Food & Function
·
2023
·Vol. 14
·期 10
·4807-4823
·
IF 6.1
Suwen Liu,Wenhong Jiang,Chang Liu,Shuo Guo,Hao Wang,Xuedong Chang
Chinese chestnut shell is a by-product of chestnut food processing and is rich in polyphenols. This study sought to investigate the effect of chestnut shell polyphenol extract (CSP) on weight loss and lipid reduction in a 12-week high-fat diet (HFD)-induced murine obesity model. CSP (300 mg per kg body weight) was administered intragastrically daily. AG490, a JAK2 protein tyrosine kinase inhibitor, was also intraperitoneally injected. The results showed that an HFD induced leptin resistance (LR). Compared to corresponding values in the HFD group, CSP treatment improved blood lipid levels, weight, and leptin levels in obese mice (p < 0.01). Additionally, CSP treatment enhanced enzyme activity by improving total antioxidant capacity, attenuating oxidative stress, and reducing fat droplet accumulation and inflammation in the liver, epididymal, and retroperitoneal adipose tissue. CSP also activated the LEPR-JAK2/STAT3-PTP1B-SOCS-3 signal transduction pathway in hypothalamus tissue and improved LR while regulating the expression of proteins related to lipid metabolism (PPARγ, FAS, and LPL) in white adipose tissue in the retroperitoneal cavity. However, the amelioration of lipid metabolism by CSP was dependent on JAK2. Molecular docking simulation further demonstrated the strong binding affinity of procyanidin C1 (−10.3983297 kcal mol−1) and procyanidin B1 (−9.12686729 kcal mol−1) to the crystal structure of JAK2. These results suggest that CSP may be used to reduce HFD-induced obesity with potential application as a functional food additive.
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Frontiers in Pharmacology
·
2023
·
IF 5.6
Li Jingyan,Wu Bingmin,Zeng Lishan,Lin Ying,Chen Qiuhe,Wang Haixia,An Lin,Zhang Jiajun,Chen Siyan,Huang Junying,Zhan Ruoting,Zhang Guifang
Background: The present study aimed to investigate the protective effect of the water extract of Amydrium sinense (Engl.) H. Li (ASWE) against hepatic fibrosis (HF) and clarify the underlying mechanism.Methods: The chemical components of ASWE were analysed by a Q-Orbitrap high-resolution mass spectrometer. In our study, an in vivo hepatic fibrosis mouse model was established via an intraperitoneal injection of olive oil containing 20% CCl4. In vitro experiments were conducted using a hepatic stellate cell line (HSC-T6) and RAW 264.7 cell line. A CCK-8 assay was performed to assess the cell viability of HSC-T6 and RAW264.7 cells treated with ASWE. Immunofluorescence staining was used to examine the intracellular localization of signal transducer and activator of transcription 3 (Stat3). Stat3 was overexpressed to analyse the role of Stat3 in the effect of ASWE on HF.Results: Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that candidate targets of ASWE, associated with protective effects against hepatic fibrosis, were related to inflammation response. ASWE ameliorated CCl4-induced liver pathological damage and reduced the liver index and alanine transaminase (ALT) and aspartate transaminase (AST) levels. ASWE also decreased the serum levels of collagen Ⅰ (Col Ⅰ) and hydroxyproline (Hyp) in CCl4-treated mice. In addition, the expression of fibrosis markers, including α-SMA protein and Acta2, Col1a1, and Col3a1 mRNA, was downregulated by ASWE treatment in vivo. The expression of these fibrosis markers was also decreased by treatment with ASWE in HSC-T6 cells. Moreover, ASWE decreased the expression of inflammatory markers, including the Tnf-α, Il6 and Il1β, in RAW264.7 cells. ASWE decreased the phosphorylation of Stat3 and total Stat3 expression and reduced the mRNA expression of the Stat3 gene in vivo and in vitro. ASWE also inhibited the nuclear shuttling of Stat3. Overexpression of Stat3 weakened the therapeutic effect of ASWE and accelerated the progression of HF.Conclusion: The results show that ASWE protects against CCl4-induced liver injury by suppressing fibrosis, inflammation, HSC activation and the Stat3 signaling pathway, which might lead to a new approach for preventing HF.
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Food Bioscience
·
2023
·
IF 5.2
Qiaoli Wu,Bing Liu,Rongxian Yu,Xiaoling Sun,Ziyan Wang,Jun Zhou,Chenyang Lu,Jing Zhang,Jiaojiao Han,Xiurong Su
Osteoarthritis (OA) is a chronic disease associated with bone and muscle degeneration that causes great disturbances to daily lives. Skipjack tuna elastin peptides (STEP) is a kind of small molecule mixed peptides extracted from skipjack tuna bulbus cordis that have multiple active functions, including anti-inflammatory activity. However, it is ambiguous whether STEP reduce OA inflammation. Zebrafish served as a model in the present research for verifying the anti-inflammatory efficacy of STEP. Then, the composition of STEP was figured out by LC-MS/MS analysis, and the potential anti-inflammatory peptides were screened by molecular docking and microscale thermophoresis (MST). Finally, in vitro experiments were conducted on the potential peptides. According to the in vivo findings, STEP protected the cartilage tissues of zebrafish and regulated the expression of inflammatory factors and the JAK2/STAT3 signaling pathway . The in vitro results showed that the potential peptides (LGVGSPPGK, GFDPSR and PGAPGGGFDI) positively regulated the inflammatory responses and the JAK2/STAT3 signaling pathway and were effective in inhibiting extracellular matrix (ECM) degeneration and chondrocyte apoptosis. As a consequence, STEP possess anti-inflammatory and chondroprotective effects and could be a functional product for the alleviation of OA.
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Cell Death Discovery
·
2023
·Vol. 9
·期 1
·1-10
·
IF 7
Wang Xianzhe,Shi Wei,Wang Xumei,Lu Jin-Jian,He Ping,Zhang Hongjie,Chen Xiuping
Though palbociclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor has been approved for treating breast cancer, two major clinical challenges remain: (i) Triple-negative breast cancer (TNBC) appears to be more resistant to palbociclib, and (ii) Palbociclib-induced senescence-associated secretory phenotype (SASP) has a pro-tumorigenic function. Here we report that combining palbociclib with the STAT3 inhibitor nifuroxazide uncouples SASP production from senescence-associated cell cycle exit. Moreover, we identified nifuroxazide as a CDK2 inhibitor that synergistically promotes palbociclib-induced growth arrest and senescence in TNBC cells. In vitro, the combination of nifuroxazide with palbociclib further inhibited the TNBC cell proliferation and enhanced palbociclib-induced cell cycle arrest and senescence. The modulation of palbociclib-induced SASP by nifuroxazide was associated with the reduction of phosphorylated-STAT3. Nifuroxazide also blocks SASP-dependent cancer cell migration. Furthermore, thermal shift assay and molecular docking of nifuroxazide with STAT3 and CDK2 revealed that it binds to their active sites and acts as a potent dual inhibitor. In vivo, the combination of nifuroxazide with palbociclib suppressed 4T1 tumor growth and lung metastasis. Our data suggest that nifuroxazide enhances the anticancer effects of palbociclib in TNBC by uncoupling SASP production from senescence-associated cell cycle exit and inhibiting CDK2 to promote tumor senescence.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2021
·
IF 4.432
Guanghui Xu,Huiqi Wan,Litao Yi,Wei Chen,Youhua Luo,Yiqi Huang,Xiaojuan Liu
Accumulating evidence showed that berberine possessed the anti-inflammatory action in various diseases caused by inflammation. However, it was still unclear whether both inhalation and injection with berberine produced pulmonary protective role in acute respiratory distress syndrome (ARDS). This study was aimed to evaluate the effects of both administration routes including inhalation and injection with berberine in ARDS induced by lipopolysaccharide (LPS) inhalation. Histopathological examination and weight of lung were evaluated. Phosphorylation of NF-κB, JAK2 and STAT3 were measured to assess the activity of inflammation related signaling pathways. Proinflammatory cytokines including interleukin (IL)-1β and tumor necrosis factor (TNF)-α in the bronchoalveolar lavage fluid (BALF) and serum were also detected. The results showed that LPS caused the lung injury, while both administration routes with berberine attenuated the injury and improved the pulmonary morphology. In addition, the primary TLR4/NF-κB and secondary JAK2/STAT3 signaling pathways which were activated by LPS in lung were totally inhibited by berberine administration. Moreover, proinflammatory cytokines in both BALF and serum were decreased by berberine. Considering that molecular docking simulation indicated that berberine could bind with TLR4, the present suggested that the inhibition of the inflammation related TLR4/NF-κB and JAK2/STAT3 signaling pathways might be involved in the pulmonary protective effect of berberine in LPS-induced ARDS.
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PHARMACEUTICAL BIOLOGY
·
2021
·
IF 3.503
Rubin Cheng,Yilan Huang,Yun Fang,Qirui Wang,Meixiu Yan,Yuqing Ge
Context A portion of patients with chronic myeloid leukaemia (CML) develop resistance to the Bcr-Abl tyrosine kinase inhibitors (TKIs), limiting the clinical applications. Previous results have demonstrated the synergistic effects between cryptotanshinone (CPT) and imatinib on apoptosis of CML cells in vitro.Objective To determine the antileukemia effects of CPT and TKIs on the resistant CML cells, and further investigate the effect of combined treatment of CPT and imatinib on tumour growth and apoptosis in the xenograft model and clarify its regulatory mechanisms.Materials and methods The combination effects of CPT and second-generation TKIs were evaluated in resistant CML cells K562-R. CPT and imatinib were orally administered once daily for 21 days on K562-R xenografts in nude mice (6 per group). Tumour proliferation and apoptosis were examined by Ki-67, PCNA and TUNEL staining. The expression levels of apoptotic markers and activities of STAT3 and eIF4E pathways were determined via immunohistochemistry staining and western blotting analysis.Results CPT significantly enhanced the antiproliferative effects of TKIs, via triggering cleavages of caspase proteins, and inhibiting activities of STAT3 and eIF4E pathways. The administration of CPT and imatinib dramatically inhibited the tumour growth of xenografts and achieved a suppression of 60.2%, which is 2.6-fold higher than that of single imatinib group. Furthermore, CPT and imatinib increased the apoptotic rates and markedly decreased the phosphorylation levels of STAT3 and eIF4E.Conclusions Our results demonstrated that CPT could significantly enhance the antileukemia efficacy of TKIs, suggesting the therapeutic potential of CPT to overcome CML resistance.
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CHEMISTRY & BIODIVERSITY
·
2018
·Vol. 15
·期 4
·e1800024
·
IF 1.617
Qi-Zhe Gong,Di Xiao,Feng Feng,Xiao-Dong Wen,Wei Qu
ent -Sauchinone, a lignan isolated from Saururus chinensis ( Lour .) Baill ., was reported that it could modulate the expression of signal transducer and activator of transcription 3 (STAT3). Since STAT3 plays a key role in invasion, migration, and metastasis of cancer, we investigated whether ent -sauchinone could exert promising inhibitory effects on the invasion and migration of the metastatic human liver cancer cell line SMMC-7721 in the present study. ent -Sauchinone was extracted from dried herbs of Saururus chinensis ( Lour .) Baill . Human liver cancer cell lines SMMC-7721 and HCCLM3 were used to test the effect of ent -sauchinone on cell viability. The IC 50 values and time-dependent effect of ent -sauchinone were determined by MTT assay. Cell migration and invasion of SMMC-7721 were evaluated by the wound healing test and transwell assay respectively, the known anti-metastasis agent curcumin was used as a positive control. Western blotting assay was used to investigate relevant molecular mechanisms of cell invasion and migration. Though ent -sauchinone didn't show high cytotoxicity, the wound healing assay and transwell migration assay revealed a profound impairment in the metastatic potential of SMMC-7721 cells due to down-regulation of N-cadherin, MMP-2, and MMP-9 proteins induced by inhibiting the phosphorylation of STAT3. These findings suggest that ent -sauchinone could be used as a promising agent to treat cancer metastasis.
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TOXICOLOGY
·
2024
·
IF 4.8
Ruoyun Dong,Li Li,Hongmei Chang,Guanling Song,Sixiu Liu
Titanium dioxide nanoparticles (TiO 2 NPs) can reduce sperm number, but the mechanisms of defective spermatogenesis induced by TiO 2 NPs have not been studied through cell-cell interactions at present. A kind of biomimetic three-dimensional blood−testis barrier microfluidic chip capable of intercellular communication was constructed with soft lithography techniques, including Sertoli cell (TM4), spermatogonia (GC-1) and vascular endothelial cell units, to study the mechanisms of TiO 2 NPs-induced defective spermatogenesis. TM4 and GC-1 cells cultured in TiO 2 NPs exposure and control chips were collected for transcriptomics and metabonomics analysis, and key proteins and metabolites in changed biological processes were validated. In TM4 cells, TiO 2 NPs suppressed glucose metabolism, especially lactate production, which reduced energy substrate supply for spermatogenesis. TiO 2 NPs also decreased the levels of key proteins and metabolites of lactate production. In GC-1 cells, TiO 2 NPs disturbed chemokine signaling pathways regulating cell proliferation and interfered with glutathione metabolism. The Cxcl13, Stat3 and p-Stat3 levels and cell proliferation rate were decreased, and the GSR, GPX4 and GSH contents were increased in GC-1 cells in chips under TiO 2 NPs treatment. The decrease in energy substrate supply for spermatogenesis and inhibition of spermatogonia proliferation could be the main mechanisms of defective spermatogenesis induced by TiO 2 NPs.
研究领域:
纳米技术
·
生殖生物学
·
细胞生物学
·
分子生物学
·
毒理学
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CURRENT MOLECULAR MEDICINE
·
2017
·Vol. 17
·期 5
·381-387
·
IF 2.345
Zhu F.,Guan Y.,Zhang R.
Rationale: Studies have implied the positive association of JAK2/STAT3 signaling with the onset and severity of acute pancreatitis (AP). However, definitive functional study of JAK2/STAT3 signaling in the pathogenesis of acute pancreatitis in vivo is missing and its potential as a therapeutic
target and the underlying mechanisms remain to be determined. Objectives: The aim of this study was to explore the role of JAK2/STAT3 signaling in the pathogenesis of hyperlipidemia-intensified caerulin-induced AP and its potential as a therapeutic target. Methods and Results: Using
the caerulin-induced acute pancreatitis rat model, we showed that JAK2/STAT3 signaling was activated in pancreas and systemic inflammation was increased during AP. Pharmacological suppression of JAK2 by its inhibitor AG490 robustly protected against tissue damage, attenuated JAK2/STAT3 signaling
and inflammatory responses. Local pancreatic tissue damage and phosphor- JAK2 in the pancreatic tissue were enhanced in animals fed with high fat diet compared to chow-diet fed animals. Interestingly, JAK2 inhibitor AG490 significantly inhibited pancreas necrosis and systemic inflammation
in animals fed with high fat or chow-diet, but did not affect STAT3 signaling. Conclusion: These results establish that JAK2 activation plays a significant role in the pathogenesis of caerulin-induced AP in animals on both chow and high-fat diets by regulating necrosis and systemic inflammation.
Thus, our results not only clarify novel signaling mechanisms in AP but also suggest that JAK2 might constitute a target in the management of hyperlipidemia-intensified caerulin-induced AP.
研究领域:
胃肠病学
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药理学
·
分子生物学
·
炎症
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ANALYTICAL CHEMISTRY
·
2026
·
IF 7.3
Chao Murilege,He Miao,Cai Yongliang,Yin Feifan,Chen Jinhua,Pan Han,Cheng Wenting,Wang Zhongyun,Xiang Yang
Obesity is a major global health concern that substantially
increases
the risk of metabolic disorders. Signal Transducer and Activator of
Transcription 3 (STAT3) plays a pivotal role in the progression of
obesity by promoting the whitening of brown adipose tissue. In this
study, a novel and highly sensitive strategy for STAT3 mRNA detection
was developed by integrating three-way junction (3WJ)-mediated strand
displacement amplification (SDA) with rolling circle amplification
(RCA). The 3WJ structure enables specific target recognition through
a proximity effect, enabling accurate discrimination of STAT3 mRNA
and triggering primary signal amplification via SDA. The resulting
SDA products serve as primers to initiate RCA, achieving secondary
signal amplification while eliminating the need for exogenous primers
and effectively reducing background signals. This method enables femtomolar
(fM)-level detection of target mRNA and exhibits excellent selectivity
and stability in complex biological matrices. Overall, the proposed
strategy provides a reliable analytical platform for sensitive STAT3
mRNA analysis and broadens its potential applications in obesity research.
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OncoTargets and Therapy
·
2023
·
IF 4
Gang Wang,Yue Jing,Lingsen Cao,Changchang Gong,Zhunan Gong,Xiangrong Cao
Activation of the transcription factor, signal transducers and activators of transcription 3 (STAT3), has been linked to the proliferation and migration of a variety of human cancer cells. These actions occur via the upregulation or downregulation of cell survival and tumor suppressor genes, respectively. Importantly, agents that can suppress STAT3 activation have the potential for use in the prevention and treatment of various cancers. In this study, an Asiatic acid (AA) derivative, N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe), is reported to dose dependently suppress constitutive STAT3 activation in gastric cancer cells. This inhibition was mediated by blockade of Janus-activated kinase 2. Additionally, AA-PMe regulated the expression of STAT3-modulated gene products, including cyclin D1, Bax, Bcl-2, c-Myc, and matrix metalloproteinase (MMP)-2 and MMP-9. Finally, transfection with both a STAT3 mimic and an inhibitor reversed the AA-PMe-driven modulation of STAT3 downstream gene products. Overall, these results suggest that AA-PMe is a novel blocker of STAT3 activation and has the potential for the prevention and treatment of gastric cancer.
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Genes & Genomics
·
2022
·Vol. 45
·期 1
·1-11
·
IF 2.164
Cao Qingfei,Ma Jiaji,Li Weitao,Hong Peng,Shen Tong,Tong Ming
Background Guanine nucleotide-binding protein 2 (GNBP2) is a GTPase that has critical roles in host immunity and some types of cancer, but its function in clear cell renal cell carcinoma (ccRCC) is not fully understood. Objective This work explored the role of GNBP2 in ccRCC progression and the underlying molecular mechanism. Methods Two public human cancer databases TNMplot and TISIDB were employed to analyze the expression pattern of GNBP2 during ccRCC progression and the correlation between GNBP2 expression and clinical features of ccRCC patients. GNBP2 functions in ccRCC cells were determined by EdU staining, flow cytometry, scratch wound assay, transwell assay, and xenograft model. Gene expression was evaluated using qPCR, Western blot, immunofluorescence staining, and immunohistochemical staining. Results GNBP2 expression was significantly elevated in ccRCC tissues and increased gradually with the increasing tumor grades. Patients with higher GNBP2 expression had shorter overall survival times. Knockdown of GNBP2 suppressed tumor cell proliferation and cell cycle progression and reduced the capability of migration and invasion, while GNBP2 overexpression exhibited protumor effects. GNBP2 silencing by RNA interference significantly inhibited the tumor growth of tumor-bearing nude mice and decreased the proliferation marker Ki67. Mechanistically, GNBP2 downregulation suppressed the STAT3 signaling transduction, as it reduced the phosphorylation of STAT3 and modulated the expression of the target genes, including c-Myc, MMP2, N-cadherin, and E-cadherin. Conclusion These findings reveal that GNBP2 promotes ccRCC progression by regulating STAT3 signaling transduction, indicating that GNBP2 might be a promising molecular target for ccRCC therapy.
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