BACKGROUND: Calculus bovis (CB), used in traditional Chinese medicine, exhibits anti-tumor effects in various cancer models. It also constitutes an integral component of a compound formulation known as Pien Tze Huang, which is indicated for the treatment of liver cancer. However, its impact on the liver cancer tumor microenvironment, particularly on tumor-associated macrophages (TAMs), is not well understood.
OBJECTIVE: To elucidate the anti-liver cancer effect of CB by inhibiting M2-TAM polarization via Wnt/β-catenin pathway modulation.
METHODS: This study identified the active components of CB using UPLC-Q-TOF-MS, evaluated its anti-neoplastic effects in a nude mouse model, and elucidated the underlying mechanisms via network pharmacology, transcriptomics, and molecular docking. In vitro assays were used to investigate the effects of CB-containing serum on HepG2 cells and M2-TAMs, and Wnt pathway modulation was validated by real-time reverse transcriptase-polymerase chain reaction and Western blot analysis.
RESULTS: This study identified 22 active components in CB, 11 of which were detected in the bloodstream. Preclinical investigations have demonstrated the ability of CB to effectively inhibit liver tumor growth. An integrated approach employing network pharmacology, transcriptomics, and molecular docking implicated the Wnt signaling pathway as a target of the antineoplastic activity of CB by suppressing M2-TAM polarization. In vitro and in vivo experiments further confirmed that CB significantly hinders M2-TAM polarization and suppresses Wnt/β-catenin pathway activation. The inhibitory effect of CB on M2-TAMs was reversed when treated with the Wnt agonist SKL2001, confirming its pathway specificity.
CONCLUSIONS: This study demonstrated that CB mediates inhibition of M2-TAM polarization through the Wnt/β-catenin pathway, contributing to the suppression of liver cancer growth.

BACKGROUND: Wnt proteins are crucial for embryonic development, stem cell growth, and tissue regeneration. Wnt signaling pathway is activated when Wnt proteins bind to cell membrane receptors.
RESULTS: We employed a luciferase reporter assay in HEK293STF cells to measure Wnt protein-induced signaling. We observed that Wnt3a uniquely promotes the Wnt/β-catenin pathway through positive cooperativity. Additionally, MFH-ND, a molecular mimic of Wnt ligands, markedly increased Wnt3a-induced signaling in a dose-responsive manner. This suggests that various Wnt ligands can synergistically enhance Wnt pathway activation.
CONCLUSIONS: The study suggests the likelihood of various Wnt ligands coexisting in a single signalosome on the cell membrane, providing new insights into the complexities of Wnt signaling mechanisms.

暂无摘要。

Objective: To explore the gene mutation characteristics and the relationship between gene mutations and long-term prognosis in clinical stage ⅠA lung adenocarcinoma patients. Methods: A retrospective analysis was conducted on 63 clinical stage ⅠA lung adenocarcinoma patients who underwent surgical resection at the Cancer Hospital of the Chinese Academy of Medical Sciences from January 2007 to October 2012, with documented postoperative recurrence or metastasis, as well as those who had a follow-up duration of 10 years or more without recurrence or metastasis. Whole exome sequencing (WES) technology was used to analyze the gene mutation profiles in tumor tissues and univariate and multivariate Cox regression analysis were used to clarify the influencing factors for patient prognosis. Results: After long term follow-up, 13 out of the 63 patients (21%) experienced recurrence or metastasis. WES technology analysis revealed that the most common tumor related gene mutations occurred in epidermal growth factor receptor (EGFR), with a mutation rate of 65.1% (41/63), followed by tumor protein p53 (TP53), fatatypical cadherin 1 (FAT1), low density lipoprotein receptor-related protein 1B (LRP1B), mechanistic target of rapamycin (MTOR), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG), and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), with mutation rates of 30.2% (19/63), 20.6% (13/63), 15.9% (10/63), 15.9% (10/63), 15.9% (10/63), and 15.9% (10/63), respectively. Multivariate Cox regression analysis showed that PIK3CG mutations (HR=21.52, 95% CI: 3.19-145.01),smoothened (SMO) mutations (HR=35.28, 95% CI: 3.12-398.39), catenin beta 1 (CTNNB1) mutations (HR=332.86, 95% CI: 15.76-7 029.05), colony stimulating factor 1 receptor (CSF1R) mutations (HR=8 109.60, 95% CI: 114.19-575 955.17), and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations (HR=23.65, 95% CI: 1.86-300.43) were independent risk factors affecting the prognosis of clinical stage ⅠA lung adenocarcinoma patients. Conclusions: PIK3CG, SMO, CTNNB1, CSF1R, BRAF gene mutations are closely related to long-term recurrence or metastasis in clinical stage ⅠA lung adenocarcinoma. Patients with these gene mutations should be given closer clinical attention.
目的： 探讨临床ⅠA期肺腺癌的基因突变特征及其与患者预后的关系，为早期肺腺癌患者的个体化治疗提供依据。 方法： 收集2007年1月至2012年10月在中国医学科学院肿瘤医院接受手术切除且随访达10年以上或随访期间出现复发或转移的临床ⅠA期肺腺癌患者63例，采用全外显子组测序（WES）技术分析肺癌组织的基因突变谱，采用单因素和多因素Cox回归分析明确患者预后影响因素。 结果： 在随访期间，63例患者中13例（20.6%）出现复发或转移。WES技术分析显示，肺癌组织中表皮生长因子受体突变频率最高，达65.1%（41/63），其次为肿瘤蛋白p53、异常类脂肪酸1、低密度脂蛋白受体相关蛋白1B、雷帕霉素机械靶点、磷脂酰肌醇4，5-双磷酸3-激酶催化亚单位γ（PIK3CG）及与SWI/SNF相关基质相关的依赖于肌动蛋白的染色质调节因子亚家族A成员4，突变频率分别为30.2%（19/63）、20.6%（13/63）、15.9%（10/63）、15.9%（10/63）、15.9%（10/63）和15.9%（10/63）。多因素Cox回归分析显示，PIK3CG突变（HR=21.52，95%CI：3.19～145.01）、平滑蛋白（SMO）突变（HR=35.28，95%CI：3.12～398.39）、β-连环蛋白1（CTNNB1）突变（HR=332.86，95%CI：15.76～7 029.05）、集落刺激因子1受体（CSF1R）突变（HR=8 109.60，95%CI：114.19～575 955.17）、v-Raf小鼠肉瘤病毒癌基因同源B（BRAF）突变（HR=23.65，95%CI：1.86～300.43）为临床ⅠA期肺腺癌患者预后的独立危险因素。 结论： PIK3CG、SMO、CTNNB1、CSF1R、BRAF基因突变与临床ⅠA期肺腺癌的远期复发和转移密切相关，应给予具有这些基因突变的肺腺癌患者更为密切的临床关注。.

暂无摘要。

Hair loss affects men and women of all ages. Myokines, which are mainly secreted by skeletal muscles during exercise, have numerous health benefits. VEGF, IGF-1, FGF and irisin are reprehensive myokines. Although VEGF, IGF-1 and FGF are positively associated with hair growth, few studies have researched the effects of irisin on hair growth. Here, we investigated whether irisin promotes hair growth using in vitro, ex vivo and in vivo patch assays, as well as mouse models. We show that irisin increases proliferation, alkaline phosphatase (ALP) activity and mitochondrial membrane potential in human dermal papilla cells (hDPCs). Irisin activated the Wnt/β-catenin signalling pathway, thereby upregulating Wnt5a, Wnt10b and LEF-1, which play an important role in hair growth. Moreover, irisin enhanced human hair shaft elongation. In vivo, patch assays revealed that irisin promotes the generation of new hair follicles, accelerates entry into the anagen phase, and significantly increases hair growth in C57BL/6 mice. However, XAV939, a Wnt/β-catenin signalling inhibitor, suppressed the irisin-mediated increase in hair shaft and hair growth. These results indicate that irisin increases hair growth via the Wnt/β-catenin pathway and highlight its therapeutic potential in hair loss treatment.

The two types of craniopharyngioma, adamantinomatous (ACP) and papillary (PCP), are clinically relevant tumours in children and adults. Although the biology of primary craniopharyngioma is starting to be unravelled, little is known about the biology of recurrence. To fill this gap in knowledge, we have analysed through methylation array, RNA sequencing and pERK1/2 immunohistochemistry a cohort of paired primary and recurrent samples (32 samples from 14 cases of ACP and 4 cases of PCP). We show the presence of copy number alterations and clonal evolution across recurrence in 6 cases of ACP, and analysis of additional whole genome sequencing data from the Children\'s Brain Tumour Network confirms chromosomal arm copy number changes in at least 7/67 ACP cases. The activation of the MAPK/ERK pathway, a feature previously shown in primary ACP, is observed in all but one recurrent cases of ACP. The only ACP without MAPK activation is an aggressive case of recurrent malignant human craniopharyngioma harbouring a CTNNB1 mutation and loss of TP53. Providing support for a functional role of this TP53 mutation, we show that Trp53 loss in a murine model of ACP results in aggressive tumours and reduced mouse survival. Finally, we characterise the tumour immune infiltrate showing differences in the cellular composition and spatial distribution between ACP and PCP. Together, these analyses have revealed novel insights into recurrent craniopharyngioma and provided preclinical evidence supporting the evaluation of MAPK pathway inhibitors and immunomodulatory approaches in clinical trials in against recurrent ACP.

Hepatic stellate cell (HSC) activation is the essential pathological process of liver fibrosis (LF). The molecular mechanisms regulating HSC activation and LF are incompletely understood. Here, we explored the effect of transcription factor SRY-related high mobility group box 7 (SOX7) on HSC activation and LF, and the underlying molecular mechanism. We found the expression levels of SOX7 were decreased in human and mouse fibrotic livers, particularly at the fibrotic foci. SOX7 was also downregulated in primary activated HSCs and TGF-β1 stimulated LX-2 cells. SOX7 knockdown promoted activation and proliferation of LX-2 cells while inhibiting their apoptosis. On the other hand, overexpression of SOX7 suppressed the activation and proliferation of HSCs. Mechanistically, SOX7 attenuates HSC activation and LF by decreasing the expression of β-catenin and phosphorylation of Smad2 and Smad3 induced by TGF-β1. Furthermore, overexpression of SOX7 using AAV8-SOX7 mouse models ameliorated the extent of LF in response to CCl4 treatment in vivo. Collectively, SOX7 suppressed HSC activation and LF. Targeting SOX7, therefore, could be a potential novel strategy to protect against LF.

The corneal epithelium is located on the most anterior surface of the eyeball and protects against external stimuli. The development of the corneal epithelium and the maintenance of corneal homeostasis are essential for the maintenance of visual acuity. It has been discovered recently via the in-depth investigation of ocular surface illnesses that the Wnt/β-catenin signaling pathway is necessary for the growth and stratification of corneal epithelial cells as well as the control of endothelial cell stability. In addition, the Wnt/β-catenin signaling pathway is directly linked to the development of common corneal illnesses such as keratoconus, fungal keratitis, and corneal neovascularization. This review mainly summarizes the role of the Wnt/β-catenin signaling pathway in the development, homeostasis, and pathobiology of cornea, hoping to provide new insights into the study of corneal epithelium and the treatment of related diseases.

Ubiquitination, a prevalent and highly dynamic reversible post-translational modification, is tightly regulated by the deubiquitinating enzymes (DUBs) superfamily. Among them, OTU Domain-Containing Ubiquitin Aldehyde-Binding Protein 1 (OTUB1) stands out as a critical member of the OTU deubiquitinating family, playing a pivotal role as a tumor regulator across various cancers. However, its specific involvement in BLCA (BLCA) and its clinical significance have remained ambiguous. This study aimed to elucidate the biofunctions of OTUB1 in BLCA and its implications for clinical prognosis. Our investigation revealed heightened OTUB1 expression in BLCA, correlating with unfavorable clinical outcomes. Through in vivo and in vitro experiments, we demonstrated that increased OTUB1 levels promote BLCA tumorigenesis and progression, along with conferring resistance to cisplatin treatment. Notably, we established a comprehensive network involving OTUB1, β-catenin, necroptosis, and BLCA, delineating their regulatory interplay. Mechanistically, we uncovered that OTUB1 exerts its influence by deubiquitinating and stabilizing β-catenin, leading to its nuclear translocation. Subsequently, nuclear β-catenin enhances the transcriptional activity of c-myc and cyclin D1 while suppressing the expression of RIPK3 and MLKL, thereby fostering BLCA progression and cisplatin resistance. Importantly, our clinical data suggest that the OTUB1/β-catenin/RIPK3/MLKL axis holds promise as a potential biomarker for BLCA.