Frontiers in Pharmacology
·
2021
·
IF 5.811
Bao Shihui,Zheng Hailun,Ye Jinyao,Huang Huirong,Zhou Bin,Yao Qing,Lin Guangyong,Zhang Hailin,Kou Longfa,Chen Ruijie
Pancreatic cancer (PC) is one of the most common malignancies and also a leading cause of cancer-related mortality worldwide. Many studies have shown that epidermal growth factor receptor (EGFR) is highly expressed in PC, which provides a potential target for PC treatment. However, EGFR inhibitors use alone was proven ineffective in clinical trials, due to the persistence of cellular feedback mechanisms which foster therapeutic resistance to single targeting of EGFR. Specifically, the signal transducer and activator of transcription 3 (STAT3) is over-activated when receiving an EGFR inhibitor and is believed to be highly involved in the failure and resistance of EGFR inhibitor treatment. Therein, we hypothesized that dual inhibition of EGFR and STAT3 strategy could address the STAT3 induced resistance during EGFR inhibitor treatment. To this end, we tried to develop poly (lactic-co-glycolic acid) (PLGA) nanoparticles to co-load Alantolactone (ALA, a novel STAT3 inhibitor) and Erlotinib (ERL, an EGFR inhibitor) for pancreatic cancer to test our guess. The loading ratio of ALA and ERL was firstly optimized in vitro to achieve a combined cancer-killing effect. Then, the ALA- and ERL-co-loaded nanoparticles (AE@NPs) were successfully prepared and characterized, and the related anticancer effects and cellular uptake of AE@NPs were studied. We also further detailly explored the underlying mechanisms. The results suggested that AE@NPs with uniform particle size and high drug load could induce significant pancreatic cancer cell apoptosis and display an ideal anticancer effect. Mechanism studies showed that AE@NPs inhibited the phosphorylation of both EGFR and STAT3, indicating the dual suppression of these two signaling pathways. Additionally, AE@NPs could also activate the ROS-p38 axis, which is not observed in the single drug treatments. Collectively, the AE@NPs prepared in this study possess great potential for pancreatic cancer treatment by dual suppressing of EGFR and STAT3 pathways and activating ROS-responsive p38 MAPK pathway.
研究领域:
肿瘤学
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药学
·
纳米技术
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Infection and Drug Resistance
·
2023
·
IF 3.9
Lingna Xu,Ren-ai Xu,Dan Zhang,Shanshan Su,Hanyan Xu,Qing Wu,Yuping Li
Background: T helper 17 (Th17) lymphocytes play an important role in Aspergillus adaptive immune response against Aspergillus fumigatus, but there is little attention focused on the different types of immunosuppressive models in which invasive pulmonary aspergillosis (IPA) develops. In addition, the expression levels of signal transducer and activator of transcription 3 (STAT3)/retinoic acid-related orphan nuclear receptor gamma (RORγt)/interleukin (IL)-17A signaling pathway, which is involved in the regulation of Th17 cells, as well as whether there are differences between two types of IPA mice models, remain unknown.Materials and methods: Six to eight weeks old female BALB/c mice were treated with cortisone acetate or cyclophosphamide to establish the immunosuppressive mice models, and then, A. fumigatus inoculum was injected to form the IPA groups and sterile saline was injected to form the control groups. Flow cytometry was performed to measure the proportion of Th17 cells in CD4+ T cells in the peripheral blood, spleen, and lung of the mice. The expression of IL-17A, RORγt, and STAT3 mRNA was detected by real-time polymerase chain reaction. Concentrations of IL-6 in the plasma and bronchoalveolar lavage fluid were measured by enzyme-linked immunosorbent assay.Results: The proportion of Th17 in the peripheral blood and lung tissue in neutropenic IPA mice showed a more significant increase than in non-neutropenic IPA mice (P<0.01). The IL-6 protein also showed the same trend in plasma and bronchoalveolar lavage fluid (P<0.01). Compared with the control groups, the expression of IL-17A at mRNA level in the lung was significantly increased, while RORγt/STAT3 mRNA was significantly decreased in the IPA groups (P<0.01).Conclusion: The expression of RORγt and STAT3 mRNA in the lung tissue in both groups was significantly decreased. IL-17 may play a negative role in the defense against Aspergillus through uprating IL-6.
研究领域:
免疫学
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微生物学
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分子生物学
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病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2025
·Vol. 22
·期 1
·1-19
·
IF 10.1
Chi Zhexi,Lu Bo,Liu Rongjun,Pan Chen,Meng Bo,Xing Xiuzhong,Yuan Hui,Wu Xuewei,Chen Yushan,Ren Yuxuan,Wu Wenwei,Miao Mengmeng,Chen Junping,Chen Xiaowei
Neuropathic pain, a debilitating nerve injury-induced condition, remains a significant clinical challenge. This study evaluates the effect of histone deacetylase 6 (HDAC6) inhibition in a spared nerve injury (SNI) mouse model. Systemic administration of the selective HDAC6 inhibitor ACY-1215 (20 mg/kg/day, 14 days), alleviated SNI-induced pain in mice of both sexes. ACY-1215 increased acetylated signal transducer and activator of transcription 3 (Ac-STAT3) and reduced phosphorylated STAT3 (p-STAT3) in the lumbar spinal cord of SNI mice. HDAC6 and p-STAT3 were expressed in spinal dorsal horn neurons, and SNI-enhanced HDAC6/STAT3 interaction was reversed by ACY-1215. Neuronal STAT3 overexpression induced pain hypersensitivity and elevated p-STAT3, tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), effects suppressed by ACY-1215. Cytokine profiling identified CC-chemokine ligand 7 (CCL7) as a key downstream effector of the HDAC6/STAT3 axis, with ACY-1215 attenuating SNI-induced CCL7 upregulation. HDAC6 knockdown in neurons reduced p-STAT3, while HDAC6 or STAT3 knockdown diminished CCL7 production. These findings demonstrate that ACY-1215 mitigates neuropathic pain by modulating STAT3 acetylation/phosphorylation and suppressing HDAC6/STAT3-driven CCL7 and cytokine release. This study underscores the role of the HDAC6/STAT3/CCL7 signaling axis in neuropathic pain and highlights the therapeutic potential of HDAC6 inhibitors for pain management.
研究领域:
神经科学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL MEDICINE
·
2024
·Vol. 221
·期 7
·e20240111
·
IF 12.6
Xue Yun,Chen Yuting,Sun Sijia,Tong Xinyuan,Chen Yujia,Tang Shijie,Wang Xue,Bi Simin,Qiu Yuqin,Zhao Qiqi,Qin Zhen,Xu Qin,Ai Yingjie,Chen Leilei,Zhang Beizhen,Liu Zhijie,Ji Minbiao,Lang Meidong,Chen Luonan,Xu Guoliang,Hu Liang,Ye Dan,Ji Hongbin
Phenotypic plasticity is a rising cancer hallmark, and lung adeno-to-squamous transition (AST) triggered by LKB1 inactivation is significantly associated with drug resistance. Mechanistic insights into AST are urgently needed to identify therapeutic vulnerability in LKB1-deficient lung cancer. Here, we find that ten-eleven translocation (TET)–mediated DNA demethylation is elevated during AST in KrasLSL-G12D/+; Lkb1L/L (KL) mice, and knockout of individual Tet genes reveals that Tet2 is required for squamous transition. TET2 promotes neutrophil infiltration through STAT3-mediated CXCL5 expression. Targeting the STAT3–CXCL5 nexus effectively inhibits squamous transition through reducing neutrophil infiltration. Interestingly, tumor-infiltrating neutrophils are laden with triglycerides and can transfer the lipid to tumor cells to promote cell proliferation and squamous transition. Pharmacological inhibition of macropinocytosis dramatically inhibits neutrophil-to–cancer cell lipid transfer and blocks squamous transition. These data uncover an epigenetic mechanism orchestrating phenotypic plasticity through regulating immune microenvironment and metabolic communication, and identify therapeutic strategies to inhibit AST.
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症生物学
✓ 已验证
DOI
PubMed
高影响因子
Clinical & Translational Oncology
·
2022
·Vol. 25
·期 3
·662-672
·
IF 3.34
Chen Jing,Huang Shuting,Li Huawen,Li Yun,Zeng Haishan,Hu Jiemei,Lin Yanchun,Cai Huihua,Deng Pengfei,Song Ting,Guan Tian,Zeng Haoyu,Liu Mubiao
Purpose Aberrant activation of STAT3 signal pathway promotes tumor progression in many solid tumor types, including cervical cancer and endometrial cancer. BBI608, the STAT3 inhibitor had been reported in previous studies for restraining cancer stem cells. However, whether BBI608 is available for inhibiting the proliferation of cervical cancer or endometrial cancer remains poorly understood. This study investigated the anti-tumor effect and molecular mechanism of BBI608 on the patient-specific primary cells (PSPC) generated from cervical and endometrial cancer in vitro. Methods PSPCs were obtained from four patients via biopsy. The cell viability was analyzed by the CCK8 assay. The PSPCs were treated with various concentrations of BBI608 or/and paclitaxel; and then, western blot was applied to investigate the expression of phosphorylated STAT3 (pSTAT3). Results The PSPCs cell viability was reduced after treated with BBI608 at a lower concentration. Western blot results showed a reduction trend of pSTAT3 after PSPCs treated with BBI608. Our results demonstrated that BBI608 at the certain concentrations worked well in reducing the cell viability of PSPC from the patients who suffered from cervical cancer and endometrial cancer. Conclusions In this study, the patient-specific primary cell (PSPC) was used as the pre-clinical model for investigating the efficiency of BBI608 in reducing cancer cells viability. BBI608, at a clinical-relevant concentration, had valid efficiency in PSPCs from the patients. The dose of drugs treatment and the measured results were more valuable for further guiding clinical trials.
研究领域:
肿瘤学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
OncoTargets and Therapy
·
2021
·
IF 4.147
Ruiqi Xu,Mengnan Zeng,Yuanyuan Wu,Shengchao Wang,Beibei Zhang,Jingke Zhang,Yuxuan Kan,Benke Li,Bing Cao,Xiaoke Zheng,Weisheng Feng
Purpose This research aims to investigate the intervention and mechanism of 50% acetone extract of C. officinalis leaves (SZYY) on melanoma xenografts. Patients and Methods Tumor size and cardiac function were measured via ultrasound. The accumulation of 2-deoxy-D-glucose (2-DG) in tumor tissue was examined with near-infrared in vivo imaging. Flow cytometry was performed to assess apoptosis and reactive oxygen species (ROS) levels in tumor and immune cells in spleen. The levels of inflammatory cytokines in serum were detected by cytometric bead array. The expression of proliferation-, apoptosis-, and angiogenesis-related proteins in tumor cells was measured to evaluate the underlying mechanisms. Subsequently, the effects of four compounds separated from SZYY on the proliferation and migration of A375 cells and STAT3 signaling were examined. The peak identification and contents of the four components were performed via high-performance liquid chromatography (HPLC). Finally, we evaluated the inhibitory effects of STAT3 overexpression on the cytotoxic activity of four constituents in A375 cells. Results SZYY inhibited the growth and glycolysis of melanoma xenograft in mice, improved cardiac function, increased the percentages of macrophages, neutrophils, and lymphocytes in spleen, reduced the levels of IL-6, IL-17A, TNF-α, and IFN-γ in serum, promoted apoptosis and oxidative stress in tumor tissues, and inhibited STAT3 phosphorylation and expression of angiogenic factors. Chemical analysis showed that SZYY is rich in loganin, rutin, triohimas C, and triohimas D, which all could restrain the proliferation and migration of A375 cells and inhibit the phosphorylation and nuclear translocation of STAT3. Moreover, STAT3 overexpression could diminish the cytotoxic activity of four compounds on A375 cells. Conclusion SZYY could exert anti-melanoma effects via inhibiting STAT3 signaling to induce apoptosis and inhibit tumor angiogenesis. Its active ingredients might be loganin, rutin, triohimas C, and triohimas D.
研究领域:
肿瘤学
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药理学
·
分子生物学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
·
2019
·
IF 4.328
Dandan Chen,Zhe Li,Peiqing Bao,Miao Chen,Miao Zhang,Fangrong Yan,Yitao Xu,Caoyu Ji,Xinyue Hu,Daniel Sanchis,Yubin Zhang,Junmei Ye
Background NF-E2-related factor 2 (Nrf2) is a transcription factor playing cytoprotective effects in various pathological processes including oxidative stress and cardiac hypertrophy. Despite being a potential therapeutic target to treat several cardiomyopathies, the signaling underlying Nrf2-dependent cardioprotective action remains largely uncharacterized. Aim This study aimed to explore the signaling mediating the role of Nrf2 in the development of hypertensive cardiac pathogenesis by analyzing the response to Angiotensin II (Ang II) in the presence or absence of Nrf2 expression, both in vivo and in vitro. Results Our results indicated that Nrf2 deficiency exacerbated cardiac damage triggered by Ang II infusion. Mechanistically, our study shows that Ang II-triggered hypertrophy and inflammation is exacerbated in the absence of Nrf2 expression and points to the involvement of the IL-6/STAT3 signaling pathway in this event. Indeed, our results show that IL-6 abundance triggered by Ang II is increased in the absence of Nrf2 and demonstrate the requirement of IL-6 in STAT3 activation and cardiac inflammation induced by Ang II. Conclusion Our results show that Nrf2 is important for the protection of the heart against Ang II-induced cardiac hypertrophy and inflammation by mechanisms involving the regulation of IL-6/STAT3-dependent signaling.
研究领域:
心脏病学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2025
·Vol. 31
·期 1
·79
·
IF 4.6
Ziqian Zhang,Xue Bai,Qian Du,Jianhong Yang
Diabetic cardiomyopathy (DCM) is a severe complication of diabetes, in which ferroptosis is a key pathogenic mechanism. This study examines how alpha-linolenic acid (ALA), a plant-derived omega-3 polyunsaturated fatty acid, protects against damage from ferroptosis in DCM. Using an in vitro model of H9C2 cardiomyocytes treated with high glucose/palmitate, combined with a high-fat diet and mouse model of low-dose streptozotocin (STZ)-induced diabetes, this research demonstrates for the first time that ALA significantly alleviates cardiac dysfunction and prevents ferroptosis. Mechanistically, ALA inhibits STAT3 phosphorylation by activating the AMPK signaling pathway, thereby reducing NCOA4-mediated ferritinophagy and mitigating mitochondrial iron overload and reactive oxygen species accumulation. It also enhances the function of the SLC7A11/GSH/GPX4 axis, reducing lipid peroxidation (LPO)-induced ferroptosis. Collectively, these findings indicate that ALA protects against diabetic cardiomyopathy by coordinating the regulation of ferritinophagy and antioxidant defense through the AMPK-STAT3 pathway, offering a potential therapeutic strategy for disease management.
研究领域:
心血管病学
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内分泌学
·
分子生物学
·
代谢性疾病
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氧化应激
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细胞死亡机制
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营养干预
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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
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皮肤病学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION
·
2024
·
IF 3.9
Zhou Y.-Y.,Zhao S.-Y.,Huang F.-J.,Zhang L.-J.,Liu Y.-L.,Wang J.,Ma X.-J.
Background and purpose Subclinical hypothyroidism (SCH) has been identified to be associated with implantation failure, in which the dysfunction of trophoblast cells is involved. In this study, the transcriptomics of aborted placenta from SCH rats were analyzed. Jupiter microtubule-associated homolog 2 (JPT2) was downregulated in the aborted placenta. This study aims to investigate its role in SCH-associated miscarriage. Methods Spontaneous abortion was observed in SCH rats generated by thyroidectomy combined with levothyroxine administration. The transcriptomics analysis was performed using aborted placenta. Afterward, the effects of JPT2 on trophoblast cells were explored using gain-and loss-of-function experiments. Results Transcriptomics analysis showed 1286 downregulated genes and 2300 upregulated genes in the aborted placenta, and JPT2 was significantly downregulated in the aborted placenta from SCH rats. Afterward, gain-and loss-of-function experiments exhibited that overexpression of JPT2 promoted the proliferation, migration, invasion, spheroid formation of HTR-8/SVneo trophoblast cells and their attachment to endometrial stromal cells, while these biological behaviors were suppressed by JPT2 knockdown. Furthermore, JPT2 accelerated the transcription of leptin receptor (LEPR), and activated signal transducer and activator of transcription 3 (STAT3) signal in a transcription factor AP-2γ-dependent manner. In addition, silencing of LEPR abolished the role of JPT2. Conclusion Our results revealed that JPT2, which was downregulated in the aborted placenta from SCH rats, promoted proliferation, migration, invasion, spheroid formation, and attachment of trophoblast cells via regulating LEPR/STAT3 axis as a transcription co-factor. It is indicated that low expression of JPT2 may contribute to the abortion in individuals with SCH.
研究领域:
内分泌学
·
生殖生物学
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分子生物学
·
转录组学
✓ 已验证
DOI
PubMed
高影响因子
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
·
2019
·Vol. 46
·期 12
·1194-1200
·
IF 2.336
Di Wu,Wei Zhang,Ying Chen,Hong Ma,Mengchang Wang
Multiple myeloma (MM) is a malignancy characterized by the proliferation of malignant plasma cells. Platycodin D (PLD) is a triterpenoid saponin that exerts anti-tumour activity through multiple mechanisms. However, the role of PLD in MM remains unknown. Here, we investigated the effect of PLD on MM cell lines NCI-H929 and U266B1, and elucidated the underlying molecular mechanism. Cell Counting Kit-8 assay showed that the proliferation of NCI-H929 and U266B1 cells was significantly decreased after PLD treatment. Transwell assay confirmed that PLD treatment suppressed migration of NCI-H929 and U266B1 cells. Flow cytometry results indicated that the apoptotic rates of bortezomib (BTZ)-treated NCI-H929 and U266B1 cells were markedly increased after PLD treatment. Western blot analysis revealed that bcl-2 expression was decreased, while bax expression was increased in PLD-treated NCI-H929 and U266B1 cells compared with that in BTZ-treated cells. Furthermore, PLD treatment blocked the activation of nuclear factor-kappa B (NF-κB) and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signalling pathways in NCI-H929 cells. Taken together, these data showed that PLD inhibited proliferation and migration, and enhanced chemosensitization to BTZ through inactivation of the NF-κB and JAK2/STAT3 pathways in MM cell lines. These findings indicated that PLD might serve as a novel therapeutic agent for the treatment of MM.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-18
·
IF 14.7
Qiu Sheng,Wu Qinan,Wang Hao,Liu Dongfang,Chen Chen,Zhu Zhiming,Zheng Hongting,Yang Gangyi,Li Ling,Yang Mengliu
Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons.
研究领域:
神经科学
·
代谢研究
·
分子生物学
·
内分泌学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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