnerability and nodal efficiency implied recovery time prolonging in patients with supplementary motor area syndrome

Supplementary motor area (SMA) syndrome is a surgery‐related complication that commonly occurs after removing SMA glioma, and needs weeks to recover. However, susceptible factors of patients suffering from SMA syndrome remain unknown. Graphic theory was applied to reveal topological properties of sensorimotor network (SMN) by processing resting‐state functional magnetic resonance images in 66 patients with SMA gliomas. Patients were classified into SMA and non‐SMA groups based on whether they suffered from SMA syndrome. We collected recovery time and used causal mediation analysis to find association between topological properties and recovery time. Compared with the non‐SMA group, higher vulnerability (left: p = .0018; right: p = .0033) and lower fault tolerance (left: p = .0022; right: p = .0248) of the whole SMN were found in the SMA group. Moreover, higher nodal properties of lesional‐hemispheric cingulate cortex (nodal efficiency: left, p = .0389; right, p = .0169; nodal vulnerability: left, p = .0185; right, p = .0085) and upper limb region of primary motor cortex (PMC; nodal efficiency: left, p = .0132; right, p = .0001; nodal vulnerability: left, p = .0091; right, p = .0209) were found in the SMA group. Nodal efficiency and nodal vulnerability of cingulate cortex and upper limb region of PMC were important predictors for SMA syndrome occurring and recovery time prolonging. Neurosurgeons should carefully deal with upper limb region of PMC and cingulate cortex, and protect them if these two region were unnecessary to damage during SMA glioma resection.     

Novel immune‐related signature based on immune cells for predicting prognosis and immunotherapy response in clear cell renal cell carcinoma

BackgroundClear cell renal cell carcinoma (ccRCC) is the most common malignant tumor of the kidney and is characterized by poor prognosis. We sought to build an immune‐related prognostic signature and investigate its relationship with immunotherapy response in ccRCC.MethodsImmune‐related genes were identified by ssGSEA and WGCNA. The prognostic signature was conducted via univariate, least absolute shrinkage and selection operator, and multivariable Cox regression analyses. Kaplan‐Meier analysis, PCA, t‐SNE, and ROC were used to evaluate the risk model.ResultsA total of 119 immune‐related genes associated with prognosis were screened out. Six immune‐related genes (CSF1, CD5L, AIM2, TIMP3, IRF6, and HHLA2) were applied to construct a prognostic signature for KIRC. Kaplan–Meier analysis showed that patients in high‐risk group had a poorer survival outcome than in low‐risk group. The 1‐, 3‐ and 5‐year AUC of the prognostic signature was 0.754, 0.715, and 0.739, respectively. Univariate and multivariate Cox regression models demonstrated that the risk signature was an independent prognostic factor for KIRC survival. GSEA analysis suggested that the high‐risk group was concentrated on immune‐related pathways. The high‐risk group with more regulatory T‐cell infiltration showed a higher expression of immune negative regulation genes. The risk score had positively relationship with TIDE score and negatively with the response of immunotherapy. The IC50 values of axitinib, sunitinib, sorafenib, and temsirolimus were lower in the high‐risk group.ConclusionOur study defined a robust signature that may be promising for predicting clinical outcomes and immunotherapy and targeted therapy response in ccRCC patients.