Nature Communications
·
2025
·Vol. 16
·期 1
·1-19
·
IF 15.7
Qi Houbao,Gao Haiting,Li Meihui,Sun Tianyong,Gu Xiufeng,Wei Li,Zhi Mengfan,Li Zixuan,Fu Dachuan,Liu Yiran,Wei Ziyi,Dou Yu,Feng Qiang
Parvimonas micra ( P. micra ), an opportunistic oral pathogen associated with multiple cancers, has limited research on its role in oral squamous cell carcinoma (OSCC). This study shows that P. micra is enriched in OSCC tissues and positively correlated with tumor metastasis and stages. P. micra infection promotes OSCC metastasis by inducing hypoxia/HIF-1α, glycolysis, and autophagy. Mechanistically, P. micra surface protein TmpC binds to CKAP4, a receptor overexpressed in OSCC, facilitating bacterial attachment and invasion. This interaction activates HIF-1α and autophagy via CKAP4-RanBP2 and CKAP4-NBR1 pathways, driving metastasis. Targeting CKAP4 with masitinib or antibodies impairs P. micra attachment and abolishes P. micra -promoted OSCC metastasis in vitro and in vivo. Together, our findings identify P. micra as a pathogen that promotes OSCC metastasis and highlight that TmpC-CKAP4 interaction could be a potential therapeutic target for OSCC.
研究领域:
肿瘤学
·
微生物学
·
分子生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Chemical Biology & Drug Design
·
2025
·Vol. 105
·期 6
·e70133
·
IF 3.3
Lin Xu,Dongsheng Yao,Tianying Lan,Yurou Chen,Dongping Chen,Minghai Shao,Yijing Zhou,Chaoyang Ye,Di Huang
Ferulic acid (FA), a natural phenolic compound, shows potential therapeutic effects on renal interstitial fibrosis, although its antifibrotic mechanism remains unclear. This study investigated the molecular mechanisms of FA by focusing on epithelial-mesenchymal transition (EMT) and related signaling pathways. By using a hypoxia-induced HK2 cell model, the optimal FA concentration was determined by CCK-8 assay, and the cells were assigned to low-, medium-, and high-FA groups. Renal fibrosis-associated protein and mRNA levels were evaluated by western blotting (WB) and reverse transcription-quantitative polymerase chain reaction. In a 5/6 nephrectomy-induced chronic renal failure rat model, renal oxygen consumption, serum creatinine, and blood urea nitrogen levels were measured, while ultrastructural and morphological changes in renal tissues were examined by transmission electron microscopy (TEM), hematoxylin–eosin (HE) staining, and Masson's trichrome staining. Renal fibrosis-related indicators were further assessed by Western Blot (WB) and immunofluorescence assay. The results showed that FA treatment significantly reduced fibronectin, HIF-1α, and α-SMA expression; inhibited partial EMT in vivo and in vitro; improved renal function; and attenuated fibrosis in kidney tissues. Combining siTwist or oe-HIF-1α transfection with FA treatment revealed that FA targeted the HIF-1α/Twist signaling pathway, impeding EMT and delaying renal fibrosis. In conclusion, FA inhibited partial EMT of tubular epithelial cells and suppressed the HIF-1α/Twist pathway, thereby mitigating renal interstitial fibrosis and providing a foundation for FA-based treatment of chronic kidney disease.
✓ 已验证
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2022
·
IF 7.31
Zhihui Yin,Demin Gao,Ke Du,Chen Han,Yuhan Liu,Ying Wang,Xiaoyan Gao
Mitochondrial oxidative stress plays an important role in the pathogenesis of Alzheimer’s disease (AD). Recently, antioxidant therapy has been considered an effective strategy for the treatment of AD. Our previous work discovered that rhein relieved mitochondrial oxidative stress in β-amyloid (Aβ) oligomer-induced primary neurons by improving the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha- (PGC-1α-) regulated mitochondrial biogenesis. While encouraging results have been provided, mechanisms underlying the beneficial effect of rhein on AD are yet to be elucidated in vivo. In this study, we evaluated the therapeutic effect of rhein on an APP/PS1 transgenic (APP/PS1) mouse model of AD and explored its antioxidant mechanisms. As a result, rhein significantly reduced Aβ burden and neuroinflammation and eventually ameliorated cognitive impairment in APP/PS1 mice. Moreover, rhein reversed oxidative stress in the brain of APP/PS1 mice and protected neurons from oxidative stress-associated apoptosis. Further study revealed that rhein promoted mitochondrial biogenesis against oxidative stress by upregulating SIRT1 and its downstream PGC-1α as well as nuclear respiratory factor 1. Improved mitochondrial biogenesis not only increased the activity of superoxide dismutase to scavenge excess reactive oxygen species (ROS) but also repaired mitochondria by mitochondrial fusion to inhibit the production of ROS from the electron transport chain. Notably, the exposure of rhein in the brain analyzed by tissue distribution study indicated that rhein could permeate into the brain to exert its therapeutic effects. In conclusion, these findings drive rhein to serve as a promising therapeutic antioxidant for the treatment of AD. Our research highlights the therapeutic efficacy for AD through regulating mitochondrial biogenesis via the SIRT1/PGC-1α pathway.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2022
·Vol. 20
·期 1
·1-16
·
IF 9.429
Liu Jie,Hu Xiaochun,Feng Lei,Lin Yun,Liang Shujing,Zhu Zhounan,Shi Shuo,Dong Chunyan
Background Non-redundant properties such as hypoxia and acidosis promote tumor metabolic adaptation and limit anti-cancer therapies. The key to the adaptation of tumor cells to hypoxia is the transcriptional and stable expression of hypoxia-inducible factor-1 alpha (HIF-1α). The phosphorylation-activated tumorigenic signal PI3K/AKT/mTOR advances the production of downstream HIF-1α to adapt to tumor hypoxia. Studies have elucidated that acid favors inhibition of mTOR signal. Nonetheless, carbonic anhydrase IX (CAIX), overexpressed on membranes of hypoxia tumor cells with pH-regulatory effects, attenuates intracellular acidity, which is unfavorable for mTOR inhibition. Herein, a drug delivery nanoplatform equipped with dual PI3K/mTOR inhibitor Dactolisib (NVP-BEZ235, BEZ235) and CAIX inhibitor 4‐(2‐aminoethyl) benzene sulfonamide (ABS) was designed to mitigate hypoxic adaptation and improve breast cancer treatment. Results ABS and PEG-NH 2 were successfully modified on the surface of hollow polydopamine (HPDA), while BEZ235 and Chlorin e6 (Ce6) were effectively loaded with the interior of HPDA to form HPDA-ABS/PEG-BEZ235/Ce6 (H-APBC) nanoparticles. The release of BEZ235 from H-APBC in acid microenvironment could mitigate PI3K/mTOR signal and resist HIF-1α-dependent tumor hypoxia adaptation. More importantly, ABS modified on the surface of H-APBC could augment intracellular acids and enhances the mTOR inhibition. The nanoplatform combined with phototherapy inhibited orthotopic breast cancer growth while reducing spontaneous lung metastasis, angiogenesis, based on altering the microenvironment adapted to hypoxia and extracellular acidosis. Conclusion Taken together, compared with free BEZ235 and ABS, the nanoplatform exhibited remarkable anti-tumor efficiency, reduced hypoxia adaptation, mitigated off-tumor toxicity of BEZ235 and solved the limited bioavailability of BEZ235 caused by weak solubility. Graphical Abstract
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
·
2021
·
IF 5.89
Dong Wenpei,Song Zhicheng,Liu Suihong,Yu Ping,Shen Zhipeng,Yang Jianjun,Yang Dongchao,Hu Qinxi,Zhang Haiguang,Gu Yan
Application of synthetic or biological meshes is the main therapy for the repair and reconstruction of abdominal wall defects, a common disease in surgery. Currently, no ideal materials are available, and there is an urgent need to find appropriate ones to satisfy clinical needs. Electrospun scaffolds have drawn attention in soft tissue reconstruction. In this study, we developed a novel method to fabricate a composite electrospun scaffold using a thermoresponsive hydrogel, poly (N-isopropylacrylamide)-block-poly (ethylene glycol), and a biodegradable polymer, polylactic acid (PLA). This scaffold provided not only a high surface area/volume ratio and a three-dimensional fibrous matrix but also high biocompatibility and sufficient mechanical strength, and could simulate the native extracellular matrix and accelerate cell adhesion and proliferation. Furthermore, rat adipose-derived stem cells (ADSCs) were seeded in the composite electrospun scaffold to enhance the defect repair and regeneration by directionally inducing ADSCs into endothelial cells. In addition, we found early vascularization in the process was regulated by the hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway. In our study, overexpression of HIF-1α/VEGF in ADSCs using a lentivirus system promoted early vascularization in the electrospun scaffolds. Overall, we expect our composite biomimetic scaffold method will be applicable and useful in abdominal wall defect regeneration and repair in the future.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2020
·Vol. 31
·期 5
·2008515
·
IF 16.836
Lili Sun,Yifan Ma,Haoyi Niu,Yutong Liu,Yuan Yuan,Changsheng Liu
Due to the limited ability for perfusion, traditional intramembranous ossification (IMO) often fails to recapitulate the natural regeneration process of most long bones and craniofacial bones. Alternatively, endochondral ossification (ECO) strategy has emerged and has been evidenced to circumvent the drawbacks in the routine application of IMO. Here, an injectable, poly(glycerol sebacate)- co -poly (ethylene glycol)/polyacrylic acid (PEGS/PAA) hydrogels are successfully developed to induce a hypoxia-mimicking environment and subsequently recapitulate ECO via in situ iron chelation. With the incorporation of PAA, these hydrogels present remarkable viscoelasticity and high efficacy of iron ion-chelating after injection, giving rise to the activation of HIF-1α signaling pathway and suppression of inflammatory responses, and thereby improving chondrogenic differentiation in the early stage and facilitating vascularization in the later stage, which consequently trigger typical ECO. More importantly, through sustained and stable expression of HIF-1α regulated by PEGS/PAA hydrogels throughout the regeneration, a harmonious chondrogenic/osteogenic balance can be struck and thereby accelerating the progress of ECO compared to the PEGS. The findings provide an efficient strategy to achieve in situ ECO via biomaterial-based iron ion-chelating and ensuing hypoxia-mimicking, representing a novel and promising concept for future application in bone regeneration.
研究领域:
生物材料
·
组织工程
·
骨科
·
再生医学
✓ 已验证
DOI
高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Hongtao Zhang,Yi Huang,Songhong Yang,Feipeng Gong,Yuncheng Gu,Qin Xie,Yanrong Ye,Xingmei Lu,Lingyun Zhong
Introduction: Sand-fired aconite slices (SFAS) demonstrate anti-heart failure effects, but the mechanism remains unclear. This study investigated myocardial mitochondrial energy metabolism as a therapeutic mechanism of SFAS in doxorubicin-induced chronic heart failure (CHF) rats.Methods: The CHF rat model was established via the intraperitoneal injection of doxorubicin (DOX). Following successful model production, rats were randomly assigned to nine groups. After drug administration, their cardiac function was assessed, and their cardiac tissue morphology and myocardial mitochondria were examined. Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), norepinephrine (NE), malondialdehyde (MDA), superoxide dismutase (SOD), free fatty acid (FFA), sodium-potassium-ATPase (Na+-k+-ATPase), calcium-magnesium-ATPase (Ca2+-Mg2+-ATPase), and adenosine triphosphate (ATP) levels were quantified using enzyme-linked immunosorbent assays (ELISAs). Fatty acid translocase (CD36), carnitine palmitoyl transferase 1 (CPT1), adenosine 5′-monophosphate-activated protein kinase (AMPK), phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK), peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α), and Sirtuin 3 (SIRT3) protein expression levels were assessed by Western blot.Results: SFAS significantly improved cardiac function in CHF rats. It increased the left ventricular ejection fraction (LVEF) (from 34.22% ± 2.03%–83.68% ± 2.34%; P < 0.001) and left ventricular shortening fraction (LVFS) (from 17.06% ± 1.08%–53.86% ± 2.82%; P < 0.001) and decreased ANP (from 551.29 ± 14.63 pg/mL to 291.96 ± 11.28 pg/mL; P < 0.05), BNP (from 743.15 ± 18.03 pg/mL to 478.75 ± 10.57 pg/mL; P < 0.001), and NE levels (from 1,105.36 ± 21.79 pg/mL to 672.67 ± 6.70 pg/mL; P < 0.001). Additionally, it decreased MDA production (from 8.89 ± 0.36 nmol/mL to 5.11 ± 0.35 nmol/mL; P < 0.05) and increased SOD activity (from 264.82 ± 4.26 pg/mL to 529.64 ± 10.27 pg/mL; P < 0.001), Na+-K+-ATPase levels (from 7.19 ± 0.65 μmol/mL to 14.08 ± 0.28 μmol/mL; P < 0.001), Ca2+-Mg2+-ATPase levels (from 0.86 ± 0.03 μmol/mL to 1.40 ± 0.02 μmol/mL; P < 0.05), CD36 levels (P < 0.05), and CPT1 levels (P < 0.01). Moreover, it improved mitochondrial structural damage and reduced the level of oxidative stress in cardiomyocytes. Furthermore, SFAS promoted FFA oxidation (from 1,477.49 ± 7.60 μmol/mL to 768.87 ± 82.53 μmol/mL; P < 0.05) and ATP production (from 2,869.85 ± 298.26 nmol/mL to 5,483.17 ± 120.03 nmol/mL; P < 0.001) and increased p-AMPK, PGC-1α, and SIRT3 levels (P < 0.05 and P < 0.01).Conclusion: By activating the AMPK/PGC-1α/SIRT3 signaling pathway, SFAS ameliorated the impaired fatty acid oxidation pathway and enhanced mitochondrial function and antioxidant capacity in cardiomyocytes, ultimately reducing myocardial damage and restoring cardiac function in CHF rats.
研究领域:
心血管药理学
·
中医药学
·
线粒体生物学
·
代谢紊乱
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-19
·
IF 10.6
Liu Yang,Ding Lei,Chen Gaojie,Wang Peiyuan,Wang Xinghuan
Tumor cells can survive when detached from the extracellular matrix (ECM) or lose cell–cell connections, a phenomenon known as anoikis-resistance (AR). AR is closely associated with tumor cell metastasis and recurrence, enabling tumor cells to disseminate, migrate, and invade after detachment. To address this issue, a novel intervention method combining intraoperative hemostasis with multifunctional nanozyme driven-enhanced chemodynamic therapy (ECDT) has been proposed, which holds the potential to weaken the AR capability of tumor cells and suppress tumor recurrence. Here, a nanocomposite containing a dendritic mesoporous nanoframework with Cu 2+ was developed using an anion-assisted approach after surface PEG grafting and glucose oxidase (GOx) anchoring (DMSN-Cu@GOx/PEG). DMSN-Cu@GOx/PEG was further encapsulated in a thermal-sensitive hydrogel (H@DMSN-Cu@GOx/PEG). DMSN-Cu@GOx/PEG utilizes its high peroxidase (POD) activity to elevate intracellular ROS levels, thereby weakening the AR capability of bladder cancer cells. Additionally, through its excellent catalase (CAT) activity, DMSN-Cu@GOx/PEG converts the high level of hydrogen peroxide (H 2 O 2 ) catalyzed by intracellular GOx into oxygen (O 2 ), effectively alleviating tumor hypoxia, downregulating hypoxia-inducible factor-1α (HIF-1α) expression, inhibiting epithelial-mesenchymal transition (EMT) processes, and ultimately suppressing the migration and invasion of bladder cancer cells. Interestingly, in vivo results showed that the thermosensitive hydrogel H@DMSN-Cu@GOx/PEG could rapidly gel at body temperature, forming a gel film on wounds to eliminate residual tumor tissue after tumor resection surgery. Importantly, H@DMSN-Cu@GOx/PEG exhibited excellent hemostatic capabilities, effectively enhancing tissue coagulation during post-tumor resection surgery and mitigating the risk of cancer cell dissemination and recurrence due to surgical bleeding. Such hydrogels undoubtedly possess strong surgical application. Our developed novel nanosystem and hydrogel can inhibit the AR capability of tumor cells and prevent recurrence post-surgery. This study represents the first report of using dendritic mesoporous silica-based nanoreactors for inhibiting the AR capability of bladder cancer cells and suppressing tumor recurrence post-surgery, providing a new avenue for developing strategies to impede tumor recurrence after surgery. Graphical Abstract
研究领域:
生物医学工程
·
纳米技术
·
癌症生物学
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2024
·
IF 18.5
Huajing Zeng,Ziyan Chen,Pengyu Wei,Haofei Huang,Bin Liu,Zengjie Fan
3D printing of articular cartilage tissue faces challenges like replicating its complex structure, time-consuming in vitro stem cell culture, and a lack of robust in situ regeneration methods for osteochondral defects (OC). In response, an innovative approach utilizing pre-designed bioink modular units for one-step printing and immediate implantation is proposed, circumventing the need for prior in vitro stem cell cultivation. The resulting printed scaffold not only accurately reproduces the three-layer structure and material gradient of articular cartilage tissue but also attains impressive compressive strength (6.3 MPa) through the reinforcement of hydroxyapatite nanofibers and the establishment of chemical bonds with hydrogels. Moreover, the scaffold integrates stem cell capturing and homing layers on its bottom and top layers via chemical crosslinking aptamer and loading poly (lactic-co-glycolic acid) (PLGA) nanospheres encapsulated with stromal cell-derived factor-1α (SDF-1α), respectively. This design enables the specific capture of bone marrow mesenchymal stem cells (BMSCs) in vivo through aptamer interaction, followed by their mobilization to home in on the hyaline cartilage layer via the chemotaxis of SDF-1α concentration gradient. Within the scaffold's microenvironment, these BMSCs undergo differentiation into distinct cells for each layer, effectively contributing to the repair of OC defects in rabbits.
研究领域:
生物医学工程
·
组织工程
·
再生医学
·
干细胞生物学
·
材料科学
✓ 已验证
产品关联
DOI
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2018
·
IF 4.235
Zhihua Wang,Sheng Yuan,Yanbing Li,Zhe Zhang,Wei Xiao,Dan Tang,Kaihe Ye,Zhijun Liu,Congcong Wang,Yixiong Zheng,Hong Nie,Heru Chen
( R , E )- N -(3-(2-acetamido-3-(benzyloxy) propanamido)propyl)-2-cyano-3-(4-hydroxy phenyl)acrylamide ( hr5F ) was design-synthesized based on bioactivity focus strategy as a potential agent to treat diabetic complicates. With in vitro enzyme assay, it is confirmed that hr5F is an effective ALR2 inhibitor with IC 50 value of 2.60 ± 0.15 nM, and selectivity index of 86.0 over ALR1, which is a little bit better than the reference Epalrestat (Epa). hr5F inhibits the increase of ALR2 enzyme activity and expression in human lens epithelial cells (HLECs) induced by high glucose. By applying western blot , it was found that hr5F alleviates the high glucose-induced superoxide overproduction insults by regulating SIRT1-PGC-1α/Nrf2 pathway, together with regulating NRF-1, mtTFA , Bax/Bcl-2 to ameliorate cell apoptosis . The in vivo effects of hr5F on short term streptozocin (STZ)-induced diabetic mice confirm the same functions disclosed in vitro . All the evidences support that hr5F may serve as a promising agent in the treatment of diabetic complications with close efficacy and broader indication than the reference Epa.
研究领域:
药理学
·
糖尿病
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF PHARMACY AND PHARMACOLOGY
·
2023
·
IF 3.3
Zeng Xiangfeng,Liu Shengyao,Yang Hua,Jia Menglei,Liu Wei,Zhu Wenting
ObjectivesThe most common cause of osteosarcoma (OS) death is lung metastasis. Currently, doxorubicin is the primary chemotherapy drug used to treat OS, however, it is not effective in inhibiting metastasis, and it has obvious cardiotoxicity. The anticancer activity of ginsenoside Rg3 has been demonstrated in a variety of malignant tumours. The aim of this study was to determine the potential role of ginsenoside Rg3 and doxorubicin in OS and the possible mechanism.MethodsThe potential synergistic effects of ginsenoside Rg3 and doxorubicin on human osteosarcoma cells 143B and U2OS, human umbilical vein endothelial cells, and mice receiving 143B xenografts and lung metastases were investigated.Key findingsOur study demonstrated that the combination of ginsenoside Rg3 and doxorubicin significantly inhibited cell proliferation, metastasis and angiogenesis in vitro. Mechanically, the anti-tumour activity of ginsenoside Rg3 and doxorubicin by modulating mTOR/HIF-1α/VEGF and EMT signalling pathways. Furthermore, ginsenoside Rg3 combined with doxorubicin inhibits tumour growth and lung metastasis in 143B-derived murine osteosarcoma models. More importantly, ginsenoside Rg3 can effectively ameliorate doxorubicin-induced weight loss and cardiotoxicity in mice.ConclusionsConsequently, we concluded that the combination of ginsenoside Rg3 and doxorubicin displayed an evidently synergistic effect, which has the potential to be used as an effective and safe therapeutic approach for OS treatment.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Tingting Wu,Lulu Wang,Chen Jian,Chen Gao,Yajing Liu,Zhiwen Fu,Chen Shi
Refractory fracture presents an intractable challenge in trauma treatment. Selective polarization of macrophages as well as the recruitment of osteogenic precursor cells play key roles in osteogenic differentiation during fracture healing. Here we constructed regulatory T cell (Treg)-derived exosomes (Treg-Exo) for the treatment of fracture. The obtained exosomes displayed a spheroid shape with a hydrated particle size of approximately 130 nm. With further purification using CD39 and CD73 antibody-modified microfluidic chips, CD39 and CD73 specifically expressing exosomes were obtained. This kind of Treg-Exo utilized the ectonucleotidases of CD39 and CD73 to catalyze the high level of ATP in the fracture area into adenosine. The generated adenosine further promoted the selective polarization of macrophages. When interacting with mesenchymal stem cells (MSCs, osteogenic precursor cells), both Treg-Exo and Treg-Exo primed macrophages facilitated the proliferation and differentiation of MSCs. After administration in vivo , Treg-Exo effectively promoted fracture healing compared with conventional T cell-derived exosome. To further improve the delivery efficacy of exosomes and integrate multiple biological processes of fracture healing, an injectable hydrogel was fabricated to co-deliver Treg-Exo and stromal cell-derived factor 1 alpha (SDF-1α). With the dual effect of Treg-Exo for macrophage polarization and SDF-1α for MSC recruitment, the multifunctional hydrogel exerted a synergistic effect on fracture repair acceleration. This study provided a promising therapeutic candidate and synergistic strategy for the clinical treatment of fracture.
研究领域:
免疫学
·
再生医学
·
骨科
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）