ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Siqi Yu,Fudong Wang,Yuan Zhang,Xiaofeng Wang,Hongyu Zhao,Qiang Zheng
Autophagy inhibition induced by paraquat (PQ) poisoning is an important factor causing multi-organ damage, including renal tissue. Dihydrocapsaicin (DHC), the main active ingredient in chili peppers, was reported to induce autophagy, but its effect on PQ-induced AKI remains unclear. Rats were intraperitoneally injected with 25 mg/kg PQ to establish AKI rat model followed immediately by DHC administration (2.5, 5, or 10 mg/kg, i.p.). Rat renal tubular epithelial cells were exposed to PQ (300 μM) in combination with DHC (25, 50, or 100 μM) for 24 h. The results showed that DHC treatment attenuated PQ-induced renal injury and dysfunction while suppressing apoptosis and oxidative stress in vivo and in vitro . Furthermore, DHC administration induced autophagy—a protective mechanism against oxidative stress and apoptosis—as demonstrated by: 1) increased autophagosome/autophagolysosome formation, 2) upregulated LC3-II and autophagy-related gene 7 expressions and reduced p62 protein level. Blocking of autophagy by 3-methyladenine (3-MA) reversed the effects of DHC. Interestingly, transcription factor sex determining region Y-box 9 (Sox9) and autophagy inducer Sestrin2 RNA levels were increased by DHC treatment. Sox9 activated Sestrin2 transcription through direct binding to its promoter region. Sox9 or Sestrin2 silencing reversed the effects of DHC. Collectively, our findings demonstrate that DHC attenuates PQ-induced AKI via Sox9/Sestrin2 axis-mediated autophagy, indicating therapeutic utility of DHC against AKI.
研究领域:
药理学
·
毒理学
·
分子生物学
·
肾脏病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL ANIMALS
·
2023
·
IF 2.4
Sheng LI,Gaoxiang OUYANG,Linhui YUAN,Xiaoxuan WU,Lijun ZHANG
Diabetic retinopathy (DR), a common complication of diabetes, involves excessive proliferation and inflammation of Muller cells and ultimately leads to vision loss and blindness. SRY-box transcription factor 9 (SOX9) has been reported to be highly expressed in Müller cells in retinal light-damaged rats, but the functional role of SOX9 in DR remains unclear. To explore this issue, the DR rat model was successfully constructed via injecting with streptozotocin (STZ, 65 mg/kg) and the retinal thicknesses and blood glucose levels were evaluated. Müller cells were treated with 25 mmol/L glucose to create a cell model in vitro. The results indicated that SOX9 expression was significantly increased in DR rat retinas and high glucose (HG)-stimulated Müller cells. HG treatment promoted the proliferation and migration capabilities of Müller cells, whereas SOX9 knockdown reversed those behaviors. Moreover, SOX9 knockdown protected against HG-induced inflammatory response, as evidenced by reduced tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 levels in serum and decreased NLRP3 inflammasome activation. Notably, SOX9, acted as a transcription factor that positively regulated thioredoxin-interacting protein (TXNIP), a positive regulator of Müller cells gliosis under HG conditions. Dual luciferase assay demonstrated that SOX9 could enhance TXNIP expression at the transcriptional level through binding to the promoter of TXNIP. Moreover, TXNIP overexpression restored the effects caused by SOX9 silencing. In conclusion, these findings demonstrate that SOX9 may accelerate the progression of DR by promoting glial cell proliferation, metastasis, and inflammation, which involves the transcriptional regulation of TXNIP, providing new theoretical fundamentals for DR therapy.
研究领域:
眼科学
·
细胞生物学
·
糖尿病
·
转录调控
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-25
·
IF 12.6
Zhang Xiaoyu,Guo Qianping,Fang Jiawei,Cheng Qi,Zhu Zhuang,Yu Qifan,Wang Huan,Hong Youzhi,Liu Chengyuan,Yang Huilin,Zhu Caihong,Li Bin,Ni Li
Nucleus pulposus cells (NPCs) undergo metabolic disorders and matrix pathological remodeling under the influence of various adverse factors during intervertebral disc degeneration (IVDD), whereas post-translational modifications (PTMs) can confer cells with the capacity to respond quickly and adapt to complex environmental changes. Here, SIRT1 protein, a key regulator within PTMs framework, was applied against the hostile degenerative microenvironment. Then, it was sequentially assembled with SOX9-expressing plasmid, an essential transcription factor to promote extracellular matrix (ECM) biosynthesis, onto a phenylboronic acid-functionalized G5-dendrimer to construct a multifunctional nanoplatform for IVDD therapy. In vitro, the nanoplatforms showed antioxidant capacity, and the ability to restore mitochondrial homeostasis and normal ECM metabolism, as well as to maintain cellular phenotypes. RNA sequencing suggested that inhibition of the Nod-like receptor signaling might be the mechanism behind their therapeutic effects. The nanoplatforms were then wrapped in a designed dynamic hydrogel, not only prolonging the retention time of the loaded cargoes, but also well maintaining the disc structure, height, and water content in vivo. Overall, this study presents a convenient assembled strategy to inhibit the multiple adverse factors, and hold promise for the IVDD treatment. Graphical abstract
研究领域:
医学
·
生物材料学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2022
·
IF 7.31
Qiang Zheng,Yuan Zhang,Xiaofeng Wang,Fudong Wang,Hongyu Zhao
Paraquat (PQ) is a widely used herbicide but can be lethal to humans. The kidney is vital for PQ elimination; therefore, explorations for therapeutic approaches for PQ-induced acute kidney injury (AKI) are of great significance. Here, the effects of a natural bioactive polyphenol isorhapontigenin (ISO) on PQ-AKI were investigated. In vitro experiments carried out in PQ-intoxicated rat renal tubular epithelial cells (NRK-52E) showed that ISO treatment inhibited PQ-induced cell apoptosis and oxidative stress, which was evidenced by the decreased proapoptotic proteins [cleaved caspase 3/9 and poly (ADP-ribose) polymerase (PARP)], the reduced oxidative stress indicators [reactive oxygen species (ROS), malondialdehyde (MDA), and lactate dehydrogenase (LDH) leakage], and the increased antioxidants [superoxide dismutase (SOD), nuclear factor E2-related factor 2 (NRF2), and oxygenase-1 (HO-1)]. Furthermore, 50 mg/kg ISO pretreatment before PQ administration significantly attenuated PQ-AKI in rats, as manifested by the improved renal tubule damage, the reduced serum and urine markers of kidney injury, and the inhibited cell apoptosis and oxidative stress in the renal cortex. Furthermore, expression of sex-determining region Y box 9 (SOX9) and Toll-interacting protein (TOLLIP) in NRK-52E cells and the renal cortex was significantly upregulated after ISO treatment. Overexpression of SOX9 increased TOLLIP transcription and attenuated PQ-induced apoptosis and oxidative stress, whereas knockdown of SOX9 impaired the protective effects of ISO on NRK-52E cells against PQ toxicity. In conclusion, the present study demonstrated that ISO modulated SOX9/TOLLIP expression to attenuate cell apoptosis and oxidative stress in PQ-AKI, suggesting the potential of ISO in treating PQ-poisoned patients.
研究领域:
药理学
·
毒理学
·
肾脏生理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2024
·
IF 13
Minfeng Zhou,Huifang Niu,Guoquan Huang,Minquan Zhou,Dandan Cui,Huarong Li,Han Wen,Hongxing Zhang,Fengxia Liang,Rui Chen
Suppressing tumor metastasis is a crucial strategy for improving survival rates in patients with colorectal cancer (CRC), with cancer stem cells (CSCs) being the primary drivers of metastasis. Current therapeutic approaches targeting CSCs are limited, and their molecular mechanisms remain unclear. To address this challenge, a biomimetic nanoparticle delivery system, CMD-BHQ3-PTL/DOX@RBCM is developed, to deliver the stem cell regulator, piceatannol (PTL). This system used carboxymethyl dextran (CMD) and Black Hole Quencher 3 (BHQ3) to encapsulate PTL and the cytotoxic drug doxorubicin (DOX) within a red blood cell membrane (RBCm), enhancing stability and biocompatibility while allowing gradual drug release under hypoxic conditions. The effects of PTL are investigated on CSCs using molecular biology experiments, plasmid construction, and high-throughput sequencing and elucidated the molecular mechanisms underlying this biomimetic nanoparticle delivery system. The therapeutic efficacy of PTL is validated at the tissue level using subcutaneous and metastatic tumor models in human and murine systems. The results demonstrated that CMD-BHQ3-PTL/DOX@RBCM effectively addressed the challenges of specificity and biocompatibility in vivo, significantly inhibiting CSC-related tumor metastasis. This inhibitory effect is closely associated with the Hippo/YAP1/SOX9 pathway. This study highlights the effectiveness of the pH-responsive biomimetic nanoparticle system CMD-BHQ3-PTL/DOX@RBCm in delivering PTL to tumor sites, with SOX9 and its upstream Hippo/YAP1 pathway playing a critical role in the underlying mechanism.
研究领域:
肿瘤学
·
分子生物学
·
纳米医学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2025
·
IF 4.5
Zhen Zhang,Hongbo Wang,Zhijun Zhang,Yaoyao Zhang,Huajing Sun,Xi Chen,Jiayu Gu,Yanling Gong
Small interfering RNA (siRNA)-based therapy, which silences disease-associated genes, has emerged as a potential therapeutic strategy for various disorders, including cancer. Lipid nanoparticles (LNPs) have become a leading platform for efficient siRNA delivery. SOX9, a family member of SRY-related high-mobility-group box (SOX) transcription factors, plays an important role in the pathogenesis and progression of colorectal cancer (CRC). Here, we developed cRGDfK peptide-modificed LNPs (R-LNPs) composed of DLin-MC3-DMA, DMG-PEG, DSPC, DSPE-PEG-cRGDfK, and cholesterol for the targeted delivery of SOX9 siRNA (siSOX9) in CRC treatment. The formulation, delivery, and antitumor effect on CRC in vitro and in vivo were explored. The optimized R-LNPs exhibited favorable physicochemical properties including a uniform particle size (159.6 ± 0.93 nm), low polydispersity index (PDI = 0.207 ± 0.016), near-neutral zeta potential (2.74 ± 0.35 mV), and high encapsulated efficiency (90.71 ± 1.63%). Additionally, R-LNPs demonstrated sustained and controlled in vitro release and good serum stability. The prepared R-LNPs were efficiently uptaken by HCT-116 via clathrin, lipid rafts, and caveolae dependent endocytosis and macropinocytosis. Subsequently, R-LNPs were colocalized with lysosomes before escaping into the cytoplasm, ensuring effective siRNA release. In vivo distribution studies confirmed tumor-specific accumulation for R-LNPs in HCT-116 xenograft models. Functionally, R-LNPs loading siSOX9 inhibited the proliferation, migration, and invasion of HCT-116 cells and Caco-2 cells (P < 0.05 or 0.01) and inhibited tumor growth and proliferation in tumor-bearing mice (P < 0.05 or 0.01). The antitumor effects were attributed to the silence of SOX9, which subsequently downregulated key oncogenic mediators, including β-catenin, cyclin D1, and c-Myc (P < 0.05 or 0.01). Furthermore, R-LNPs demonstrated favorable safety in in vivo application. In conclusion, our cRGDfK-modified LNPs loading siSOX9 represent a promising targeted therapeutic strategy for CRC, offering both efficacy and biocompatibility.
研究领域:
药剂学
·
肿瘤学
·
纳米技术
·
分子生物学
·
药物递送
·
生物技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
iScience
·
2021
·
IF 5.458
Shenghui Liu,Dan Qin,Yi Yan,Jiayan Wu,Lihua Meng,Wendong Huang,Liqiang Wang,Xiangmei Chen,Lisheng Zhang
Summary Recent research has indicated the adult liver Sox9 + cells located in the portal triads contribute to the physiological maintenance of liver mass and injury repair. However, the physiology and pathology regulation mechanisms of adult liver Sox9 + cells remain unknown. Here, PPARα and FXR bound to the shared site in Sox9 promoter with opposite transcriptional outputs. PPARα activation enhanced the fatty acid β-oxidation, oxidative phosphorylation (OXPHOS), and adenosine triphosphate (ATP) production, thus promoting proliferation and differentiation of Sox9 + hepatocytes along periportal (PP)-perivenous (PV) axis. However, FXR activation increased glycolysis but decreased OXPHOS and ATP production, therefore preventing proliferation of Sox9 + hepatocytes along PP-PV axis by promoting Sox9 + hepatocyte self-renewal. Our research indicates that metabolic nuclear receptors play critical roles in liver progenitor Sox9 + hepatocyte homeostasis to initiate or terminate liver injury-induced cell proliferation and differentiation, suggesting that PPARα and FXR are potential therapeutic targets for modulating liver regeneration.
研究领域:
分子生物学
·
肝病学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
TISSUE & CELL
·
2023
·
IF 2.6
Yujun Zhao,Xiaotie Wang,Keke Nie
Background Osteoarthritis is a main cause of deformity in aging people. The chondrogenesis of human adipose-derived stem cells (hADSCs) has a positive effect on the cure of osteoarthritis. However, the regulatory mechanism of hADSC chondrogenesis still needs further exploration. This research investigates the role of interferon regulatory factor 1 (IRF1) in the chondrogenesis of hADSCs. Methods hADSCs were purchased and cultured. The interaction between IRF1 and hypoxia inducible lipid droplet associated (HILPDA) was predicted by bioinformatics analysis, and verified through dual-luciferase reporter and chromatin immunoprecipitation assays. The expressions of IRF1 and HILPDA in osteoarthritis cartilage samples were measured through qRT-PCR. After hADSCs were transfected or further induced for chondrogenesis, the chondrogenesis was visualized by Alcian blue staining, and the expressions of IRF1, HILPDA and chondrogenesis-related factors (SOX9, Aggrecan , COL2A1, MMP13, MMP3) were determined through qRT-PCR or Western blot . Results HILPDA bound to IRF1 in hADSCs. IRF1 and HILPDA levels were up-regulated during the chondrogenesis of hADSCs. Overexpressions of IRF1 and HILPDA promoted the chondrogenesis of hADSCs with the up-regulation of SOX9 , Aggrecan and COL2A1 and the down-regulation of MMP13 and MMP3 ; however, IRF1 silencing generated the opposite effects. Besides, HILPDA overexpression reversed the effects of IRF1 silencing on inhibiting chondrogenesis of hADSCs and regulating the expressions of chondrogenesis-related factors. Conclusion IRF1 promotes the chondrogenesis of hADSCs through up-regulating HILPDA level, providing novel biomarkers for treating osteoarthritis.
研究领域:
干细胞生物学
·
骨科
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomedical Materials
·
2022
·Vol. 17
·期 2
·024105
·
IF 4.103
Yuheng Cao,Haobo He,Kaili Cao,Yongyang Liu,Dehua Huang,Tuanwei Li,Guangcun Chen
Controllable regulation of stem cell differentiation is a critical concern in stem cell-based regenerative medicine. In particular, there are still great challenges in controlling the directional differentiation of neural stem cells (NSCs) into neurons. Herein, we developed a novel linear-branched poly(β-amino esters) (S4-TMPTA-BDA-DT, STBD) through a two-step reaction. The synthesized linear-branched polymers possess multiple positively charged amine terminus and degradable intermolecular ester bonds, thus endowing them with excellent properties such as high gene load, efficient gene delivery, and effective gene release and transcription in cells. In the mCherry transfection test, a high transfection efficiency of approximately 70% was achieved in primary NSCs after a single transfection. Moreover, STBD also showed high biocompatibility to NSCs without disturbing their viability and neural differentiation. With the high gene delivery property, STBD is capable of delivering siRNA (shSOX9) expression plasmid into NSCs to significantly interfere with the expression of SOX9, thus enhancing the neuronal differentiation and maturation of NSCs. The STBD/DNA nano-polyplex represents a powerful non-viral approach of gene delivery for manipulating the differentiation of stem cells, showing broad application prospects in NSC-based regenerative therapy for treating neurodegenerative diseases.
研究领域:
再生医学
·
基因治疗
·
干细胞生物学
·
神经科学
✓ 已验证
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Wenjie Zhang,Wenliang Xue,Zhaoli Jia,Rong Yang,Penghui Wang,Yi Hu,Xiaoyan Tan,Qiang Chen,Bo Chi
Regenerating damaged cartilage remains a challenge due to limited cell availability and inefficient chondrogenic differentiation. Here, we present a photo-driven dynamic hydrogel with a double-network structure to meet this challenge. The fabrication strategy involves a combination of a photosensitive host–guest network with a covalent network, providing tunable mechanical cues that effectively regulate bone marrow mesenchymal stem cells (BMSCs) behavior within their microenvironment while maintaining macroscopical stability. Employing a two-step stiffness-tunable process mediated by controlled low-dose light exposure, the hydrogel exerts precise control over BMSCs proliferation and orchestrates chondrogenic differentiation, leading to the upregulation of crucial chondrogenic genes, notably SOX9 and ACAN. Empirical evidence derived from histological analysis substantiates the functional efficacy of the hydrogel, confirming the regenerative potential of cartilage tissues. This study presents an innovative and promising strategy for stem cell culture, in vitro differentiation, and cell delivery, with implications for cartilage defect repair and tissue regeneration.
研究领域:
组织工程
·
干细胞生物学
·
生物医学材料
·
再生医学
✓ 已验证
产品关联
DOI
高影响因子
CURRENT MEDICINAL CHEMISTRY
·
2024
·
IF 3.5
Shang JingJing,Xiong Chenwei,Jiang Wei,Yu Zhentang,Zhang Junjie,Zhang Yi,Han Long,Miao Kaisong,Yu Changlin,Huang Yong,Zhou Xindie
Background: Osteoarthritis (OA) is a chronic joint disease, usually accompanied by degeneration
of the articular cartilage, fibrosis, bone hyperplasia around the joint, and damage to the
entire articular surface. Gossypol is a natural phenolic compound isolated from the seed of cotton
plants, and gossypol acetic acid (GAA) is a medicinal form of Gossypol. Recently, various biological
activities of GAA, including anti-inflammatory and anti-tumor effects, have been widely reported.
However, its effect on chondrocytes in OA has yet to be determined.
Methods: In this study, we investigated the effect of GAA on ferroptosis in OA chondrocytes. The
effect of GAA on the cell viability and cytotoxicity of chondrocytes in rat cells was investigated
using CCK8. Western blotting, Reverse-transcription PCR (RT-PCR), and immunofluorescence
staining were used to elucidate the molecular mechanisms and signaling pathways of GAA inhibition
of ferroptosis in OA chondrocytes. The effect of GAA on reactive oxygen species (ROS) production
and lipid peroxidation levels in chondrocytes was examined using dihydroethidium (DHE)
staining and fluorescent dye BODIPY581/591 C11. in vivo, micro-CT imaging, hematoxylin
and eosin staining, Safranin O-Fast staining, and immunohistochemistry were performed to evaluate
the effects of GAA on OA cartilage.
Results: The results showed that GAA treatment regulated the expression of chondrocyte extracellular
matrix (ECM) related factors, including ADAMTS5, MMP13, SOX9, Aggrecan, and
COL1A2 and reduced the ROS and lipid peroxidation levels. Besides, Erastin could reverse the effects
of GAA on chondrocytes. Similar to GAA, 5-AZA caused the reduction of ROS and lipid
peroxidation levels and reversed the effect of IL-1β on the expression of ECM-related factors in
OA chondrocytes. The above results clarified that GAA alleviated the ferroptosis of chondrocytes
in OA by inhibiting GPX4 methylation.
Conclusion: Our findings revealed that GAA might be developed as a drug for treating OA clinically.
研究领域:
药理学
·
骨科
·
细胞生物学
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
BIOLOGICAL TRACE ELEMENT RESEARCH
·
2019
·Vol. 193
·期 2
·422-433
·
IF 2.431
Hu Peilin,Du Jie,Zhang Shuai,Wang Ting,Li Jun,Chen Gang,Zhou Guangqian
Osteoarthritis (OA), a common degenerative disease affecting articular cartilage, is caused by multiple factors, and currently, there are few approaches to effectively delay its progression. This study aimed to evaluate whether a strontium compound (in the form of strontium gluconate, Glu-Sr) could reduce OA pathology severity in osteoarthritic rat models by directly targeting chondrocytes, including catabolic/anabolic activities and/or chondrogenic differentiation. Glu-Sr was administered to OA rats by oral gavage beginning during OA induction and continuing for 8 weeks. Glu-Sr treatment was found to significantly reduce cartilage degeneration and delay OA progression. Further examination showed that collagen II, Sox9, and aggrecan (ACAN) genes were up-regulated whereas IL-1β was down-regulated in chondrocytes isolated from Glu-Sr-treated rats. Glu-Sr also antagonized the catabolic effects of IL-1β on chondrocytes. Furthermore, Glu-Sr was shown to promote the chondrogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs), possibly through promoting chondrogenic gene expression, including CTGF and FGF1, as revealed by RNA-sequencing (RNA-seq). These results suggest that systemic administration of Glu-Sr may be useful in prophylactic and therapeutic treatment of chronic cartilage degradation through affecting multiple steps from chondrogenic differentiation of progenitors to matrix formation in mature chondrocytes.
研究领域:
风湿病学
·
骨科
·
分子生物学
·
干细胞研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）