Drug Discoveries and Therapeutics
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2025
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IF 1.5
Fangzhou Dou,Shasha Hu,Daoran Lu,Jianjun Gao
Chronic inflammation in the colon has been recognized as a key pathogenic mechanism driving colorectal cancer development. TRPA1 (transient receptor potential ankyrin 1), a key member of the TRP cation channel superfamily, is closely implicated in inflammatory processes and has emerged as a promising therapeutic target for anti-inflammatory drug development. However, the precise role of TRPA1 in colorectal carcinogenesis and its potential as a therapeutic target for colorectal cancer (CRC) remain incompletely understood. In this study, we demonstrate that Trpa1 knockout significantly exacerbates DSS-induced colitis-associated tumorigenesis in murine models, a phenomenon mechanistically linked to Trpa1 deficiency-mediated aggravation of inflammatory bowel pathology. RNAseq and gene knockout effect analysis revealed a consistently low expression pattern of TRPA1 across colorectal cancer cell lines (n = 58, median log2(TPM+1) = 0.025), with limited impact on cell viability upon TRPA1 knockout. Notably, analysis of human clinical specimens revealed substantial downregulation of TRPA1 expression in CRC compared to adjacent normal tissues. Kaplan-Meier survival analysis further indicated that patients with TRPA1-low tumors exhibited significantly poorer overall survival outcomes. These collective data suggest a tumor-suppressive role for TRPA1 in colorectal carcinogenesis, potentially through its immunomodulatory functions within the colitis-cancer transformation axis.
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Cell Death & Disease
·
2026
·Vol. 17
·期 1
·226
·
IF 12.2
Rao Yongjuan,Wang Yunran,Gao Jie,Guan Xun,Lv Sixuan,Gu Junlian,Wang Kefang
Overactive bladder (OAB) is strongly linked to intravesical inflammatory responses. Transient receptor potential ankyrin-1 (TRPA1) is a key sensor and signaling molecule in bladder function, crucial for initiating and maintaining inflammation. However, the mechanisms underlying TRPA1-mediated inflammatory processes in OAB remain unclear. This study aims to elucidate the molecular mechanisms of TRPA1 and the contribution of inflammatory pathways to OAB. Elevated TRPA1 expression was observed in urinary sediment cells from OAB patients and in bladder tissues from OAB animal models. Mechanistically, TRPA1 drives the progression of OAB by activating the Nod-Like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome and triggering pyroptosis. Notably, treatment with HC-030031 effectively mitigated inflammatory responses and restored bladder function, whereas Nlrp3 overexpression negated these therapeutic benefits. Furthermore, TRPA1-mediated upregulation of NLRP3 was dependent on the transcription factors MAZ and SMAD3, highlighting a novel regulatory axis. Our findings establish TRPA1 as a pivotal mediator in the progression of OAB by activating the NLRP3 inflammasome and thereby inducing pyroptosis. Targeting TRPA1 or the NLRP3 signaling pathway represents a promising therapeutic strategy for OAB, offering new insights into disease management and potential improvements in patient outcomes.
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Advanced Healthcare Materials
·
2021
·Vol. 11
·期 8
·2102506
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IF 9.933
Boying Li,Shuxi Ren,Dong Gao,Ning Li,Manman Wu,Hongbo Yuan,Mei Zhou,Chengfen Xing
Cancer cells survive by relying on oxidative stress defense against the accumulation of reactive oxygen species (ROS) during tumor formation. ROS-sensitive TRPA1 ion channels are overexpressed in breast cancer cells and induce a large influx of Ca 2+ which upregulates the anti-apoptotic pathway to lead breast cancer cells to produce oxidative stress defense and enhance the resistance to ROS related chemotherapy. Targeting and inhibiting the TRPA1 ion channels are critical for breaking down the oxidative stress defense system and overcoming cellular resistance. Here, near-infrared (NIR) light-responsive conjugated polymer nanoparticles are designed and prepared to promote apoptosis of breast cancer cells, reduce cell drug resistance and suppress tumor growth through the remote and precise regulation of TRPA1 ion channels. Upon 808 nm laser irradiation, the nanoparticles block the formation of Ca 2+ /CaM complex and regulate the content of MCL-1 protein. Especially, the nanoparticles overcome drug resistance of cancer cells, therefore accelerating apoptosis of cancer cells and suppressing tumor growth in mice. Compared with carboplatin, the volume of tumor induced by NPs-H decreases by 54.1%. This work provides a strategy to disrupt the oxidative stress defense system and downregulate the antiapoptotic signaling pathway in cancer cells.
研究领域:
癌症生物学
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纳米技术
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药学
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生物医学工程
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Bioactive Materials
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2024
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IF 18
Chuanlu Lin,Yiqiang Hu,Ze Lin,Longyu Du,Yixin Hu,Lizhi Ouyang,Xudong Xie,Peng Cheng,Jiewen Liao,Li Lu,Ruiyin Zeng,Ping Xia,Zhiyong Hou,Guohui Liu,Hankun Hu
Ferroptosis plays a crucial role in the progression of diabetic wounds, suggesting potential therapeutic strategies to target ferroptosis. Transient receptor potential ankyrin 1 (TRPA1) is a non-selective calcium channel that acts as a receptor for a variety of physical or chemical stimuli. Cinnamaldehyde (CA) is a specific TRPA1 agonist. In in vitro experiments, we observed that high glucose (HG) treatment induced endothelial cell ferroptosis, impairing cell function. CA successfully inhibited endothelial cell ferroptosis, improving migration, proliferation, and tube formation. Further mechanistic studies showed that CA-activated TRPA1-induced Ca 2+ influx promoted the phosphorylation of calmodulin-dependent protein kinase II (CaMKII) and nuclear factor-E 2-related factor 2 (Nrf2) translocation, which contributed to the elevation of glutathione peroxidase 4 (GPX4), leading to the inhibition of endothelial cell ferroptosis. In addition, CA was incorporated into an MMP-9-responsive injectable duplex hybrid hydrogel (CA@HA-Gel), allowing its efficient sustained release into diabetic wounds in an inflammation-responsive manner. The results showed that CA@HA-Gel inhibited wound endothelial cell ferroptosis and significantly promoted diabetic wound healing. In summary, the results presented in this study emphasize the potential therapeutic application of CA@HA-Gel in the treatment of diseases associated with ferroptosis.
研究领域:
药理学
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生物医学工程
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细胞生物学
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伤口愈合
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Translational Pediatrics
·
2025
·Vol. 14
·期 6
·1213
·
IF 1.7
Zihong Shan,Chenghui He,Qingyao Yang,Jingjing Xiong,Meng Li,Mingyao Meng,Yongkun Huang
Background Previous research has indicated that chenodeoxycholic acid (CDCA) plays a significant role in intestinal motility and is implicated in some gastrointestinal (GI) disorders. However, the impact of CDCA on defecation patterns in infants, particularly those who are breastfed, remains unclear. This study explored the relationship between CDCA and defecation frequency in breastfed infants, focusing on the underlying mechanisms. Methods We measured CDCA levels in stool samples of infants with varying defecation frequencies using metabolomics, along with studies to explore the impact of CDCA on murine colonic transit and with in vitro cellular studies to elucidate the underlying physiological mechanisms. Results In our murine model, CDCA treatment increased GI transit distance, enhanced fecal water content, and reduced transit time, without causing significant colonic damage. Additionally, CDCA treatment enhanced 5-hydroxytryptamine (5-HT) secretion and upregulated signaling molecules such as tryptophan hydroxylase 1 (Tph1), G protein-coupled bile acid receptor 1 (TGR5), and transient receptor potential ankyrin 1 (TRPA1). Selective inhibition of these pathways suppressed 5-HT secretion and normalized intestinal motility parameters, confirming their mechanistic role. Moreover, CDCA treatment of rat insulinoma-derived RIN-14B cells also resulted in increased 5-HT secretion. Conclusions These findings reveal that CDCA significantly correlates with defecation frequency in breastfed infants and likely influences intestinal motility through the TGR5/TRPA1-5-HT signaling axis.
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Frontiers in Medicine
·
2024
·
IF 3.1
Zhongzhu Ai,Dongfeng Yuan,Jingyi Cai,Ruotong Dong,Wei Liu,Daonian Zhou
Background: Pruritus ani (PA), a neurofunctional dermatosis, is one of the most common complications of hemorrhoids, which seriously affects the quality of life of patients. Medical hemorrhoid gel (MHG), a product mainly composed of herbal medicine, is widely used for treatment of PA clinically. This study aim to assess the alleviating effect and mechanism of MHG on PA based on rectal epidermis-spinal cord-brain axis using animal models.Methods: A chloroquine-induced mouse itching model and a croton oil preparation-induced rat hemorrhoid model were established to evaluate anti-PA effect of MHG. Scratching behaviors of mice were recorded, and histopathology of mice skin and rat ano-rectal tissues was observed through H&E staining. Network pharmacology and western blotting were employed to explore potential mechanism of MHG.Results: The study indicated that MHG significantly alleviated chloroquine-induced skin itching and improved pathological injuries in mice skin and rat ano-rectal tissues. Network pharmacology suggested that MHG might regulate the JAK/STAT signaling pathway. Experimental findings showed that MHG significantly downregulated TRPV1 and TRPA1 in rectal tissue, c-Fos and GRPR in spinal cord tissue, and 5-HT1a protein in brain tissue, while upregulating TRPM8 protein in rectal tissue. Furthermore, MHG inhibited the activation of the JAK2/STAT3 signaling pathway in the rectal epidermis-spinal cord-brain axis.Conclusion: MHG improves PA by inhibiting the transmission of itching signals in rectal epidermis-spinal cord-brain axis via the JAK2/STAT3 signaling pathway, providing experimental evidence for its clinical application.
研究领域:
药理学
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神经科学
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皮肤病学
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分子生物学
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PHYTOMEDICINE
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2022
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IF 6.656
Di Zhang,Bei Jing,Zhenni Chen,Xin Li,Huimei Shi,Yachun Zheng,Shiquan Chang,Guoping Zhao
Background Nonsteroidal anti-inflammatory drugs are used to relieve sciatica, but their effects are not satisfactory. Purpose This study aimed to explore the therapeutic effects of ferulic acid on sciatica. Methods Thirty-two SD rats were randomly divided into 4 groups, i.e., sham operation group, chronic constriction injury (CCI) group, mecobalamin group, and ferulic acid group. We conducted behavioural tests, ELISA, PCR, Western blots, and immunofluorescence analysis. Specific inhibitors were used in cell experiments to explore the related mechanisms. Results Thermal hyperalgesia was induced after CCI operation, and ferulic acid relieved thermal hyperalgesia. In addition, ferulic acid decreased the IL1β, IL6, TNF-α, and CRP mRNA levels; the IBA-1, iNOS, IL1β, RhoA, RhoA-GTP, COX2, Rock1, TRPV1, TRPA1, and p-p38MAPK levels in dorsal root ganglion (DRG) neurons; and the LPS, CRP, substance P (SP), and prostaglandin E2 (PGE2) levels in serum, and these levels were higher in the CCI group. In the cell experiments, LPS induced M1 polarization of GMI-R1 cells via the RhoA/Rock pathway. Ferulic acid attenuated LPS-induced M1 polarization by decreasing the levels of M1 polarization markers, including IL1β, IL6, TNF-α, iNOS, and CD32, and increased M2 polarization by increasing the levels of M2 polarization markers, including CD206 and Arg-1. LPS treatment clearly increased the iNOS, IL1β, RhoA, Rock1, Rock2 and p-p38 MAPK levels and reduced Arg-1 expression, and ferulic acid reversed these changes. Conclusion Ferulic acid can inhibit peripheral sensitization by reducing the levels of inflammatory factors, TRPA1 and TRPV1 through the RhoA/p38 MAPK pathway to alleviate sciatica.
研究领域:
药理学
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神经科学
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免疫学
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分子生物学
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BioScience Trends
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2026
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IF 5
Fangzhou Dou,Jing Li,Daoran Lu,Yueyi Sun,Shasha Hu,Jianjun Gao
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited treatment options. Transient receptor potential ankyrin 1 (TRPA1) has been implicated in inflammation and pain, but its role in UC remains a subject of debate. The current study investigated the effects of TRPA1 inhibition in both acute and subacute murine models of dextran sulfate sodium (DSS)-induced colitis. Genetic knockout of Trpa1 or pharmacological inhibition with A967079 significantly ameliorated inflammation in the acute model, reducing the disease activity index (DAI), colon shortening, histopathological damage, and TNF-α secretion from macrophages. In contrast, TRPA1 suppression exacerbated subacute colitis and worsened weight loss, DAI, colon shortening, and histopathology. Mechanistically, Trpa1 deletion promoted CD4+ T cell polarization toward the Th1 subtype in subacute colitis, increasing IFN-γ levels. These findings reveal a dual role for TRPA1 in colonic inflammation: it mediates pro-inflammatory effects primarily via innate immune cells in the acute phase but has anti-inflammatory effects by modulating adaptive immunity in the subacute phase. These findings provide new insights into the context-dependent roles of TRPA1 and suggest that TRPA1 may represent a context-specific and stage-dependent therapeutic target in UC.
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NEUROPHARMACOLOGY
·
2025
·
IF 4.6
Liu-Ying Wu,Meng-Nan Zhai,Xue-Qiang Bai,Cheng He,Yun-Ying Guo,Yu-Qi Zhang,Juan Wang,Yong-Tao Gao,Qi-Feng Tu,Mei Liu,Jun-Jie Chen,Zhi-Jun Zhang
Effective treatments for oxaliplatin-induced cold hypersensitivity remain a significant clinical challenge, primarily due to gaps in our understanding of the underlying pathophysiology. Our previous studies have indicated that kinesin-12 (KIF15) is expressed in neurons, suggesting its potential involvement in neurodevelopment and neuronal plasticity. However, its role in mediating chemotherapy-induced pain in primary sensory neurons has not yet been reported. In this study, we found that KIF15-knockout (Kif15-KO) mice showed an increase in cold sensitivity, with this heightened cold hypersensitivity being dependent on the accumulation of the TRP ankyrin 1 (TRPA1) channel on the cell membrane. We further demonstrated that in a model of oxaliplatin-induced peripheral neuropathy (OIPN), KIF15 expression was markedly reduced, coinciding with an increase in TRPA1 membrane localization and a physical interaction between KIF15 and Annexin A2 in peripheral sensory neurons. This suggests a mechanistic link where the loss of KIF15 disrupts the function of Annexin A2, enhancing the localization of TRPA1 on the cell membrane of dorsal root ganglion (DRG) neurons, thereby contributing to cold hypersensitivity. Our results offer a new understanding of the molecular mechanisms underlying chemotherapy-induced cold hypersensitivity, highlighting KIF15 as a key regulator and a potential therapeutic target for conditions like OIPN.
研究领域:
神经生物学
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药理学
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疼痛研究
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Nature Communications
·
2025
·Vol. 16
·期 1
·1-20
·
IF 15.7
Luo Xiaobin,Yang Jia,Zhao Yonggang,Nagayasu Toshitatsu,Chen Junlin,Hu Peilun,He Zhi,Li Zifan,Wu Jun,Zhao Zhe,Duan Guman,Sun Xiaodan,Zhao Lingyun,Pan Yongwei,Wang Xiumei
Chronic allodynia stemming from peripheral stump neuromas can persist for extended periods, significantly compromising patients’ quality of life. Conventional managements for nerve stumps have demonstrated limited effectiveness in ensuring their orderly termination. In this study, we present a spatially confined conduit strategy, designed to enhance the self-organization of regenerating nerves after truncation. This innovative approach elegantly enables the autonomous slowing of axonal outgrowth in response to the gradually constricting space, concurrently suppressing neuroinflammation through YAP-mediated mechanotransduction activation. Meanwhile, the decelerating axons exhibit excellent alignment and remyelination, thereby helping to prevent failure modes in nerve self-organization, such as axonal twisting in congested regions and overgrowth beyond the conduit’s capacity. Additionally, proteins associated with mechanical allodynia, including TRPA1 and CGRP, exhibit a gradual reduction in expression as spatial constraints tighten, a trend inversely validated by the administration of the YAP-targeted inhibitor Verteporfin. This spatially confined conduit strategy significantly alleviates allodynia, thus preventing autotomy behavior and reducing pain-induced gait alterations.
研究领域:
神经科学
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生物医学工程
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疼痛研究
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分子生物学
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
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IF 5.7
Yanan Zhang,Shaoya Rong,Shude Pang,Xiujun Fu,Yunxian Wang,Xuelu Ding,Shuai Liang,Ruihong Guo,Hui Dong
Vascular endothelial dysfunction drives sepsis progression and multi-organ failure. Although TRPA1 and TMEM16A are expressed in the vasculature, their roles in arteriolar vasorelaxation remain unclear. The vasorelaxant effects of TRPA1 and TMEM16A on the second-order branch of mesenteric resistance arteries were investigated in healthy and septic mice using a Mulvany-style wire myograph. Fluorescent Ca 2+ assays were employed to assess cytosolic Ca 2+ ([Ca 2+ ] i ) in vascular endothelial cells (VECs). A mouse sepsis model was constructed through the method of cecal ligation and puncture (CLP). Both TRPA1 and TMEM16A activation induced endothelium-dependent hyperpolarization (EDH)-mediated relaxation via functional coupling: TRPA1 triggered Ca 2+ influx and Ca 2+ -induced Ca 2+ release, amplifying TMEM16A activity. In sepsis, while ACh/EDH responses were impaired, TRPA1/TMEM16A-mediated relaxation remained intact. Channel activation improved septic mouse survival and restored ACh responses, with plasma and assay agonist concentrations in comparable ranges. This study not only elucidates the protective role of endothelial TRPA1 and TMEM16A channels against sepsis-induced vascular inflammation but also provides potential new targets for sepsis therapy.
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