MOLECULES
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2026
·Vol. 31
·期 6
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IF 5.1
Leyuan Huang,Xu Zhou,Guanfeng He,Haixin Li,Xiaoying Chen,Jingwen Xu,Lei Zhou
Magnolia officinalisRehder & E.H.Wilson. bark is famous as a traditional herbal medicine used in prescriptions for treating gastrointestinal discomfort, respiratory and inflammatory disorders. Magnolol, one of its principal bioactive constituents, exhibits potent anti-inflammatory and immunomodulatory properties. However, its therapeutic mechanisms in allergic rhinitis (AR) remain to be elucidated. In this study, the anti-allergic effects and molecular mechanisms ofM.officinalisbark aqueous extract (MOAE) and magnolol were investigated using an ovalbumin (OVA)-induced AR mouse model. Nasal symptoms, histopathological alterations, and serum inflammatory mediators, including histamine and immunoglobulins (IgE, IgG1, IgG2a), were evaluated to assess efficacy. Both MOAE and magnolol significantly alleviated nasal rubbing and sneezing, reduced eosinophil infiltration and mucus hypersecretion, and improved tissue morphology in nasal and lung sections. Moreover, treatment markedly decreased serum levels of histamine and OVA-specific antibodies. Integrative network pharmacology, RNA sequencing, and molecular docking analyses revealed 33 co-regulated target genes mainly involved in the NF-κB and MAPK signaling pathways, suggesting that modulation of these pathways underlies the observed anti-inflammatory effects. These findings demonstrate that MOAE and magnolol exert protective effects against AR through the regulation of key inflammatory signaling cascades. This study provides modern pharmacological evidence supporting the traditional use ofM.officinalisbark and highlights its potential as a natural therapeutic candidate for AR.
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Yuan Yin,Panyang Gu,Hanyu Jiang,Yumei Yang,Shujun Wang,Fei Yuan,Wenrui Zhong,Miao Chen,Meichun Deng
The widespread use of plastic products has led to a serious environmental problem, with nanoplastics ubiquitously contaminating the environment and sustaining human exposure, yet the impacts of nanoplastics on human health remain poorly understood. In this study, based on preliminary epidemiological investigations, we found that abnormal pain perception exists in populations chronically exposed to manufacturing environments that mainly produce polystyrene plastics. Further mechanistic studies demonstrated that high-dose polystyrene nanoparticles (PS NPs) induce pain hypersensitivity and elucidated their molecular underpinnings. Upon high-dose PS NPs exposure, microglia in the spinal dorsal horn internalized a fraction of the PS NPs, which were subsequently found to bind to mitogen-activated-protein-kinases (MAPK) pathway components (ERK, JNK, and p38). Molecular dynamics simulations further suggested that this binding could induce conformational alterations in the MAPK components, potentially enhancing the flexibility of their phosphorylation sites (Thr-X-Tyr) and thereby facilitating activation by upstream kinases. As a canonical inflammatory and pain-associated pathway, MAPK activation elevates neuroinflammatory cascades in the spinal dorsal horn, driving neuronal hyperexcitability and, consequently, pain hypersensitivity. Notably, the PS NPs-induced hypersensitivity was reversed by microglial depletion (PLX5622) and inhibition of the MAPK pathway. Collectively, our findings delineate PS NPs-triggered sensory pathophysiology and establish a proof-of-concept mechanistic nexus between environmental pollutants and aberrant somatosensation.
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Nanomedicine
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2026
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IF 4.6
Yingchao Gao,Ning Zhang,Jun-Fei Zhang,Zhengqi Fei
Objective This study aimed to develop chitosan-based nanoparticles (ChNPs) for Triptolide (TPL) delivery to mitigate intervertebral disc degeneration (IDD).Methods TPL-magnesium (Mg) ChNPs were prepared by mixing TPL, magnesium sulfate, and chitosan under controlled stirring, followed by nanoparticle characterization. An in vitro IDD model was established by stimulating nucleus pulposus cells (NPCs) with IL-1β. The therapeutic effect and biosafety of TPL-Mg ChNPs was assessed using cell counting kit-8. In an in vivo IDD rat model, pathology of intervertebral discs was evaluated via micro-computed tomography and histological staining. Western blotting, immunofluorescence, and immunohistochemistry were used to assess MAPK signaling, mitophagy activity, and extracellular matrix (ECM) programs.Results TPL inhibited the proliferation of IL-1β-induced NPCs. TPL was complexed with Mg2+, and further coated with chitosan via electrostatic adsorption to obtain TPL-Mg ChNPs. TPL-Mg ChNPs exhibited physical stability and biosafety, and could control drug release. TPL-Mg ChNPs were internalized by damaged NPCs within 4 hours and inhibited reactive oxygen species release. In vitro, TPL-Mg ChNPs protected NPCs and maintained ECM metabolic balance. In vivo, TPL-Mg ChNPs significantly improved IDD pathology in rats by inhibiting MAPK signaling and activating mitophagy.Conclusion TPL-Mg ChNPs ameliorate IDD progression by inhibiting the MAPK pathway and activating mitophagy.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Liyun Jie,He Huang,LuYing Sha,Lidan Zhang,Ye Wang,Yu Cao
Cutaneous squamous cell carcinoma (cSCC) is a common type of skin tumor with high incidence and significant disease burden. Current clinical treatments face challenges such as high recurrence rates and drug resistance, making the discovery of novel drugs and therapeutic targets critically important. Previous studies have confirmed that Mangiferin(MF) can inhibit the proliferation of various tumors, promote apoptosis, and regulate cellular oxidative stress. This study investigated the therapeutic effects and mechanisms of MF in cutaneous squamous cell carcinoma (cSCC). CCK-8 and EDU assays demonstrated that MF significantly inhibited A431 cell proliferation, induced apoptosis, and caused G0/G1 phase arrest. Network pharmacology, molecular docking, and molecular dynamics simulations identified HSP90α as a direct target of MF, which was highly expressed in clinical cSCC tissues and validated through CETSA and DARTS experiments. Genetic manipulation experiments revealed that HSP90α knockdown promoted apoptosis, while its overexpression accelerated proliferation and attenuated MF's effects. Mechanistically, MF induced ROS generation, leading to mitochondrial and DNA damage, which could be reversed by the antioxidant NAC. Furthermore, ROS-mediated activation of the MAPK pathway contributed to apoptosis and DNA damage. In vivo, MF effectively suppressed cSCC growth without causing organ toxicity. In conclusion, MF inhibits cSCC progression both in vitro and in vivo with minimal toxicity, primarily through targeting HSP90α and activating the ROS/MAPK pathway.
研究领域:
肿瘤学
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药理学
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分子生物学
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皮肤病学
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信号转导
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Nutrients
·
2023
·Vol. 15
·期 6
·1340
·
IF 5.9
Yu Li,Bo He,Chao Zhang,Yanji He,Tianyang Xia,Chunyu Zeng
Cardiac hypertrophy is accompanied by increased myocardial oxidative stress, and whether naringenin, a natural antioxidant, is effective in the therapy of cardiac hypertrophy remains unknown. In the present study, different dosage regimens (25, 50, and 100 mg/kg/d for three weeks) of naringenin (NAR) were orally gavaged in an isoprenaline (ISO) (7.5mg/kg)-induced cardiac hypertrophic C57BL/6J mouse model. The administration of ISO led to significant cardiac hypertrophy, which was alleviated by pretreatment with naringenin in both in vivo and in vitro experiments. Naringenin inhibited ISO-induced oxidative stress, as demonstrated by the increased SOD activity, decreased MDA level and NOX2 expression, and inhibited MAPK signaling. Meanwhile, after the pretreatment with compound C (a selective AMPK inhibitor), the anti-hypertrophic and anti-oxidative stress effects of naringenin were blocked, suggesting the protective effect of naringenin on cardiac hypertrophy. Our present study indicated that naringenin attenuated ISO-induced cardiac hypertrophy by regulating the AMPK/NOX2/MAPK signaling pathway.Keywords:naringenin;cardiac hypertrophy;oxidative stress;AMPK;NOX2
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DIGESTIVE DISEASES AND SCIENCES
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2022
·Vol. 67
·期 10
·4780-4796
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IF 3.487
Duan Houyu,Ding Xiang,Luo Hesheng
Background and Aims KISS-1 is an established tumor suppressor that inhibits metastases in various malignancies. However, little is known regarding its role in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to identify the possible mechanisms of KISS-1 in ESCC metastasis. Methods The expression levels of KISS-1 mRNA and protein in ESCC samples and cell lines were analyzed by qRT-PCR, IHC, and western blotting. Bisulfite sequencing PCR (BSP) and methylation-specific PCR (MSP) were used to analyze the methylation pattern of KISS-1 promoter in ESCC cells with or without 5-Aza-dC treatment. The role of KISS-1 in the progression and metastasis of ESCC was analyzed through in vitro functional assays. Results KISS-1 mRNA and protein were markedly downregulated in ESCC tissues and cell lines compared to the respective controls. Hypermethylation of KISS-1 promoter correlated to its lower expression levels in ESCC, and KISS-1 demethylation inhibited tumor progression. Ectopic KISS-1 overexpression inhibited tumor cell metastasis in vitro. In addition, KISS-1 overexpression downregulated the matrix metalloproteinase 2 and 9 (MMP2 and 9) and inhibited epithelial–mesenchymal transition (EMT). Finally, KISS-1 downregulated phosphorylated extracellular regulated protein kinase 1/2 (ERK1/2) and phosphorylated p38 mitogen-activated protein kinase (MAPK) without affecting their total expression levels in the ESCC cells. MAPK/ERK and p38 MAPK agonists reversed the suppressive effects of KISS-1. Conclusions The hypermethylation of KISS-1 promoter partly contributed to its downregulation in ESCC. KISS-1 inhibits the metastasis of ESCC cells by targeting the MMP2/9/ERK/p38 MAPK axis.
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EXPERIMENTAL CELL RESEARCH
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2023
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IF 3.7
Xinmiao Jiang,Qiong Yan,Jiaqi He,Zeqi Zheng,Xiaoping Peng,Xiaoyan Cao,Fangbin Zhou,Jungang Nie,Ting Kang
Background Hyperglycemia-induced vascular endothelial cell dysfunction is a major factor contributing to diabetic lower extremity ischemia. We intend to investigate the role of Dusp2 in hyperglycemia-induced vascular endothelial cell dysfunction and related mechanisms. Methods The human umbilical vein endothelial cells (HUVECs) were treated with high glucose (HG) as the cell model. Streptozotocin injection was performed to induce diabetes and femoral artery ligation was to induce hind limb ischemia in mice. The levels of Dusp2, p-p38 MAPK, E2F4, and p38 MAPK were evaluated by Western blot or quantitative real-time PCR. The laser Doppler perfusion imaging was conducted to measure blood flow recovery. The cell counting kit-8, transwell, and tube formation assay were performed to evaluate cell proliferation, migration, and angiogenesis, respectively. CD31 immunohistochemical staining was carried out to detect the capillary density of gastrocnemius. The dual-luciferase reporter gene assay and Chromatin immunoprecipitation assay were executed to explore the interaction between E2F4 and Dusp2. Results Dusp2 was highly expressed in HG-induced HUVECs and diabetic lower extremity ischemia model mice. Interference with Dusp2 promoted cell proliferation, migration, and angiogenesis, as well as alleviated mouse diabetic hindlimb ischemia. Dusp2 knockdown up-regulated p-p38 MAPK levels. We verified the binding between E2F4 and Dusp2. Overexpressing E2F4 suppressed Dusp2 levels and promoted cell proliferation, migration, and angiogenesis, co-overexpression of Dusp2 reversed the results. Conclusions Overexpressing E2F4 promotes endothelial cell proliferation, migration, and angiogenesis by inhibiting Dusp2 expression and activating p38 MAPK to alleviate vascular endothelial cell dysfunction under HG stimulation.
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Journal of Inflammation Research
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2023
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IF 4.5
Yunbo Yan,Linqian Yu,Binyang Chen,Chang’an Cao,Hairong Zhao,Qiang Wang,De Xie,Yuemei Xi,Chenggui Zhang,Jidong Cheng
Background Gouty arthritis is characterized by the accumulation of monosodium urate crystals (MSU) in the synovial joints and surrounding tissues. Mastoparan M (Mast-M) is a biologically active peptide composed of 14 amino acids, extracted from wasp venom. This study aims to assess the impact of Mast-M on in vitro and in vivo gouty arthritis induced by lipolyaccharide (LPS) plus MSU crystal stimulation.Methods PMA-differentiated THP-1 macrophages were pre-treated with Mast-M or left untreated, followed by stimulation with LPS and MSU crystals. Cell lysates were collected to assess the expression of the NLRP3 inflammasome, inflammatory signaling pathways, and oxidative stress. Furthermore, to evaluate the in vivo anti-inflammatory effect of Mast-M, an experimental acute gouty arthritis mouse model was established through intra-articular injection of MSU crystals.Results Mast-M treatment demonstrated significant inhibition of the phosphorylation of MAPKs/NF-κB signaling pathways and reduction in oxidative stress expression in LPS and MSU-induced THP-1 macrophages. This resulted in the suppression of downstream NLRP3 inflammasome activation and IL-1β release. In vivo, Mast-M effectively attenuated the inflammation induced by MSU in mice with gouty arthritis. Specifically, Mast-M reduced swelling in the paws, inhibited the infiltration of neutrophils and macrophages into periarticular tissue, and decreased the activation of the NLRP3 inflammasome and IL-1β production.Conclusion Mast-M significantly improves gouty arthritis, and its potential mechanism may be achieved by inhibiting the MAPK/NF-κB pathway and alleviating oxidative stress, thus suppressing the activation of NLRP3 inflammasomes.
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COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
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2021
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IF 3.228
Jianqing Chen,Bing Shao,Jinliang Wang,Zhiqiang Shen,Honggui Liu,Shu Li
Chlorpyrifos (CPF) is an organophosphate insecticide and can cause cell death of animals. In the study, the common carp were exposed to CPF at 0 μg/L (the control group), 1.16 μg/L (the low dose group), 11.6 μg/L (the medium dose group), and 116 μg/L (the high dose group), respectively. The carp were euthanized at the 30th day and gills were collected immediately. The ultrastructural and histopathological observations showed obvious necrosis characteristics and inflammatory injury in the CPF-treated groups. CPF exposure activated the MAPK pathway, in which the mRNA and protein expressions of extracellular signal-regulated (ERK), p38 MAP kinase (p38), and c-Jun N-terminal kinase (JNK) were increased; the mRNAs and proteins of NF-κB and TNF-α were activated; and the mRNAs and proteins of necroptosis related genes were changed (the mRNA and protein expression of RIPK1 , RIPK3 , MLKL, and FADD were increased and caspase-8 was decreased) with concentration dependency. Taken together, we concluded that CPF exposure activated the MAPK/NF-κB/TNF-α pathway, promoted inflammatory injure and evoked necroptosis in common carp gills. In addition, CPF-induced inflammation and necroptosis was concentration dependency. The toxic effects of CPF on gills provided data for both aquaculture and toxicological studies.
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JOURNAL OF ETHNOPHARMACOLOGY
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2019
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IF 3.414
Lei Peng,Chenxi Hu,Chaozheng Zhang,Yingying Lu,Shuli Man,Long Ma
Ethnopharmacological relevance Conyza blinii H.Lév. is a type of natural plant distributed in southwest of China. Its dried overground section can be used in traditional Chinese medicine (TCM) for treating infections, inflammations and occasionally cancers. CBS ( Conyza blinii saponin), mainly composed of triterpenoidal saponins of Conyza blinii H.Lév. CBS is considered as the major active fraction of this species. The current investigation have focused on the mechanisms of CBS with regard to its anti-cancer activity. Hence it is of high relevance of identifying the anti-cancer efficacy of ethnomedicine . Aim of the study To understand the anti-cancer mechanism of CBS using both in vitro and in vivo experiments. Materials and methods CBS ( Conyza blinii saponin) was obtained as described previously. We tested the anti-cancer activity of CBS using in vitro HeLa cell models and in vivo animal models. We adopted immunoblot , RT-PCR (reverse transcription polymerase chain reaction), luciferase reporter assay and flow cytometry to study relevant proteins, genes, pathways and cellular ROS (reactive oxygen species) responsible for anti-cancer activity of CBS. More, 24 tumour-xenografted mice were grouped randomly as ‘control’, ‘cisplatin’ (as positive control), ‘low dose’ and ‘high dose’ groups. The IL-1β, TNF-α, PGE2 and IL-2 in the blood serum and the tumour tissue of mice were measured. Results and conclusions We have found that CBS is capable of inducing apoptotic cancer cell death via both caspase-dependent and -independent pathways. CBS inhibits the activation of TGF-β signaling pathway in a dose- and time-dependent manner. Phospho-ERK, phospho-JNK and phospho-p38 MAPK are significantly suppressed by CBS. Furthermore, some inflammation mediators including IL-1β, TNF-α and PGE2 from animal samples were found decreased in CBS-treated mice models. In contrast, the level of IL-2, a cytokine commonly used for treating cancers, increased reversely. Last, we have discovered that CBS is able to decrease the expression of Nrf2, inhibit the activation of ARE and increase ROS level in HeLa cells. In summary, we have confirmed that the anti-cancer activity of CBS is possibly related to its TGF-β, MAPK, Nrf2 signaling pathways as well as some cancer related inflammation mediators and cytokines.
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Frontiers in Oncology
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2019
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IF 4.137
Roy Gaurab,Guan Su,Liu Hexiang,Zhang Lei
Hepatocellular carcinoma (HCC) is the fourth largest cause of cancer-related deaths worldwide with limited therapeutic interventions. Renewed interest in natural products as drug leads has resulted in a paradigm shift toward the rapid screening of medicinal plants for the discovery of new chemical entities. Rotundic acid (RA), a plant-derived triterpenoid, has been anecdotally reported to possess anti-inflammatory and cardio-protective abilities. The present study highlights the anti-cancer efficacy of RA on HCC in vitro and in vivo. The inhibitory effects of RA on HCC cell viability was determined by MTT. Soft agar colony formation and clonogenic assays also showed that RA inhibited HCC cell proliferation. Flow cytometry, confocal, and western blot results further indicated that RA induced cell cycle arrest, DNA damage, and apoptosis by modulating the AKT/mTOR and MAPK pathways. Besides the suppression of migration and invasion, tube formation and VEGF-ELISA revealed the anti-angiogenic abilities of RA on HCC. Moreover, RA also inhibited tumor growth in a HepG2 xenograft mouse model. To our best knowledge, this is the first extensive study of the anticancer activity of RA on HCC. The results demonstrate that RA could be a potential drug candidate for HCC treatment.
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CELLULAR AND MOLECULAR NEUROBIOLOGY
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2016
·Vol. 36
·期 8
·1365-1375
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IF 2.328
Lin Xuemei,Wu Songdi,Wang Qing,Shi Yaling,Liu Guozheng,Zhi Jin,Wang Fang
Neuronal oxidative stress (OS) injury has been proven to be associated with many neurodegenerative diseases, and thus, antioxidation treatment is an effective method for treating these diseases. Saikosaponin-D (SSD) is a sapogenin extracted from Bupleurum falcatum and has been shown to have many pharmacological activities. The main purpose of this study was to investigate whether and how SSD protects PC12 cells from H 2 O 2 -induced apoptosis. The non-toxic level of SSD significantly mitigated the H 2 O 2 -induced decrease in cell viability, reduced the apoptosis rate, improved the nuclear morphology, and reduced caspase-3 activation and poly ADP-ribose polymerase (PARP) cleavage. Additionally, exogenous H 2 O 2 -induced apoptosis by damaging the intracellular antioxidation system. SSD significantly slowed the H 2 O 2 -induced release of malonic dialdehyde (MDA) and lactate dehydrogenase and increased the activity of superoxide dismutase (SOD) and the total antioxidant capacity, thereby reducing apoptosis. More importantly, SSD effectively blocked H 2 O 2 -induced phosphorylation of extracellular-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38MAPK), and specific inhibitors of ERK, JNK, and p38-reduced OS injury and apoptosis, suggesting that SSD reduces OS injury and apoptosis via MAPK signalling pathways. Finally, we confirmed that SSD significantly reduced H 2 O 2 -induced reactive oxygen species (ROS) accumulation, and the ROS inhibitor blocked the apoptosis caused by MAPK activation and cellular oxidative damage. In short, our study confirmed that SSD reduces H 2 O 2 -induced PC12 cell apoptosis by removing ROS and blocking MAPK-dependent oxidative damage.
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