p38 MAPK Inhibitor NJK14047 Suppresses CDNB-Induced Atopic Dermatitis-Like Symptoms in BALB/c Mice

Atopic dermatitis (AD) is a chronic inflammatory skin disorder. Suppression of MAPKs and NF-κB is implicated as a vital mechanism of action of several traditional Chinese medicines for AD therapy. Although overexpression of MAPK mRNA in the skin tissue has been shown in the AD model, the roles of each MAPK in AD pathogenesis have rarely been studied. This study examined the effect of NJK14047, an inhibitor of p38 MAPKs, on AD-like skin lesions induced in BALB/c mice by sensitization and challenges with 1-chloro-2,4-dinitrobenzene (CDNB) on dorsal skin and ears, respectively. After induction of AD, NJK14047 (2.5 mg/kg) or dexamethasone (10 mg/kg) was administrated for 3 weeks via intraperitoneal injection. Following its administration, NJK14047 suppressed CDNB-induced AD-like symptoms such as skin hypertrophy and suppressed mast cell infiltration into the skin lesions. It also reduced CDNB-induced increase in T_H2 cytokine (IL-13) and T_H1 cytokines (interferon-γ and IL-12A) levels but did not decrease serum IgE level. Furthermore, NJK14047 blocked CDNB-induced lymph node enlargement. These results suggest that NJK14047, a p38 MAPK inhibitor, might be an optimal therapeutic option with unique modes of action for AD treatment.     

呼出气一氧化氮联合脉冲振荡检查在学龄前儿童哮喘中的诊断价值研究

目的探讨呼出气一氧化氮（fractional exhaled nitric oxide，FeNO）联合脉冲振荡（impulse oscillometry，IOS）肺功能检查对学龄前儿童哮喘的诊断价值，并建立最佳预测模型。方法回顾性纳入2019年9月至2020年12月收治的3~5岁喘息儿童156例，分为哮喘组（52例）和非哮喘组（104例）。对2组患儿的IOS参数、FeNO及临床资料进行分析比较，通过多因素logistic回归建立最佳预测模型。结果哮喘组频率5 Hz时呼吸系统总阻抗（respiratory system impedance at 5 Hz，Z5）、频率5 Hz和20 Hz时阻抗（resistance of respiratory system at 5 Hz and 20 Hz，R5和R20）、共振频率、电抗面积（reactance of area，AX）和FeNO水平均高于非哮喘组，频率5 Hz时电抗差值小于非哮喘组（P<0.05）。受试者工作特征曲线分析显示Z5、R5、R20和FeNO对哮喘诊断有价值（P<0.05）。多因素logistic回归分析建立的最佳预测模型为R20+AX+FeNO，其曲线下面积为0.858（P<0.05），灵敏度为78.8%，特异度为76.9%。结论FeNO联合IOS检查有助于学龄前儿童哮喘的诊断，由R20+AX+FeNO组成的模型在学龄前儿童哮喘的诊断中具有一定价值。     

百里醌对肝缺血-再灌注损伤的作用研究

目的  探讨百里醌对肝缺血-再灌注损伤(IRI)的作用及其机制。方法  30只C57小鼠随机均分为假手术(Sham)组、IRI组和百里醌(Thy)组(每组各10只)。术前1 h, Thy组给予百里醌(40 ml/kg)腹腔注射, Sham组和IRI组给予无水乙醇(40 ml/kg)腹腔注射。IRI组和Thy组建立小鼠肝IRI模型。再灌注4 h后收集血清和肝脏标本。光学显微镜下观察肝组织病理学改变, 并予病理损伤评分; 采用逆转录聚合酶链反应(RT-PCR)检测肝组织肿瘤坏死因子(TNF)-α、单核细胞趋化蛋白(MCP)-1和白细胞介素(IL)-6的信使核糖核酸(mRNA)表达水平; 采用酶链免疫吸附试验(ELISA)检测血清中TNF-α、MCP-1和IL-6的蛋白表达水平; 采用硫代巴比妥酸(TBA)法检测肝组织丙二醛(MDA)的含量; 采用ELISA法测定肝组织过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GPx)、超氧化物歧化酶(SOD)活性; 采用肝组织免疫印迹法(Western blot)检测Wnt、β-catenin、p53的蛋白表达水平。结果  与Sham组比较, IRI组肝组织损伤严重, 损伤评分明显增加(P < 0.05), 肝组织和血清中的TNF-α、MCP-1、IL-6和肝组织MDA、Wnt、β-catenin、p53的表达均明显增多(P < 0.05~0.001), 而肝组织CAT、GPx与SOD活性均明显降低(均为P < 0.001)。与IRI组比较, Thy组肝组织损伤较轻, 损伤评分明显减少(P < 0.05), 肝组织和血清中的TNF-α、MCP-1、IL-6和肝组织MDA、Wnt、β-catenin、p53的表达均明显减少(均为P < 0.05), 而肝组织CAT、GPx与SOD活性均明显增高(均为P < 0.05)。结论  百里醌通过减轻炎症反应和氧化应激而减轻肝IRI, 其作用机制与抑制Wnt/β-catenin/p53信号通路激活有关。     

CircSTAM inhibits migration and invasion of trophoblast cells by regulating miR-148a-5p/PTEN axis

BackgroundThe mechanisms underlying the pathogenesis of preeclampsia (PE) remains unclear. Exploring the molecular players in PE progression can provide insights into targeted therapy.MethodsThe expression levels of circSTAM in placental chorionic tissues of PE patients and normal pregnant women were compared by RT-qPCR. CircSTAM was knocked down by small interfering RNA to investigate its role in migration, invasion and epithelial-mesenchymal transformation (EMT) of trophoblast HTR-8/SVneo cells. The downstream target of circSTAM was predicted using online bioinformatics resources, and their molecular interaction was examined by luciferase reporter assay.ResultsCircSTAM was upregulated in PE placenta tissues in comparison to normal placental tissues. CircSTAM knockdown significantly enhanced cellular invasion, migration, as well as EMT. Mir-148a-5p was identified as a target of circSTAM to regulate cell migration and invasion. Mir-148a-5p negatively regulated PTEN expression in trophoblast HTR-8 /SVneo cells.ConclusionIn summary, circSTAM upregulation in PE trophoblasts promoted the invasion, migration and EMT. CircSTAM may modulate trophoblast phenotype by impinging on mir-148a-5p/PTEN axis. These data provided novel insights into the pathogenesis of PE.     

HLA-B27 negative reactive arthritis versus HLA-B27 positive reactive arthritis: A retrospective study

Reactive arthritis (ReA) is defined as inflammatory arthritis secondary to an extra-articular infection with a key genetic background, HLA-B27. However, to date, the diagnosis and classification remain incomplete. The study focused on the similarities and differences in clinical manifestation, imaging features, and laboratory inspection between HLA-B27 negative patients and HLA-B27 positive patients in order to provide a reference for future development of diagnostic and classification criteria. Twenty-five ReA (19 HLA-B27 negative patients and 6 HLA-B27 positive patients) were included in this retrospective study. Clinical data, including demographics, clinical symptoms, imaging features, and laboratory inspection, were collected. The chi-square test and Mann–Whitney U test were used in the analysis. HLA-B27 negative group showed more involvement of upper extremities and small joints, while HLA-B27 positive group performed more axial symptoms. No significant difference was found in imaging features (ultrasound and magnetic resonance imaging) or laboratory inspection (microbes culture and infection-related indicators) between the 2 groups. ReA patients with different genetic backgrounds show various manifestations, although they encounter similar infections.     

Fusobacterium nucleatum induces excess methyltransferase‐like 3‐mediated microRNA‐4717‐3p maturation to promote colorectal cancer cell proliferation

Fusobacterium nucleatum infection plays vital roles in colorectal cancer (CRC) progression. Overexpression of microRNA‐4717‐3p (miR‐4717) was reported to be upregulated in F. nucleatum positive CRC tissues, however, the underlying mechanism is unknown. In this study, we found that miR‐4717 promoted CRC cell proliferation in vitro and growth of CRC in vivo following F. nucleatum infection. MicroRNA‐4717 suppressed the expression of mitogen‐activated protein kinase kinase 4 (MAP2K4), a tumor suppressor, by directly targeting its 3′‐UTR. Furthermore, we confirmed that methyltransferase‐like 3 (METTL3)‐dependent m⁶A methylation could methylate primary (pri)‐miR‐4717, which further promoted the maturation of pri‐miR‐4717, and METTL3 positively regulated CRC cell proliferation through miR‐4717/MAP2K4 pathways. In conclusion, F. nucleatum‐induced miR‐4717 excessive maturation through METTL3‐dependent m⁶A modification promotes CRC cell proliferation, which provides a potential therapeutic target and diagnostic biomarker for CRC.     

In vitro and in vivo study of GSK2830371 and RG7388 combination in liver adenocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is an adenocarcinoma arising from the intrahepatic bile duct and accounts for the second highest incidence of primary liver cancers after hepatocellular carcinoma. The lack of effective treatment leads to a poor prognosis for advanced iCCA, so new targeted therapy is needed. The impairment of wild-type (WT) p53 tumor suppressor function by its negative regulators frequently occurs in iCCA. Therefore, restoration of WT p53 function by inhibiting its negative regulators is a therapeutic strategy being explored for cancer treatment. Combining an MDM2 inhibitor (MDM2i, RG7388) to stabilize p53 and a WIP1 inhibitor (WIP1i, GSK2830371) to increase p53 phosphorylation enhances p53 function. The combination of MDM2 and WIP1 inhibitors has been reported in several cancer types but in vivo studies are lacking. In the current study, liver adenocarcinoma cell lines, RBE and SK-Hep-1, were treated with RG7388 alone and in combination with GSK2830371. Cell proliferation, clonogenicity, protein and mRNA expressions, and cell cycle distribution were performed to investigate the effect and mechanism of growth suppression. To evaluate the antitumor efficacy of RG7388 and GSK2830371 in vivo, SK-Hep-1 xenografts in NOD-SCID mice were treated with combination therapy for two weeks. The combination of MDM2i and WIP1i significantly increased the growth inhibition, cytotoxicty, p53 protein expression, and phosphorylation (Ser15), leading to transactivation of downstream targets (p21^WAF1 and MDM2). The in vivo results demonstrated that the combination treatment can significantly inhibit tumor growth. In this study, the liver adenocarcinoma cell lines responded to combination treatment via reactivation of p53 function evidenced by increased p53 expression, phosphorylation and expression of its downstream targets. This efficacy was also demonstrated in vivo. The current research provides a novel strategy for targeting the p53 pathway in liver adenocarcinoma that warrants further investigation.     

TRIM27 is an adverse prognostic biomarker and associated with immune and molecular profiles in right-sided colon cancer

Right-sided colon cancer (RCC), as an independent tumor entity, shows a poor prognosis. It is imperative to detect immune microenvironment-related genes for predicting RCC patient prognosis and study their function in RCC. Tripartite motif-containing 27 (TRIM27) was identified as a risk signature from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets by using weighted gene co-expression network analysis, differentially expressed analysis, and univariate Cox analysis. It predicted a poorer overall survival and increased lymph node metastasis, which were then validated in our 48 clinical samples. Using immunohistochemistry, TRIM27 was found to be highly expressed in both cancer cells and surrounding immunocytes, and its expression in tumor or immune cells both predicted a poorer prognosis. Thereafter, the functional mechanism, immune and molecular characteristics of TRIM27 were investigated using gene set enrichment analysis (GSEA), ESTIMATE, CIBERSORT, and gene set variation analysis (GSVA) at the single-cell, somatic mutation, and RNA-seq level. Patients with highly expressed TRIM27 presented lower CD4⁺ T cell infiltration and activation of the mTORC1/glycolysis pathway. In addition, patients with highly expressed TRIM27 were characterized by hypermetabolism, higher tumor purity, more BRAF mutation, and more chromosomal instability. Collectively, TRIM27 is an important immune-related prognostic biomarker in patients with RCC. It may function via activating the mTORC1/glycolysis pathway and suppressing CD4⁺ T cells. These results indicated that TRIM27 could be a promising therapeutic target in RCC.     

Somatic Mutations of TP53 Identified by Targeted Next-Generation Sequencing Are Poor Prognostic Factors for Primary Operable Breast Cancer: A Single-Center Study

Few studies have reported on the clinical utility of targeted next-generation sequencing (NGS) for breast cancer in Korea. We retrospectively reviewed the targeted NGS data of 219 patients with breast cancer who underwent surgical resection between August 2018 and April 2021. Here, we described the mutational profiles of breast cancer and examined their prognostic implications. The most frequently mutated gene was PIK3CA (n = 97/219, 44.3%), followed by TP53 (n = 79/219, 36.1%), AKT1 (n = 23/219, 10.5%), and GATA3 (n = 20/219, 9.1%). TP53 mutations were associated with aggressive histologic features. We followed up for 31 (range, 1–39) months and observed 11 (5.0%) recurrences: nine were TP53 mutant and two were TP53 wild-type. Multivariable analysis revealed that TP53 mutation was an independent prognostic factor for recurrence (p = 0.012). Although no drug is currently available for TP53 mutations, it is valuable to know the mutational status of TP53 for the precise management of breast cancer.