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
·
神经科学
·
皮肤病学
·
分子生物学
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DOI
PubMed
高影响因子
NEUROSCIENCE
·
2024
·
IF 2.9
Xuxing Pei,Bing Li,Xiaodong Xu,Hui Zhang
Patients receiving neuraxial treatment with morphine for pain relief often experience a distressing pruritus. Neuroinflammation-mediated plasticity of sensory synapses in the spinal cord is critical for the development of pain and itch. Caspase-6, as an intracellular cysteine protease, is capable of inducing central nociceptive sensitization through regulating synaptic transmission and plasticity. Given the tight interaction between protein kinase Mζ (PKMζ) and excitatory synaptic plasticity, this pre-clinical study investigates whether caspase-6 contributes to morphine-induced itch and chronic itch via PKMζ. Intrathecal morphine and contact dermatitis were used to cause pruritus in mice. Morphine antinociception, itch-induced scratching behaviors, spinal activity of caspase-6, and phosphorylation of PKMζ and ERK were examined. Caspase-6 inhibitor Z-VEID-FMK, exogenous caspase-6 and PKMζ inhibitor ZIP were utilized to reveal the mechanisms and prevention of itch. Herein, we report that morphine induces significant scratching behaviors, which is accompanied by an increase in spinal caspase-6 cleavage and PKMζ phosphorylation (but not expression). Intrathecal injection of Z-VEID-FMK drastically reduces morphine-induced scratch bouts and spinal phosphorylation of PKMζ, without abolishing morphine analgesia. Moreover, intrathecal strategies of ZIP dose-dependently reduce morphine-induced itch-like behaviors. Spinal phosphorylation of ERK following neuraxial morphine is down-regulated by ZIP therapy. Recombinant caspase-6 directly exhibits scratching behaviors and spinal phosphorylation of ERK, which is compensated by PKMζ inhibition. Also, spinal inhibition of caspase-6 and PKMζ reduces the generation and maintenance of dermatitis-induced chronic itch. Together, these findings demonstrate that spinal caspase-6 modulation of PKMζ phosphorylation is important in the development of morphine-induced itch and dermatitis-induced itch in mice.
研究领域:
神经科学
·
疼痛管理
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药理学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Gut Microbes
·
2025
·
IF 11
Tong Jin,Si-Yuan Li,Hong-Li Zheng,Xiao-Dan Liu,Yue Huang,Gan Ma,Ya-Xuan Zhao,Xiao-Tian Zhao,Li Yang,Qi-Hui Wang,Hong-Jun Wang,Chengyong Gu,Zhiqiang Pan,Fuqing Lin
The gut microbiota has been linked to a number of neurological disorders. However, it is unclear whether the gut microbiota is involved in the genesis of chronic itch, a refractory condition that afflicts patients both physically and mentally. Here, we report that depletion of gut microbiota enhances tolerance to itch in mice orally administered with antibiotics (ABX) and mice free of germ. Of note, oral gavage with Bacteroides fragilis (B. fragilis), a prominent species of the genus Bacteroides with most differential change, corrected the ABX-induced itch dysfunction through its driven metabolite acetyl-l-carnitine (ALC). Mechanistically, gut microbiota or B. fragilis depletion caused a decrease in RNA N6-methyladenosine (m6A) demethylase FTO expression in the dorsal horn and a consequent increase in RNA m6A sites in Mas-related G protein-coupled receptor F (MrgprF) mRNA, leading to decreased MRGPRF protein. The downregulation of FTO was triggered by inactivation of ETS proto-oncogene 1 (ETS1), a transcription factor that binds to the Fto promoter. These findings support a gut microbe – spinal connection in modulation of itch sensation in RNA m6A epigenetic-dependent manner and highlight a critical role of ALC in linking the altered B. fragilis and itch dysfunction.
研究领域:
神经科学
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微生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2019
·Vol. 44
·期 3
·835-846
·
IF 2.928
Bao‑Wen Liu,Zhi‑Xiao Li,Zhi‑Gang He,Qian Wang,Cheng Liu,Xian‑Wei Zhang,Hui Yang,Hong‑Bing Xiang
In this study, we focused on several itch‑related molecules and receptors in the spinal cord with the goal of clarifying the specific mediators that regulate itch sensation. We investigated the involvement of serotonin receptors, opioid receptors, glia cell markers and chemokines (ligands and receptors) in models of acetone/ether/water (AEW)‑ and diphenylcyclopropenone (DCP)‑induced chronic itch. Using reverse transcription‑quantitative polymerase chain reaction, we examined the expression profiles of these mediators in the lower cervical spinal cord (C5‑8) of two models of chronic itch. We found that the gene expression levels of opioid receptor mu 1 (Oprm1), 5‑hydroxytryptamine receptor 1A (Htr1a) and 5‑hydroxytryptamine receptor 6 (Htr6) were upregulated. Among the chemokines, the expression levels of C‑C motif chemokine ligand (Ccl)21, Cxcl3 and Cxcl16 and their receptors, Ccr7, Cxcr2 and Cxcr6, were simultaneously upregulated in the spinal cords of the mice in both models of chronic itch. By contrast, the expression levels of Ccl2, Ccl3, Ccl4 and Ccl22 were downregulated. These findings indicate that multiple mediators, such as chemokines in the spinal cord, are altered and may be central candidates in further research into the mechanisms involved in the development of chronic itch.
研究领域:
神经生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Yuanyuan Ding,Tianyou Ma,Yonghui Zhang,Chenrui Zhao,Chao Wang,Zhao Wang
Background Allergic contact dermatitis (ACD) is one of the most common dermatoses, which has high disease burden and quality of life impairment. Anti-histamine is not effective in a part of the ACD patients. Thus, the discovery of novel antipruritic therapy is of highly demand. Objective In this study, we investigated the anti-pruritic effects of rosmarinic acid (RA) and explored the underlying mechanism. Method SPF Balb/c mice were randomly divided into control group, ACD model group, RA group (1.0 mg/kg) and loratadine (LORA) group (1.5 mg/kg). Back epidermal thickness was recorded. H&E staining was used for pathological observation. Mast cell degranulation was assessed by toluidine blue staining. ELISA assay was employed to detect cytokines levels. Cortistatin-14 (CST-14) and Mas-related G protein-coupled receptor X2 (MRGPRX2) expression was detetcted by RT-PCR and western blot. Molecular docking assay was used to predict the affinity of RA and MRGPRX2. Surface plasmon resonance (SPR) assay was used to verify structure affinity of RA and MRGPRX2. Results RA treatment significantly decreased epidermal keratinization and inflammatory cell infiltration in ACD mouse model. Administration of RA significantly reduced secretion of histamine, IL-13, and mRNA expression of CST-14. Furthermore, RA treatment increased mRNA expression of MRGPRX2. In addition, Molecular docking results predict that RA has a good affinity with MRGPRX2. RA displayed a structure affinity ( K D = 8.89 × 10 -4 ) with MRGPRX2 by SPR. RA inhibited CST-14 and Compound 48/80 (C48/80)-induced mast cell activation via MRGPRX2-PLCγ1-PKC-NF-κB signaling pathway. Conclusion RA exhibits anti-pruritic and anti-inflammatory effects in ACD mice by inhibiting MRGPRX2-PLCγ1-PKC-NF-κB signaling pathway. RA might emerge as a potential drug for the treatment of pruritus and skin inflammation in the setting of ACD.
研究领域:
皮肤科
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免疫学
·
药理学
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产品关联
DOI
PubMed
高影响因子
Neuroscience Bulletin
·
2017
·Vol. 34
·期 1
·54-63
·
IF 2.624
Jing Peng-Bo,Cao De-Li,Li Si-Si,Zhu Meixuan,Bai Xue-Qiang,Wu Xiao-Bo,Gao Yong-Jing
Recent studies have shown that the chemokine receptor CXCR3 and its ligand CXCL10 in the dorsal root ganglion mediate itch in experimental allergic contact dermatitis (ACD). CXCR3 in the spinal cord also contributes to the maintenance of neuropathic pain. However, whether spinal CXCR3 is involved in acute or chronic itch remains unclear. Here, we report that Cxcr3
−/− mice showed normal scratching in acute itch models but reduced scratching in chronic itch models of dry skin and ACD. In contrast, both formalin-induced acute pain and complete Freund’s adjuvant-induced chronic inflammatory pain were reduced in Cxcr3
−/− mice. In addition, the expression of CXCR3 and CXCL10 was increased in the spinal cord in the dry skin model induced by acetone and diethyl ether followed by water (AEW). Intrathecal injection of a CXCR3 antagonist alleviated AEW-induced itch. Furthermore, touch-elicited itch (alloknesis) after compound 48/80 or AEW treatment was suppressed in Cxcr3
−/− mice. Finally, AEW-induced astrocyte activation was inhibited in Cxcr3
−/− mice. Taken together, these data suggest that spinal CXCR3 mediates chronic itch and alloknesis, and targeting CXCR3 may provide effective treatment for chronic pruritus.
研究领域:
神经科学
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免疫学
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疼痛研究
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皮肤科
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产品关联
DOI
PubMed
高影响因子
Journal of Inflammation Research
·
2022
·
IF 4.631
Fan Ye,Yucui Jiang,Jian Zhang,Yingxin Zong,Mei Yu,Cuihua Chen,Chan Zhu,Yan Yang,Keke Jia,Gongxi Chen,Zongxiang Tang
Background Senecio scandens Buch.-Ham (S. scandens) belongs to the Compositae family. As a Traditional Chinese medicine, S. scandens has been used in China to treat conjunctivitis, mastitis and vaginitis, it also has the function of antibacterial and relieving itching.Methods Water extract of S. scandens (WSS) was prepared and its quality was controlled by HPLC. The antipruritic effects of WSS were evaluated by itch behavioral experiments. The oxazolone and compound 48/80 were induced to mice scratch behavior, scratch was recorded 30 min after sensitization. The relationship between the antipruritic mechanism and MrgprB2 on mast cell was studied by using mast cell-deficient Kit (W-sh) “Sash” mice and MrgprB2−/− mice. The mast cells were observed by toluidine blue staining. In vitro, the effects of WSS on MrgprB2 were studied by calcium imaging; The whole-cell patch clamp method recorded the MrgprB2 mediate voltage-dependent currents in mast cells.Results The content of rutin (0.012%) and hyperin (0.014%) in the WSS were determined. WSS could ameliorate the pruritus induced by Oxazolone (inhibition was 41.19%, p = 0.004) and compound 48/80 (inhibition was 50.29%, p = 0.001). Meanwhile, WSS could reduce the number of mast cells in mice skin tissue with allergic contact dermatitis (ACD) (p = 0.002) or compound 48/80 (p = 0.013). In addition, WSS could inhibit the calcium influx (1 mg/mL: p = 0.001, 3 mg/mL: p < 0.0001) and the voltage-dependent currents induced by activation of MrgprB2 on mast cell. WSS also attenuated the calcium influx induced by compound 48/80 in HEK293 cells overexpressing MrgprB2/X2.Conclusion These results showed that WSS could ameliorate pruritus by inhibiting MrgprB2 receptor on mast cells.
研究领域:
药理学
·
免疫学
·
中药学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Medicine
·
2021
·
IF 5.093
Li Yujuan,Zhang Wencui,Sun Tainning,Liu Baowen,Manyande Anne,Xu Weiguo,Xiang Hong-Bing
The high incidence of patients with chronic itch highlights the importance of fundamental research. Recent advances in the interface of gut microbiota have shed new light into exploring this phenomenon. However, it is unknown whether gut microbiota plays a role in chronic itch in rodents with or without cognitive dysfunction. In this study, the role of gut microbiota in diphenylcyclopropenone (DCP)-evoked chronic itch was investigated in mice and hierarchical cluster analysis of novel object recognition test (ORT) results were used to classify DCP-evoked itch model in mice with or without cognitive dysfunction (CD)-like phenotype and 16S ribosomal RNA (rRNA) gene sequencing was used to compare gut bacterial composition between CD (Susceptible) and Non-CD phenotypes (Unsusceptible) in chronic itch mice. Results showed that the microbiota composition was significantly altered by DCP-evoked chronic itch and chronic itch induced novel object recognition-related CD. However, abnormal gut microbiota composition induced by chronic itch may not be correlated with novel object recognition-related CD.
研究领域:
神经科学
·
微生物学
·
行为科学
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产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2025
·
IF 6.9
Kangtai Xu,Xuefei Liu,Qian Zeng,Yaqi Liu,Leyan Shan,Luyao Ji,Yifei Wu,Jiawei Wu,Yiming Chen,Yitong Li,Songqiang Huang,Changyu Jiang,Xin Hong,Chaoran Wu,Zilong Wang
Chronic itch is a devastating clinical condition, and its central mechanisms remain poorly understood. We reported that spinal cannabinoid receptor type 2 (CB 2 R) activation exerts antipruritic effects and that itch escalates in mice lacking Cnr2 in mouse models of dermatitis and psoriasis. In the spinal cord, CB 2 R is mainly expressed in microglia, and microglial ablation or inhibition attenuated chronic itch, suggesting that microglial activation contributes to chronic itch. Particularly, conditional Cnr2 deletion in microglia also exacerbated chronic itch in mice. Single-cell RNA sequencing and molecular mechanistic studies suggest that CB 2 R activation reprogrammed microglia by inducing anti-inflammatory suppressor of cytokine signaling 3 (SOCS3) and reducing itch-related p38 and signal transducer and activator of transcription 1 (STAT1) phosphorylation. Finally, CB 2 R activation suppressed neuronal excitability and synaptic transmission in gastrin-releasing peptide (GRP)/GRP receptor (GRPR) interneurons and ascending projection neurons by inhibiting microglia-derived cytokines. These findings demonstrate that microglial activation contributes to chronic itch, while CB 2 R activation in microglia alleviates chronic itch via neuro-immune interactions.
研究领域:
神经科学
·
免疫学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Chinese Herbal Medicines
·
2024
·
IF 4.7
Shuang He,Xiaoling Liang,Weixiong Chen,Yangji Nima,Yi Li,Zihui Gu,Siyue Lai,Fei Zhong,Caixiong Qiu,Yuying Mo,Jiajun Tang,Guanyi Wu
Objective This study aims to elucidate the therapeutic potential of osthole for the treatment of atopic dermatitis (AD), focusing on its ability to alleviate chronic pruritus (CP) and the underlying molecular mechanisms. Methods In this study, we investigated the anti-inflammatory effects of osthole in both a 2,4-dichloronitrobenzene (DNCB)-induced AD mouse model and tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) stimulated human immortalized epidermal (HaCaT) cells. The anti-itch effect of osthole was specifically assessed in the AD mouse model. Using methods such as hematoxylin and eosin (HE) staining, enzyme-linked immunosorbent assay (ELISA), western blot (WB), quantitative real-time PCR (qRT-PCR), and immunofluorescence staining. Results Osthole improved skin damage and clinical dermatitis scores, reduced scratching bouts, and decreased epidermal thickness in AD-like mice. It also reduced the levels of interleukin (IL)-31 and IL-31 receptor A (IL-31 RA) in both skin tissues and HaCaT cells. Furthermore, Osthole suppressed the protein expression levels of phosphor-p65 (p-p65) and phosphor-inhibitor of nuclear factor kappa-Bα (p-IκBα). Meanwhile, it increased the protein expression levels of peroxisome proliferator-activated receptor α (PPARα) and PPARγ in HaCaT cells. Conclusion These findings indicated that osthole effectively inhibited CP in AD by activating PPARα, PPARγ, repressing the NF-κB signaling pathway, as well as the expression of IL-31 and IL-31 RA.
研究领域:
药理学
·
免疫学
·
皮肤病学
✓ 已验证
DOI
高影响因子
Scientific Reports
·
2023
·Vol. 13
·期 1
·1-13
·
IF 4.6
Xu Rui-Qi,Ma Ling,Chen Timson,Zhang Wei-Xiong,Chang Kuan,Wang Jing
Biosurfactants are attracting much interest due to their potential application as therapeutic agents in the medical and cosmetic field. Previous studies have demonstrated that biosurfactant such as sophorolipid (SL) exhibits immunomodulatory effects. In this article, we found the potential of sophorolipid for inhibiting histamine-induced itch and preliminarily explored its molecular basis. First, behavioral tests indicated that SL can remit the histamine-induced scratching behaviors of mice. Second, SL can suppress the the calcium influx induced by histamine, HTMT and VUF8430 in HaCaT cells. RT-PCR analysis showed that the histamine-induced upregulation of mRNA levels of phospholipase Cγ1, 1,4,5-trisphosphate receptor (IP3R), and protein kinase Cα can be inhibted by SL, suggesting that SL may impede the PLC/IP3R signaling pathway activated by histamine. In further tests, the capsaicin-induced calcium influx can also be inhibited by SL. The immunofluorescence and molecular docking analysis indicated that SL acts as an inhibitor of transient receptor potential vanilloid-1 (TRPV1) activation to decrease calcium influx against stimuli. In summary, these results revealed that SL may inhibit histamine-induced itch by decreasing PLC/IP3R signaling pathway activation and modulating TRPV1 activity. This paper indicates that SL can be a useful treatment for histamine-dependent itch.
研究领域:
药理学
·
皮肤病学
·
分子生物学
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EMBO REPORTS
·
2023
·
IF 7.7
Zhi-Jun Zhang,Han-Yu Shao,Chuan Liu,Hao-Lin Song,Xiao-Bo Wu,De-Li Cao,Meixuan Zhu,Yuan-Yuan Fu,Juan Wang,Yong-Jing Gao
A11 dopaminergic neurons regulate somatosensory transduction by projecting from the diencephalon to the spinal cord, but the function of this descending projection in itch remained elusive. Here, we report that dopaminergic projection neurons from the A11 nucleus to the spinal dorsal horn (dopaminergicA11-SDH) are activated by pruritogens. Inhibition of these neurons alleviates itch-induced scratching behaviors. Furthermore, chemogenetic inhibition of spinal dopamine receptor D1-expressing (DRD1+) neurons decreases acute or chronic itch-induced scratching. Mechanistically, spinal DRD1+ neurons are excitatory and mostly co-localize with gastrin-releasing peptide (GRP), an endogenous neuropeptide for itch. In addition, DRD1+ neurons form synapses with GRP receptor-expressing (GRPR+) neurons and activate these neurons via AMPA receptor (AMPAR). Finally, spontaneous itch and enhanced acute itch induced by activating spinal DRD1+ neurons are relieved by antagonists against AMPAR and GRPR. Thus, the descending dopaminergic pathway facilitates spinal itch transmission via activating DRD1+ neurons and releasing glutamate and GRP, which directly augments GRPR signaling. Interruption of this descending pathway may be used to treat chronic itch.
研究领域:
神经科学
·
药理学
·
疼痛研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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