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：Transient receptor potential vanilloid subtype 1 (TRPV1), a polymodally activated, calcium-permeable non-selective cation channel, is broadly present in all parts of the body, with notable expression in the nociceptive neurons. Both physiological and pathological functions rely heavily on this ion channel, mediating responses to a variety of stimuli and contributing to the maintenance of bodily homeostasis. Its unique ability to respond to temperature changes, chemical ligands, and voltage fluctuations positions TRPV1 as a key target in understanding and modulating normal bodily functions, in addition to diagnosing and treating diseases. This review synthesizes current knowledge on the structure, gating mechanisms, and physiological and pathological roles of TRPV1, highlighting its potential as a therapeutic target across multiple disease states. By providing a comprehensive overview of the multifaceted functions of TRPV1, this review aims to inform and inspire future research, finally contributing to the advancement of new therapeutic techniques focusing on TRPV1 to enhance human health.  

    Yi LIU, Fuqin DUAN, Runpeng LIN, Subinuer SHABUERJIANG, Fan YANG, Aerziguli AIERKEN

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  • Review

    Abstract：Poly(ADP-ribose) polymerase (PARP) is a family of proteins that play a crucial role in diverse cellular processes, including DNA repair, cell death, and changes in chromatin structure. PARP inhibitors (PARPi) have been recognized as notable agents in the realm of anticancer therapeutics owing to their capacity to specifically impact DNA repair pathways, thereby inducing targeted death of cancerous cells, particularly in cancers with homologous recombination deficiency (HRD). These inhibitors have been approved for the treatment of several cancers, such as ovarian, breast, and pancreatic cancers. Despite their promising therapeutic attributes, developing resistance to PARPi presents a formidable obstacle, curtailing their overall efficacy. This article presents a comprehensive description of the potential mechanisms related to PARPi resistance, an in-depth study of potential strategies to overcome resistance, and an assessment of the therapeutic potential of the PARPi in combination with alternative therapies.  

    Muhammad SHOAIB, Zeeshan Ahmad BHUTTA, Ahsan JAVED, Muhammad Nabeel AMJAD, Wenzhu LI, Kyung-Chul CHOI, Wanxia PU

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  • Review

    Abstract：Real-world studies (RWSs) have emerged as a transformative force in oncology research, complementing traditional randomized controlled trials (RCTs) by providing comprehensive insights into cancer care within routine clinical settings. This review examines the evolving landscape of RWSs in oncology, focusing on their implementation, methodological considerations, and impact on precision medicine. We systematically analyze how RWSs leverage diverse data sources, including electronic health records (EHRs), insurance claims, and patient registries, to generate evidence that bridges the gap between controlled clinical trials and real-world clinical practice. The review underscores the key contributions of RWSs, including capturing therapeutic outcomes in traditionally underrepresented populations, expanding drug indications, and evaluating long-term safety and effectiveness in routine clinical settings. While acknowledging significant challenges, including data quality variability and privacy concerns, we discuss how emerging technologies like artificial intelligence are helping to address these limitations. The integration of RWSs with traditional clinical research is revolutionizing the paradigm of precision oncology and enabling more personalized treatment approaches based on real-world evidence.  

    Jingxin JIANG, Weiwei PAN, Liyang SUN, Liwei PANG, Hailang CHEN, Jian HUANG, Wuzhen CHEN

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  • Research Article

    Abstract：Protein interacting with C kinase 1 (PICK1) interacts with a variety of membrane proteins and receptors involved in nervous system diseases and multiple cancers. However, the role of PICK1 in gastric cancer remains unclear. In the present work, we explored the expression and interactions of PICK1 with Toll-like receptor 4 (TLR4) in gastric cancer. Clinical data analysis showed that PICK1 expression decreases and is predictive of worse outcomes in patients with gastric cancer. High PICK1 levels attenuate the proliferation and migration of gastric cancer cells, which is dependent on the TLR4/myeloid differentiation primary response 88 (MyD88) signaling pathway. Furthermore, in vitro experiments demonstrated that PICK1 affects the trafficking and degradation of TLR4 and promotes TLR4 degradation via autophagy in gastric cancer cells. Molecular dynamics simulations highlighted the binding strength and stability of the TLR4-PICK1 complex. Our study provides new insights into the cellular and pathological functions of PICK1 in gastric cancer.  

    Kaiqiang LI, Yimin YANG, Yaling WANG, Jing JIN, Qianni WANG, Lina PENG, Aibo XU, Xuling LUO, Wei YANG, Peng XU, Bingyu CHEN, Ke HAO, Zhen WANG

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  • Research Article

    Abstract：Premenstrual dysphoric disorder (PMDD), a subtype of premenstrual syndrome (PMS), involves physical and emotional symptoms that impact patients’ daily lives and productivity. A reliable, side-effect-free clinical intervention is needed. Shuyu capsule is an effective traditional Chinese medicine preparation for PMDD used in the clinics, but its therapeutic mechanism remains unclear. Previous research has suggested that the γ-aminobutyric acidergic (GABAergic) system in the periaqueductal gray (PAG) may play a role in treating PMDD with traditional Chinese medicine, but there is a lack of functional verification. This study aims to reveal the potential mechanism of the Shuyu capsule in treating PMDD. The study employed an experimental design using female C57BL/6J and Vgat-Cre mice to assess the effects of Shuyu capsules on PMDD, with a focus on the GABAergic system in the dorsal PAG (dPAG). Assessments were conducted using the forced swimming test (FST) to gauge depression-like behaviors and western blot (WB) and immunofluorescence (IF) to measure the numbers of active GABAergic neurons and the γ-aminobutyric acid type A receptor (GABAAR) δ subunit (GABRD) expression. Chemogenetic techniques and adeno-associated virus were specifically used to activate GABAergic neurons and knock down the expression of subunits, respectively, providing insights into the neurobiological mechanisms underpinning the therapeutic effects of Shuyu capsules in treating PMDD. After being stressed by FST, the immobility duration of PMDD mice in the late dioestrus (LD) phase decreased after the Shuyu capsule intervention, implying that it can improve the estrous cycle-dependent depression-like phenotype in PMDD mice. Additionally, the application of Shuyu capsule can downregulate the expression of GABRD and reverse the downtrend of activated GABAergic neurons in the dPAG of PMDD model mice. We also found that single-target manipulation was enough to improve the depression-like behavior of PMDD model mice. Transgenic mice with GABRD knockout were established, and their behaviors were tested, revealing changes in their exploratory behaviors, indicating that the GABRD may be closely related to anxiety disorders. Shuyu capsule plays an anti-PMDD role by activating GABAergic neurons and downregulating the expression of GABRD in the dPAG. This provides a theoretical basis for the clinical treatment of PMDD with traditional Chinese medicine and promotes the development of drugs for treating PMDD.  

    Jialing XU, Kun LIU, Yaru CUI, Hao ZHANG, Xinyu WANG, Minghui HU, Zifa LI, Peng GAO, Wei LIU, Mingqi QIAO, Wenqiang CUI, Xiwen GENG, Sheng WEI

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  • Research Article

    Abstract：This study used molecular dynamics simulations, B-factor analysis, and saturation mutagenesis screening to enhance the thermal stability of the trans-epoxysuccinate hydrolase (TESH) derived from Pseudomonas koreensis. Eleven mutants that influence this characteristic were selected, yielding four mutants with improved activity. Among them, mutants A142C and S178Q exhibited lower Michaelis constant (Km) values, and their kcat/Km ratios (kcat, catalytic constant) were 3.7 and 0.9 times higher than those of the wild type, respectively. The values of half-life at 50 ℃ (T1/250) of the two mutants were increased by 107% and 59%, respectively, compared to the wild type. Molecular docking and molecular dynamics simulations indicated that the two mutants showed stronger substrate interaction, lower binding energy, and reduced root mean square deviation compared to the wild type, along with decreased electrostatic potential energy and increased hydrophobicity near their mutation sites. The study of protein thermal stability engineering and associated mechanisms provides a valuable reference and holds practical significance for the industrial production of meso-tartaric acid.  

    Wenna BAO, Jinfeng YAO, Haifeng PAN, Ronglin ZHU, Xinying LI, Hongxiu LIAO

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  • Correspondence

    Abstract：肠道中种类庞杂的微生物群落统称为肠道菌群，其与宿主间相互影响，形成了复杂的共生体系统。肠道菌群与动物健康关系密切，具有消化、合成维生素以及合成其他重要代谢物和神经递质的功能。多项研究表明，菌群相关代谢产物可通过直接或间接方式调节宿主的生理功能和免疫反应，以维持局部及全身的稳态平衡。我们利用葡聚糖硫酸钠诱导的结肠炎小鼠模型证实，肠道共生细菌纽约杜伯氏菌及其人类同源菌无害梭菌，可通过产生短链脂肪酸（特别是丙酸）和赖氨酸调节免疫耐受，从而缓解结肠炎。赖氨酸可通过芳烃受体激活树突状细胞中的吲哚胺2,3-双加氧酶1（IDO1），诱导调节性T淋巴细胞（Treg）产生免疫抑制的肠道微环境，该研究可为炎症性肠病提供一种潜在的治疗策略。  

    Shuyu TU, Yanan ZHANG, Li ZHANG, Shu Jeffrey ZHU

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