Frontiers in Pharmacology
·
2025
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IF 4.8
Jinpeng Lv,Duo Meng,Huansha Zhang,Wenhui Xu,Xiaohong An,Chuanwei Yin,Kun Zou,Rongyin Gao
Introduction: Apigenin, a natural flavonoid with well-established antioxidant, anticancer, and anti-inflammatory activities, has recently attracted attention for its pigmentation-promoting effects. However, the underlying molecular mechanisms driving its melanogenic activity remain incompletely understood.Method: To investigate apigenin‘s effects on melanogenesis, human epidermal melanocytes (HEMCs), zebrafish embryos, and human skin explants were treated with apigenin. Melanin content, dendrite formation, and melanosome maturation were evaluated using spectrophotometry and transmission electron microscopy. Key signaling molecules and proteins involved in melanogenesis and melanosome transport were assessed by Western blotting and immunohistochemistry. The role of the c-KIT receptor was further explored through pharmacological inhibition and genetic knockdown approaches. Functional pigmentation was evaluated by assessing UVB-induced DNA damage markers.Results: Apigenin (10 μM) significantly increased melanin production by 1.8-fold in HEMCs, enhanced dendritic morphology, and promoted stage III–IV melanosome formation. Mechanistically, apigenin induced melanogenesis independently of the MC1R/cAMP/PKA pathway by directly binding to the c-KIT receptor, activating the Raf-1/ERK/RSK cascade, and upregulating MITF. This led to elevated expression of tyrosinase, TRP-1, TRP-2, and melanosome transport proteins Rab27a and Cdc42. Inhibition or knockdown of c-KIT abrogated these effects. In vivo, apigenin restored pigmentation in PTU-induced depigmented zebrafish and increased melanin content by 1.3-fold in human skin explants. Histological analysis confirmed effective melanin transfer to keratinocytes. Additionally, apigenin-treated skin showed reduced UVB-induced DNA damage, indicating enhanced photoprotection.Discussion: These findings demonstrate that apigenin stimulates melanogenesis through a novel c-KIT-dependent signaling pathway and promotes functional pigmentation with photoprotective benefits. Given its dietary origin, favorable safety profile, and multifaceted mechanisms, apigenin holds promise as a therapeutic agent for vitiligo and a natural pigmentation enhancer for dermatological use.
研究领域:
细胞生物学
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皮肤病学
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药理学
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DOI
PubMed
高影响因子
Human Cell
·
2024
·
IF 3.4
Zhang Ke,Zhang Hailing,Wang Bing,Gao Shanshan,Sun Caiping,Jia Cong,Cui Jinquan
Abnormal functions of trophoblast cells are associated with the pathogenesis of preeclampsia (PE). Nuclear receptor subfamily 2 group F member 1 (NR2F1) acts as a transcriptionally regulator in many diseases, but its role in PE remains unknown. Hypoxia/reoxygenation (H/R)-stimulated HTR-8/SVneo cells were used to mimic PE injury in vitro. NR2F1 overexpression alleviated trophoblast apoptosis, as evidenced by the decreased number of TUNEL-positive cells and the downregulation of caspase 3 and caspase 9 expression in cells. NR2F1 overexpression increased the invasion and migration ability of HTR-8/SVneo cells, accompanied by increased protein levels of matrix metalloproteinase (MMP)-2 and MMP-9. mRNA-seq was applied to explore the underlying mechanism of NR2F1, identifying growth differentiation factor 15 (GDF15) as the possible downstream effector. Dual-luciferase reporter, ChIP-qPCR, and DNA pull-down assays confirmed that NR2F1 bound to the promoter of GDF15 and transcriptionally inhibited its expression. GDF15 overexpression increased apoptosis and decreased the ability of invasion and migration in HTR-8/SVneo cells expressing NR2F1. MAPK pathway was involved in the regulation of PE. Administration of p38 inhibitor, ERK inhibitor, and JNK inhibitor reversed the effect of simultaneous overexpression NR2F1 and GDF15 on trophoblast apoptosis, invasion, and migration. Our findings demonstrated that NR2F1 overexpression inhibited trophoblast apoptosis and promoted trophoblast invasion and migration. NR2F1 might negatively regulate GDF15 expression by binding to its promoter region, which further inhibited MAPK signaling pathway in PE. Our study highlights that NR2F1 might sever as a potential target in PE. Graphical abstract
研究领域:
妇产科学
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分子生物学
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细胞生物学
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转录调控
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信号传导
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DOI
PubMed
高影响因子
Materials Today Bio
·
2025
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IF 10.2
Shaoyin Wei,Dong Yang,Zeyu Shou,Yipiao Zhang,Shengwu Zheng,Xingjie Zan,Lianxin Li,Chunwu Zhang
Defective diabetic wound healing is a major clinical challenge, where hyperglycemia at the wound site induces excessive reactive oxygen species (ROS) which activate the MAPK pathway (particularly p38 MAPK), resulting in sustained release of inflammatory factors and cellular damage/apoptosis. Polyphenols are efficient ROS scavengers which reduce the level of inflammation at the wound site and promote wound healing, but the low bioavailability limits their biomedical application. This study developed a simple and highly efficient method for preparing proanthocyanidin (PC) capsules through hydrogen bonding and hydrophobic interactions among PC molecules. PC capsules can continuously scavenge free radicals and release proanthocyanidins, significantly enhancing their bioavailability. A single dose of PC capsules accelerates wound healing in diabetic mice by regulating the p38 MAPK signaling cascade, reducing inflammatory mediator concentration, inhibiting cell apoptosis, and remodeling the wound microenvironment. This research makes an important contribution to the field of enhancing polyphenol bioavailability for wound healing and reveals the potential of modulating the MAPK pathway for treating other inflammation and oxidative stress-related diseases.
研究领域:
药理学
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伤口愈合
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糖尿病
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炎症
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氧化应激
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信号传导
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DOI
PubMed
高影响因子
Cancers
·
2022
·Vol. 14
·期 9
·2338
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IF 6.575
Chunyuan Tang,Ying Zhou,Wen Sun,Haihong Hu,Yuxi Liu,Lu Chen,Fengting Ou,Su Zeng,Nengming Lin,Lushan Yu
Simple SummaryColorectal cancer (CRC) claimed more than 900,000 lives globally in 2020. Therefore, its pathogenetic landscape calls for in-depth investigation. Recently, more attention has been paid to oncogenesis driven by noncoding RNAs and even peptides encoded by noncoding RNAs. Here, we report aLINC01234-encoded peptide named MEK1-binding oncopeptide (MBOP), which exists endogenously and is highly expressed in CRC. Through in vivo and in vitro migration and proliferation assays, we demonstrated the oncogenic role of MBOP. In addition, we performed immunoprecipitation assays to identify the interacting proteins and pathways, and MBOP was found to interact with MEK1 and activate the MEK1/pERK/MMP2/MMP9 signaling pathway. Moreover, the ubiquitin–protease-system-mediated degradation of MBOP was elucidated, where the E3 ubiquitin-protein transferase MAEA and RMND5A play vital roles. In conclusion, oncopeptide MBOP plays a substantial role in the tumorigenesis of CRC, and it could be a candidate prognostic biomarker for clinical treatment.AbstractColorectal cancer (CRC) ranks third in incidence rate and second in mortality rate of malignancy worldwide, and the diagnosis and therapeutics of it remain to be further studied. With the emergence of noncoding RNAs (ncRNAs) and potential peptides derived from ncRNAs across various biological processes, we here aimed to identify a ncRNA-derived peptide possible for revealing the oncogenesis of CRC. Through combined predictive analysis of the coding potential of a batch of long noncoding RNAs (lncRNAs), the existence of an 85 amino-acid-peptide, named MEK1-binding oncopeptide (MBOP) and encoded fromLINC01234was confirmed. Mass spectrometry and Western blot assays indicated the overexpression of MBOP in CRC tissues and cell lines compared to adjacent noncancerous tissues and the normal colonic epithelial cell line. In vivo and in vitro migration and proliferation assays defined MBOP as an oncogenic peptide. Immunoprecipitation trials showed that MEK1 was the key interacting protein of MBOP, and MBOP promoted the MEK1/pERK/MMP2/MMP9 axis in CRC. Two E3-ligase enzymes MAEA and RMND5A mediated the ubiquitin–protease-system-related degradation of MBOP. This study indicates that MBOP might be a candidate prognostic indicator and a potential target for clinical therapy of CRC.Keywords:peptide;MBOP;LncRNA;colorectal cancer;MAPK signaling pathway
研究领域:
肿瘤学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
Cell Death & Disease
·
2023
·Vol. 14
·期 6
·1-12
·
IF 9
Yang Long,Huang Wen,Bai Xiaoyu,Wang Haoyu,Wang Xiaolei,Xiao Huiyuan,Li Yanlei
The incidence of bladder cancer (BLCA) in men is higher than that in women. Differences in androgen levels between men and women are considered the main causes of incidence rate differences. In this study, dihydrotestosterone (DHT) significantly increased the proliferation and invasion of BLCA cells. In addition, BLCA formation and metastatic rates were higher in N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-treated male mice than in female and castrated male mice in vivo. However, immunohistochemistry showed that androgen receptor (AR) was expressed at low levels in normal and BLCA tissues of men and women. The classical AR pathway considers that DHT binds to AR and induces it to enter the nucleus, where it functions as a transcription factor. Here, a non-AR combination pathway of androgen that promoted BLCA development was investigated. The EPPK1 protein was bombarded with DHT, as determined by biotinylated DHT-binding pull-down experiments. EPPK1 was highly expressed in BLCA tissues, and EPPK1 knockdown significantly inhibited BLCA cell proliferation and invasion promoted by DHT. Moreover, JUP expression was elevated in DHT-treated high-EPPK1 expressing cells, and JUP knockdown inhibited cell proliferation and invasion. EPPK1 overexpression increased tumour growth and JUP expression in nude mice. Furthermore, DHT increased the expression of the MAPK signals p38, p-p38, and c-Jun, and c-Jun could bind to the JUP promoter. However, the promotion of p38, p-p38, and c-Jun expression by DHT was not observed in EPPK1 knockdown cells, and a p38 inhibitor suppressed the DHT-induced effects, indicating that p38 MAPK may be involved in the regulation of DHT-dependent EPPK1-JUP-promoted BLCA cell proliferation and invasion. The growth of bladder tumours in BBN-treated mice was inhibited by the addition of the hormone inhibitor goserelin. Our findings indicated the potential oncogenic role and mechanism of DHT in BLCA pathogenesis through a non-AR pathway, which may serve as a novel therapeutic target for BLCA.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Chen Wu,Zhongyun Zhang,Lijie Bai,Shuhui Lei,Min Zou,Zilu Bao,Zhaoxiang Ren,Kaiqun Liu,Hui-Hong Gong,Wenjun Ma,Lvyi Chen
Ethnopharmacological relevance Gout, a painful joint disease with a prevalence ranging from 0.86% to 2.2% in China over the past decade. Traditional medicine has long utilized the medicinal and edible Piper longum L. (PL) fruit spikes for treating gout and other joint conditions like rheumatoid arthritis. However, the exact mechanisms behind its effectiveness remain unclear. Aim of the study This study aimed to investigate the potential of alcoholic extracts from PL fruit spikes as a safe and effective treatment for gout. We used a combined network pharmacology and experimental validation approach to evaluate the mechanisms behind the anti-gout properties of PL. Materials and methods UPLC-Q/TOF-MS analysis determined the major components of PL. Subsequently, network pharmacology analysis predicted potential molecular targets and related signaling pathways for the anti-gout activity of PL. Molecular docking simulations further explored the interactions between PL compounds and proteins and characterized the properties of potential bioactive secondary metabolites. Mouse models of air pouch inflammation and hyperuricemia were further established, and the anti-gout mechanism of PL was confirmed by examining the expression of proteins related to the MAPK and PI3K-AKT pathways in the tissue. Results Our analysis revealed 220 bioactive secondary metabolites within PL extracts. Network pharmacology and molecular docking results indicated that these metabolites primarily combat gout by modulating the PI3K-AKT and MAPK signaling pathways. In vivo experiments have also proven that PL at a dose of 100 mg/kg can optimally reduce acute inflammation of gout and kidney damage caused by high uric acid. The anti-gout mechanism involves the PI3K-AKT/MAPK signaling pathway and its downstream NF-κB pathway. Conclusion This study provides compelling evidence for PL's therapeutic potential in gout management by modulating key inflammatory pathways. The findings offer a strong foundation for future clinical exploration of PL as a gout treatment option.
研究领域:
药理学
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民族药理学
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分子生物学
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炎症研究
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传统医学
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
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2022
·Vol. 37
·期 2
·578-591
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IF 6.388
Na Yang,Chunpeng Zou,Wu Luo,Diyun Xu,Mengyang Wang,Yi Wang,Gaojun Wu,Peiren Shan,Guang Liang
Chronic inflammation plays an important role in hypertensive heart failure. Suppressing angiotensin II (Ang II)-induced cardiac inflammation may contribute to the treatment of hypertension-associated heart failure. Sclareol, a natural product initially isolated from the leaves and flowers of Salvia sclarea , possesses antiinflammatory and immune-regulation activity in various systems. However, its effect on Ang II-induced cardiac remodeling remains unknown. In this study, we have explored the potential effects of sclareol on Ang II-induced heart failure. In vivo experiments were conducted in mice with Ang II-pump infusion for 28 days. Sclareol administration at 5 mg·kg −1 ·d −1 significantly reduced the expression of myocardial injury markers. Sclareol also exerts protective effects against Ang II-induced cardiac dysfunction in mice which is associated with alleviated cardiac inflammation and fibrosis. Transcriptome analysis revealed that inhibition of the Ang II-activated mitogen-activated protein kinase (MAPK) pathway contributed to the protective effect of sclareol. Sclareol inhibits Ang II-activated MAPKs pathway to reduce inflammatory response in mouse hearts and cultured cardiomyocytes. Blockage of MAPKs in cardiomyocytes abolished the antiinflammatory effects of sclareol. In conclusion, we show that sclareol protects hearts against Ang II-induced injuries through inhibiting MAPK-mediated inflammation, indicating the potential use of sclareol in the prevention of hypertensive heart failure.
研究领域:
心脏病学
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药理学
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分子生物学
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炎症研究
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产品关联
DOI
PubMed
高影响因子
Journal of Hard Tissue Biology
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2023
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IF 0.4
Wanjun Xu,Yina Wang
Dental pulp stem cells (DPSCs) invoke wide interest due to their roles in in dentin regeneration and repair, and more research is required to illustrate the molecular basis. In this study, we induced osteogenic differentiation in human DPSCs to investigate the role of interferon-induced transmembrane (IFITM) family in osteogenic differentiation. Our results demonstrated that genes of the IFITM family, IFITM1, IFITM3, and IFITM5 were upregulated during the osteogenic differentiation of DPSCs. Loss-of-function and gain-of-function assays indicated that IFITM3 knockdown suppressed osteogenic differentiation, assessed by the reduction of alkaline phosphatase (ALP) activity, nodule mineralization, and the expressions of several osteogenic differentiation-associated genes; in contrast, IFITM3 overexpression increased ALP activity, nodule mineralization, and the expressions of osteogenic differentiation-associated genes. Further investigation revealed that IFITM3 was involved in the regulation of mitogen-activated protein kinase (MAPK) signaling during osteogenic differentiation, and pharmacological inhibition of both ERK and p38 suppressed the effects of IFITM3 overexpression in osteogenic differentiation. These results suggest that IFITM3 promotes osteogenic differentiation of DPSCs by regulating MAPK signaling. Our findings enhance the existing knowledge on the role of IFITM family in osteogenic differentiation and the molecular basis of IFITM3.
研究领域:
干细胞生物学
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分子生物学
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牙科再生医学
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DOI
高影响因子
Antioxidants
·
2021
·Vol. 10
·期 12
·2019
·
IF 6.313
Zebin Huang,Lingna Xie,Yongyu Xu,Kai Zhao,Xuetong Li,Jiaben Zhong,Yujing Lu,Xuetao Xu,Susan Goodin,Kun Zhang,Lanyue Zhang,Chunlian Li,Xi Zheng
Zingiber striolatumDiels (Z. striolatum), a widely popular vegetable in China, is famous for its medicinal and nutritional values. However, the anti-inflammatory effects of essential oil fromZ. striolatum(EOZS) remain unclear. In this study, EOZS from seven regions in China were extracted and analyzed by GC–MS. LPS-induced RAW264.7 cells and 12-O-Tetradecanoylphorbol 13-acetate (TPA)-stimulated mice were used to evaluate the anti-inflammatory effects of EOZS. Results show that 116 compounds were identified in EOZS from seven locations. Samples 2, 4 and 5 showed the best capability on DPPH radical scavenging and NO inhibition. They also significantly reduced the production of ROS, pro-inflammatory cytokines, macrophage morphological changes, migration and phagocytic capability. Transcriptomics revealed MAPK and NF-κB signaling pathways may be involved in the anti-inflammatory mechanism, and the predictions were proven by Western blotting. In TPA-induced mice, EOZS reduced the degree of ear swelling and local immune cell infiltration by blocking the activation of MAPK and NF-κB signaling pathways, which was consistent with the in vitro experimental results. Our research unveils the antioxidant capability and potential molecular mechanism of EOZS in regulating inflammatory response, and suggests the application of EOZS as a natural antioxidant and anti-inflammatory agent in the pharmaceutical and functional food industries.Keywords:Zingiber striolatumDiels;essential oil;oxidant stress;anti-inflammatory activity;MAPK;NF-κB
研究领域:
药理学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
Cell Reports
·
2025
·
IF 6.9
Zaoqu Liu,Yuhao Ba,Dan Shan,Xing Zhou,Anning Zuo,Yuyuan Zhang,Hui Xu,Shutong Liu,Benyu Liu,Yanan Zhao,Siyuan Weng,Ruizhi Wang,Jinhai Deng,Peng Luo,Quan Cheng,Xin Hu,Shuaixi Yang,Fubing Wang,Xinwei Han
Cancer-associated fibroblasts (CAFs) display significant functional and molecular heterogeneity within the tumor microenvironment, playing diverse roles in cancer progression. Employing single-cell RNA sequencing data of colorectal cancer (CRC), we identified a subset of matrix CAFs (mCAFs) as a critical subtype that secretes THBS2, a molecule linked to advanced cancer stages and poor prognosis. Spatial transcriptomics and multiplex immunohistochemistry revealed clear spatial colocalization between THBS2-producing mCAFs and tumor cells. Mechanically, CAF-secreted THBS2 binds to CD47 on tumor cells, triggering the MAPK/ERK5 signaling pathway, which enhances tumor progression. The tumor-promoting role of THBS2 was further validated using fibroblast-specific THBS2 knockout mice, patient-derived organoids, and xenografts. Moreover, the transcription factor CREB3L1 was identified as a regulator of the transformation of normal fibroblasts into THBS2-producing mCAFs. These findings underscore the pivotal role of THBS2 in CRC progression and highlight the therapeutic potential of targeting the THBS2-CD47 axis and CREB3L1 in CRC.
研究领域:
肿瘤学
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分子生物学
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医学
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DOI
PubMed
高影响因子
ORAL DISEASES
·
2023
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IF 3.8
Jiaxin Lv,Qiaona Wang,Dongyu Liu,Catherine Huihan Chu,Heyang Zhou,Guoqing Li,Jin Wu,Kunzhan Cai,Chunbo Tang
Objectives Diabetes mellitus (DM) induces oxidative tissue impairment and suppresses bone formation. Some studies have shown that phytic acid has antioxidant and anti-diabetic properties. This study aimed to investigate the potential of calcium phytate (Ca-phytate) to reverse inhibited osteogenesis of human bone marrow mesenchymal stem cells (hBMSCs) in a high glucose (HG) environment and to determine the underlying mechanism. Materials and Methods hBMSCs were exposed to HG and palmitic acid to simulate DM in vitro. Osteogenic differentiation was measured using alkaline phosphatase staining and activity assay, alizarin red S staining, qRT-PCR, Western blot and immunofluorescence staining. A critical-size cranial defect model of type 2 diabetes mellitus (T2DM) rats was established to evaluate bone regeneration. A specific pathway inhibitor was used to explore whether the MAPK/JNK pathway was involved. Results Treatment with 34 μM Ca-phytate had the highest effect on osteogenic differentiation in HG. Ca-phytate improved cranial bone defect healing in T2DM rats. The long-term HG environment inhibited the activation of the MAPK/JNK signalling pathway, which was restored by Ca-phytate. Blocking the JNK pathway reduced the Ca-phytate-mediated osteogenic differentiation of hBMSCs. Conclusion Ca-phytate induced bone regeneration in vivo and reversed HG-inhibited osteogenesis of hBMSCs in vitro via the MAPK/JNK signalling pathway.
研究领域:
医学
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细胞生物学
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内分泌学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Yancen Li,Chengyu Wan,Fan Li,Guang Xin,Tao Wang,Qilong Zhou,Tingyu Wen,Shiyi Li,Xiaoting Chen,Wen Huang
Background: Isatidis Folium, a botanical drug widely used in traditional medicine, is known for its anti-inflammatory properties, including heat-clearing, detoxifying, and blood-cooling effects. Although its potential in sepsis treatment has been suggested, the bioactive metabolites and underlying mechanisms remain poorly understood.Methods: Network pharmacology and molecular docking were employed to identify the therapeutic effects and mechanisms of Indirubin, the major bioactive metabolite of Isatidis Folium, in sepsis treatment. In vivo, a cecal ligation and puncture (CLP)-induced mouse sepsis model was used to evaluate the protective effects of Indirubin through histopathological analysis, ELISA, and biochemical assays. In vitro, RAW264.7 cells were stimulated with LPS and treated with varying concentrations of Indirubin. The anti-inflammatory effects of Indirubin were assessed using ELISA, apoptosis assays, and Western blotting.Results: Network pharmacology analysis identified Indirubin as the major bioactive metabolite of Isatidis Folium and EGFR and SRC as its key molecular targets. Experimental validation demonstrated that Indirubin significantly improved survival rates, alleviated tissue injury, and suppressed inflammatory responses in sepsis models. Mechanistically, Indirubin inhibited LPS-induced activation of the EGFR/SRC/PI3K and NF-κB/MAPK pathways in macrophages, significantly reducing cell death and inflammation in RAW264.7 cells.Conclusion: Indirubin, the primary bioactive metabolite of Isatidis Folium, exerts protective effects against sepsis by targeting the EGFR/SRC/PI3K and NF-κB/MAPK signaling pathways in macrophages. These findings provide a mechanistic basis for the development of Indirubin as a multi-target therapeutic agent for sepsis treatment.
研究领域:
药理学
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免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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