Editors-in-Chief

Shu-Min DUAN

Zhi-Hong LIU

ISSN 1673-1581

CN 33-1356/Q

Published by

Zhejiang University Press

2022 JIF 4.7

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  • Review

    Abstract：Oral squamous cell carcinoma (OSCC) poses significant challenges in terms of diagnosis and treatment, with high rates of morbidity and mortality. Emerging evidence highlights the critical involvement of Wingless/Int-1 (Wnt) ligands and receptors in OSCC pathogenesis. Dysregulated Wnt signaling pathways contribute to tumor initiation, progression, and therapy resistance by promoting cellular proliferation, epithelial‒mesenchymal transition (EMT), and the maintenance of cancer stem cells (CSCs). Targeting Wnt signaling presents a promising therapeutic avenue, yet its complex interplay with other signaling pathways requires a deeper understanding to implement effective intervention. This study sheds light on the current knowledge of the roles of Wnt ligands and receptors in OSCC, emphasizing their potential as diagnostic biomarkers and therapeutic targets. Future research directions involve elucidating context-specific Wnt signaling dynamics and exploring combination therapies to improve clinical outcomes for OSCC patients.  

    Muhammad TUFAIL, Caiyun HE, Canhua JIANG, Ning LI

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  • Review

    Abstract：Macrophages are sensitive cells to various external mechanical forces in the environment, such as stretch, shear, and pressure. Mechanical forces can be recognized by mechanical signal receptors on the cell surface, such as cell adhesion molecules and ion channels, and transformed into intracellular biological signals, in turn activating different signaling pathways and thereby regulating the phagocytosis, migration, and polarization of macrophages. The phenomenon in which macrophages transform into different activated phenotypes and perform different functions under varying environmental stimuli is also known as macrophage polarization. In this review, we discuss the roles of mechanically sensitive integrins and ion channels in the mechanical signal sensing of macrophages. We expound on several downstream signaling pathways closely related to integrins and ion channels, such as the nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) pathways, which have made good research progress. In addition, we summarize some in vitro experiments on the regulation of macrophage polarization by external mechanical forces, some current cell models for macrophages in vitro, and some commonly used force application devices, with the aim to provide convenience for future in vitro research on macrophages. This paper offers a deep understanding of the mechanical sensitivity and conduction mechanisms of macrophages, which can provide new ideas for the treatment of human diseases.  

    Dan YU, Chenlu XU, Jinpeng JIANG, Wenyi SHEN, Huiyong ZHU

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  • Research Article

    Abstract：Asthma is a complex and chronic inflammatory airway disease associated with the abnormal activation of immune cells. T-cell senescence is linked to immune dysfunction and persistent inflammation, but the relationship between asthma and T-cell senescence remains unexplored. This study reveals significantly higher percentages of cluster of differentiation 4-positive (CD4+) senescent T cells (Tsens) in asthma patients than in healthy controls, while CD8+ Tsen percentages do not appear to increase. CD4+ Tsen percentages in both the blood and sputum are positively correlated with fractional exhaled nitric oxide (FeNO) values, eosinophil abundance, and T helper type 2 (Th2) cell abundance in the blood. The clinical manifestations of asthma were recreated in a house dust mite (HDM)-induced mouse model. In HDM-exposed mice, CD4+ Tsen percentages were also elevated in the lungs. To counteract T-cell senescence, therapeutic interventions, including interleukin-4 (IL-4) antibodies and dexamethasone, were administered to the mice. IL-4 neutralization reduced CD4+ Tsen percentages and inhibited p38 mitogen-activated protein kinase (MAPK) activation. Adoptive transfer of CD4+ Tsens did not induce spontaneous asthma in phosphate-buffered saline (PBS)-treated mice but exacerbated type 2 inflammation in HDM-treated mice. Our study revealed a significant increase in CD4+ Tsen (CD57+CD28-) abundance in asthma patients and suggested that type 2 inflammation drives CD4+ T-cell senescence in asthma. Furthermore, adoptive transfer of CD4+ Tsens appears to exacerbate type 2 inflammation.  

    Huan LIU, Zemin LI, Yongchang SUN, Abudureyimujiang AILI, Chun CHANG

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  • Research Article

    Abstract：Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors worldwide. This necessitates the development of innovative drugs with high efficiency, low toxicity, and good tolerance. Bitter melon extract has been reported to have potent anticancer activity against OSCC. We evaluated the effects of nine triterpenoids from bitter melon extract on OSCC using cell counting kit-8 (CCK-8) proliferation and Transwell migration assays. Among the nine triterpenoids, momordicine I (MI) exhibited the strongest anticancer activity against OSCC. Animal experiments also showed that MI inhibited OSCC cell growth in vivo. Additionally, MI decreased the mitochondrial membrane potential and promoted apoptosis in OSCC. RNA-sequencing (RNA-seq) analysis revealed that MI induced an unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, which was confirmed by western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cellular thermal shift assay (CETSA) and mass spectrometry (MS) analysis, combined with molecular docking, identified ribosomal proteins (ribosomal protein L7 (RPL7), RPL11, RPL12, RPL18, RPL30, RPL38, RPS13, and RPS25) as MI targets. By targeting ribosomal proteins, MI likely disrupts ribosome-mediated protein folding, leading to the UPR and ER stress. In summary, MI targets ribosomal proteins to induce ER stress and inhibit OSCC, highlighting its therapeutic potential.  

    Jianlu KONG, Ziyu ZHU, Yijie HU, Siyi ZHOU, Tianyi GU, Xiao SHEN, Huiming WANG, Mengfei YU, Yu LIU

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  • Research Article

    Abstract：Acute respiratory distress syndrome (ARDS) is a form of progressive hypoxemia that can be brought on by a variety of cardiorespiratory or systemic disorders, such as coronavirus disease 2019 (COVID-19). The binding of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus spike protein to the cell membrane is mediated through its binding to angiotensin-converting enzyme 2 (ACE2) receptors, resulting in viral entry, replication, and induction of a signaling cascade inducing pro-inflammatory responses that are linked to a higher mortality rate and the progression of ARDS, leading to multi-organ failure in these patients. We aimed to analyze the relationships between circulating gene expression levels of ACE2, Toll-like receptor 4 (TLR4), and interleukin-17 (IL-17) and the clinical severity of COVID-19, as well as the associated pathogenic conditions, in hospitalized patients. Sixty COVID-19 patients (34 mild/moderate COVID-19 and 26 COVID-19 with severe ARDS manifestation) and 60 healthy controls were included. The patient group was also subdivided according to outcomes into 32 recoveries and 28 deaths. ACE2, TLR4, and IL-17 levels were assessed by quantitative polymerase chain reaction (qPCR) in addition to all routine baseline laboratory investigations, including complete blood count (CBC) with differential analysis and the levels of C-reactive protein (CRP), ferritin, and d-dimer. ACE2, TLR4, and IL-17 serum expression levels were significantly higher in the COVID-19 group and subgroups and were correlated with different laboratory and clinical parameters. The serum expression levels of ACE2, TLR4, and IL-17 were accurate in differentiating between the patient groups and controls, with 86.7%, 91.7%, and 95.0% sensitivity and 96.7%, 98.3%, and 98.3% specificity, respectively, and correlated with more severe disease courses in COVID-19 patients. Higher levels are associated with overwhelmingly distressing outcomes. Our results allow us to conclude that increased circulating gene expression levels of ACE2, TLR4, and IL-17 are important in assessing the severity of COVID-19. Consequently, targeting these biomarkers may offer additional therapeutic options for COVID-19 patients in the future.  

    Marwa A. DAHPY, Ragaa H. SALAMA, Abdel-Raheim M. A. MEKI, Ashraf Zein El-ABEDEEN, Maiada K. HASHEM, Ebtsam S. ABDULKAREEM, Mohamed MOHANY, Sinisa DJURASEVIC, Amal N. IBRAHIM, Nourhan M. HUSSEIN, Shima Gafar MANSOR, Mohamed Ramadan IZZALDIN, Marwa K. KHAIRALLAH, Suzan Eid Elshishtawy IBRAHIM, Alzahra ABDELBADEA, Islam Khaled Ali HARBY, Fatma Y. A. ABBAS, Rasha M. ALI, Marwa A. SABET, Salwa Seif ElDIN, Abdelraouf M. S. ABDELRAOUF, Amira A. KAMEL

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  • Perspective

    Abstract：In the realm of precision psychiatry of mood disorders, the evolution of interpersonal psychotherapy (IPT) is gaining momentum, necessitating a personalized approach that also takes into account cultural aspects. This study underscores the importance of incorporating cultural factors into the dissemination and application of IPT in Asia. Through a comprehensive analysis of a case illuminating how cultural influences impact the onset and treatment outcomes of depression, we emphasize the critical need for culturally informed IPT practices in China. This personalized approach not only enhances treatment outcomes but also paves the way for further research on adapting IPT to diverse cultural contexts in Asia.  

    Xiaoyi ZHOU, Haoyang ZHAO, Guoxun FENG, Jianbo HU, Sarah E. BLEDSOE, Manli HUANG

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  • Correspondence

    Abstract：硬化性肺细胞瘤（PSP）最初被称为肺硬化性血管瘤（PSH），曾被认为来源于血管丰富的内皮细胞。然而近期相关研究表明，该肿瘤实际来源于肺泡上皮细胞。尽管以往研究普遍认为PSP是一种罕见的良性肺肿瘤，但已有报道显示其可发生肺及淋巴结等部位的转移，提示其具有潜在恶行生物学行为。正电子发射计算机断层显像（PET/CT）可显示出PSP对18F-氟脱氧葡萄（18FDG）的摄取程度不一，最大标准化摄取值（SUVmax）从背景值到6.4不等。因此，PSP很容易被误诊为其他恶性肿瘤，从而接受不必要的手术切除或不恰当治疗。本文报告了一例罕见的年轻PSP患者病例，其PET/CT显示右肺巨大肿块伴右肺门淋巴结肿大，肿瘤和淋巴结的SUVmax分别为6.1和5.1，属于已有文献报道中最高的摄取值之一。目前，PSP病灶淋巴结转移和/或18FDG高摄取的原因尚不明确，其是否与肿瘤发生部位、大小、血供以及患者的年龄、性别和吸烟史相关，仍无定论。此外，本研究进一步回顾分析了近十年来PSP淋巴结转移和/或18FDG高摄取的文献，通过统计分析肿瘤大小，淋巴结转移和18FDG摄取等情况，发现淋巴结的转移与和/或18FDG高摄取与肿瘤大小正相关（R=0.642，R2=0.454，P<0.001）。综上，对于年轻患者，若其影像出现肺部边界清楚的较大肿块，即使伴有淋巴结转移和/或18FDG高摄取，仍需要考虑PSP的可能。  

    Jingfeng XU, Yilei ZHAO, Qiuli WU, Feng CHEN

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