Biomaterials Research
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2024
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IF 8.1
Chenyang Li,Shuai Wang,Chenghui Liao,Ying Li,Yunfeng Zhou,Haiqiang Wu,Wei Xiong
Klotho (KLO) is an anti-fibrotic protein expressed in the kidneys and has been decreasing in the development of renal fibrosis (RF). However, restoring the decline in KLO levels remains a great challenge during RF treatment. Herein, an injectable KLO-loaded chitosan (CS) hydrogel (KLO-Gel) is designed to achieve localized and prolonged release of KLO in the RF treatment. KLO-Gel was prepared by cross-linking CS with β-glycerophosphate (β-GP), followed by rapid (within 3 min) thermosensitive gelation at 37 °C. Furthermore, KLO-Gel exhibited a slow and sustained release (over 14 d) of KLO both in PBS and in the kidneys of mice with unilateral ureter obstruction (UUO). A single local injection of KLO-Gel into the renal capsule of UUO mice was more effective at reducing RF (i.e., maintaining renal function and tissue structure, alleviating extracellular matrix accumulation, and inhibiting the TGF-β1/Smad2/3 signaling pathway) over a 14-d period than daily intraperitoneal injections of free KLO or captopril. Crucially, CS was found to induce endogenous KLO secretion, highlighting the added value of using CS in RF treatment. Overall, this study demonstrated that KLO-Gel enhanced the anti-fibrotic efficacy of KLO while minimizing its off-target toxicity, and its clinical potential awaits further validation.
研究领域:
药理学
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生物医学工程
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肾脏病学
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产品关联
DOI
PubMed
高影响因子
AMERICAN JOURNAL OF CHINESE MEDICINE
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2024
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IF 4.8
Xiaowei Zhang,Jiajun Wang,Shixie Xiang,Liang Zhao,Mingzhen Lv,Yafei Duan,Gai Gao,Pan Wang,Jenny Jie Chen,Jiangyan Xu,Zhishen Xie,Zhenqiang Zhang
Diabetic kidney disease (DKD) has become the primary cause of end-stage renal disease (ESRD), causing an urgent need for preventive strategies for DKD. Astragaloside I (ASI), a bioactive saponin extracted from Astragalus membranaceus (Fisch.) Bunge has been demonstrated to possess a variety of biological activities. This study investigates the therapeutic potential of ASI in DKD and the underlying molecular mechanism using db/db mice in vivo and high glucose (HG)-induced SV40-MES-13 cells in vitro . The results indicated that ASI significantly ameliorated renal dysfunction and mitigated the pathological alterations in the renal tissues of db/db mice. Moreover, ASI was found to reduce the levels of renal fibrosis makers and suppress the activation of TGF- β 1/Smad2/3 pathway in both db/db mice and HG-induced SV40-MES-13 cells. Furthermore, ASI downregulated HDAC3 expression, upregulated Klotho expression, and enhanced Klotho release. ASI is directly bound to HDAC3, and the beneficial effects of ASI on Klotho/TGF- β 1/Smad2/3-mediciated renal fibrosis in DKD were reversed by the HDAC3 agonist ITSA-1. In conclusion, ASI attenuates renal fibrosis in DKD, and may act through concurrently inhibiting HDAC3 and TGF- β 1, thereby regulating HDAC3-mediciated Klotho/TGF- β 1/Smad2/3 pathway.
研究领域:
药理学
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肾病学
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分子生物学
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糖尿病
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH
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2024
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IF 1.6
Guangxin Pan,Sha Li,Guoping Xiong,Pei Zhang,Li Zhang,Yanru Yao,Gang Lei
Background Metformin (Met) has been reported to play the key role in the pathogenesis of polycystic ovary syndrome (PCOS). However, the precise mechanisms underlying the actions of Met in PCOS remain incompletely understood. This study aimed to confirm the mechanism of Met interacting with a long non-coding RNA LINC00548 in PCOS. Methods Ovarian granulosa cells (OGCs) were incubated 500 nM dihydrotestosterone (DHT) to construct PCOS in vitro model and then were treated 20 μM Met. A series of cell experiments including Cell Counting Kit-8, Terminal uridine nucleotide end labeling, and flow cytometry were performed to confirm the changes of OGC survival ability. Quantitative real-time polymerase chain reaction was conducted to determine the levels of LINC00548, whereas Western blotting was applied to determine the levels of androgen receptor (AR) and klotho. Results Met improved the cell viability and suppressed cell apoptosis in DHT-treated OGCs. LINC00548 downregulated in DHT-treated OGCs was upregulated by Met, and its overexpression further enhanced the positive effects of Met on the survival ability of DHT-treated OGCs. In addition, Met could induce the upregulation of LINC00548 to suppress the activation of AR/klotho pathway in DHT-treated OGCs. Conclusion Overall, this study discovers that Met enhances the survival ability of OGCs in PCOS by elevating LINC00548 expression to suppress AR/klotho pathway.
研究领域:
内分泌学
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妇科学
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分子生物学
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DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2023
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IF 5.1
Asmaa S.A. Hammad,Mohamed M. Sayed-Ahmed,Sara Mohamed Naguib Abdel Hafez,Ahmed R.N. Ibrahim,Mohamed M.A. Khalifa,Mahmoud El-Daly
Chemotherapy-induced peripheral neuropathy is a common adverse effect associated with a number of chemotherapeutic agents including paclitaxel (PTX) which is used in a wide range of solid tumors . Development of PTX-induced peripheral neuropathy (PIPN) during cancer treatment requires dose reduction which limits its clinical benefits. This study is conducted to investigate the role of toll like receptor-4 (TLR4) /p38 signaling and Klotho protein expression in PIPN and the role of trimetazidine (TMZ) in this pathway. Sixty-four male Swiss albino mice were divided into 4 groups (n = 16); Group (1) injected intraperitoneally (IP) with ethanol/tween 80/saline for 8 successive days. Group (2) received TMZ (5 mg/kg, IP, day) for 8 successive days. Group (3) treated with 4 doses of PTX (4.5 mg/kg, IP) every other day over a period of 7 days. Group (4) received a combination of TMZ as group 2 and PTX as group 3. The Effect of TMZ on the antitumor activity of PTX was studied in another set of solid Ehrlich carcinoma (SEC)-bearing mice that was similarly divided as the above-mentioned set. TMZ mitigated tactile allodynia , thermal hypoalgesia , numbness and fine motor discoordination associated with PTX in Swiss mice. The results of the current study show that the neuroprotective effect of TMZ can be attributed to inhibition of TLR4/p38 signaling which also includes a reduction in matrix metalloproteinase-9 (MMP9) protein levels as well as the proinflammatory interleukin-1β (IL-1β) and preserving the levels of the anti-inflammatory IL-10. Moreover, the current study is the first to demonstrate that PTX reduces the neuronal levels of klotho protein and showed its modulation via cotreatment with TMZ. In addition, this study showed that TMZ neither alter the growth of SEC nor the antitumor activity of PTX. In conclusion, we suggest that (1) Inhibition of Klotho protein and upregulation of TLR4/p38 signals in nerve tissues may contribute to PIPN. (2) TMZ attenuates PIPN by modulating TLR4/p38 and Klotho protein expression without interfering with its antitumor activity.
研究领域:
肿瘤学
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药理学
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神经科学
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免疫学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Gaolin Wen,Lingling Xue,Mengdi Qiu,Junlan Qiu,Xinhua Zhu,Haozhen Ren
Hepatocellular carcinoma (HCC), ranking as the fourth most prevalent cancer globally, has garnered significant attention due to its high invasiveness and mortality rates. However, drug therapies face challenges of inadequate efficacy and unclear mechanisms. Here, we propose a novel biohybrid hydrogel that targets β-klotho (KLB) for HCC treatment. As a dual-network hydrogel, this gel combines gelatin methacryloyl (GelMA) and polyvinyl alcohol (PVA) to ensure biocompatibility while enhancing controlled drug release. Notably, it exhibits good storage stability, high drug load capacity, and efficient water absorption. By introducing the HDAC3 inhibitor RGFP966, we can selectively inhibit the activation of KLB. This deactivation effectively blocks the FGF21-KLB signaling pathway and inhibits the progression of HCC. Importantly, we have successfully validated this unique phenomenon both in vivo and in vitro, providing substantial evidence for the efficacy of this hydrogel-based anti-tumor drug delivery system as a promising strategy for HCC treatment. This innovative research outcome brings new hope to the field of tumor therapy, providing a reliable theoretical foundation for future clinical applications.
研究领域:
肿瘤学
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药学
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生物材料
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DOI
高影响因子
TISSUE & CELL
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2025
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IF 2.5
Guixiang Zeng,Jingjing Lian,Jiajia Shen,Yuan Shi
Objective The Klotho protein is associated with various aging-related diseases. Previous studies have shown that Klotho expression is reduced in placental and cord blood samples from growth-restricted fetuses, but the underlying mechanisms affecting fetal development remain unclear. This study investigates the effects of Klotho protein on the human placental choriocarcinoma cell line (JEG-3) and explores the mechanisms involved. Methods The JEG-3 cell line, which retains characteristics of trophoblast cells, is widely used to study pregnancy-related pathologies. Placental trophoblast cells act as “multifunctional hubs” at the maternal-fetal interface, performing transportation, endocrine regulation, and immune modulation. The GH/IGF-1 pathway plays a crucial role in embryonic growth and immune tolerance, and its abnormal activation is linked to preeclampsia and fetal growth restriction. To investigate the impacts of Klotho protein on the functional characteristics of JEG-3 cells, we designed two experimental setups concentrating on the low expression and high expression of Klotho protein. The research examined the expression levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) in JEG-3 cells, along with changes in multiple cellular functions, under these two experimental conditions. Results qPCR and flow cytometry analyses showed that in the Klotho low - expression (KL -) tests, the levels of IGF - 1 mRNA in the KL - group were significantly elevated (P < 0.01, P < 0.05), while the levels of GH mRNA were significantly reduced (P < 0.001, P < 0.0001). The cell scratch test demonstrated that the cell migration capacity in the KL - group was improved (P < 0.05). The Cell Counting Kit - 8 (CCK8) test verified an increase in cell viability (P < 0.0001). Reactive oxygen species (ROS) detection showed a significant rise in ROS levels (P < < 0.001). The glucose uptake experiment indicated a decrease in glucose uptake in the KL - group (P < 0.0001). The human recombinant Klotho protein was over - expressed in the JEG - 3 cell line. Quantitative polymerase chain reaction (qPCR) and flow cytometry analyses disclosed that in the rKL + group, the levels of IGF - 1 were lowered and the levels of GH were raised (P < 0.05, P < 0.05). The cell scratch test showed that the cell migration rate in the rKL + group was diminished (P < 0.01). The CCK8 test confirmed a decrease in cell viability (P < 0.0001). The ROS detection indicated a significant decrease in ROS levels (P < 0.05). The glucose uptake experiment showed a increase in glucose uptake (P < 0.0001). Conclusions Klotho protein affects the expression of GH and IGF-1 in JEG-3 cells, leading to the dysfunction of GH/IGF-1 axis, which subsequently impacts the proliferation, migration, anti-inflammatory response, and glucose metabolism of placental trophoblast cells, ultimately affecting placental function and fetal intrauterine development. Summary sentence Reduced Klotho protein expression in JEG-3 cells leads to increased IGF-1, decreased GH, enhanced cell proliferation and migration, elevated inflammatory responses, and metabolic imbalances, potentially contributing to placental dysfunction in growth-restricted fetuses.
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产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2026
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IF 5.9
Wenjie Zhang,Lingxin Zeng,Ying Li,Xinggang Yang,Wei Xiong
Phosphatidylserine liposomes target injured renal tubules. • Spermine-modified chitosan enables responsive drug release. • Targeted dihydroartemisinin delivery restores Klotho and reduces fibrosis. Restoration of endogenous Klotho represents a promising strategy for suppressing renal fibrosis, but efficient delivery of Klotho-restoring therapeutics to injured renal tubules remains challenging. Here, we developed dihydroartemisinin (DHA)-loaded phosphatidylserine liposomes coated with spermine-modified chitosan (DHA-PSLPs@SC) to achieve sequential kidney injury molecule-1 (KIM-1) targeting and spermine oxidase (SMOX)-responsive release, thereby enhancing renal delivery of DHA to restore endogenous Klotho and attenuate renal fibrosis. Dioleoylphosphatidylserine (DOPS) was incorporated to facilitate uptake by KIM-1-expressing injured tubular epithelial cells, whereas the spermine-modified chitosan (SC) coating was designed to promote cargo release in the SMOX-enriched fibrotic cellular environment. The optimized DHA-PSLPs@SC exhibited a diameter of 102.3 nm, a zeta potential of 33.8 mV, and an encapsulation efficiency of 69.4%. In H₂O₂-injured HK-2 cells, DOPS-containing liposomes displayed enhanced uptake and colocalization with KIM-1, while KIM-1 antibody blockade markedly reduced their internalization. In TGF-β1-stimulated NRK-52E cells, the SC coating preserved cellular uptake and increased cumulative DHA release to 74.2% at 12 h, while DHA-PSLPs@SC more effectively restored Klotho and suppressed fibrotic markers than free DHA or non-targeted liposomes. In unilateral ureteral obstruction (UUO) mice, PSLPs@SC preferentially accumulated in obstructed kidneys, with approximately 2.7-fold higher renal accumulation than non-targeted liposomes at 2 h. DHA-PSLPs@SC improved renal function, reduced tubular injury and collagen deposition, restored renal Klotho, and suppressed fibrosis. These findings support sequential KIM-1 targeting and SMOX-responsive release as a strategy to enhance renal delivery and antifibrotic efficacy of DHA, restore endogenous Klotho, and attenuate renal fibrosis.
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DOI
PubMed
高影响因子
EBioMedicine
·
2021
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IF 8.143
Qi Pan,Shushan Lin,Yu Li,Liang Liu,Xiaoping Li,Xianglei Gao,Jiangyu Yan,Baohua Gu,Xiaofeng Chen,Wenjia Li,Xinfa Tang,Chao Chen,Lixin Guo
Background Fibroblast growth factor 21 (FGF21) has become a promising therapeutic target for metabolic diseases such as type 2 diabetes (T2D), obesity and non-alcoholic steatohepatitis. However, the clinical application of natural FGF21 molecule is limited because of its instability in vitro and short half-life in vivo . To improve FGF21’s therapeutic property, we screened high receptor binding FGF21 analogs and made FGF21-Fc-GLP-1 dual-targeted constructs to investigate their activity in a number of experiments . Methods Utilizing phage display high-throughput screening we identified mutations that could improve β-Klotho binding property of FGF21. IgG4 Fc was fused to FGF21 variants to extend the in vivo half-life. We further explored the potential synergistic actions of FGF21 with the incretin glucagon-like peptide-1 (GLP-1) by generating GLP-1-Fc-FGF21 dual agonists. Findings Two Fc-FGF21 variants showed enhanced β-Klotho binding affinity in vitro as well as improved glucose lowering effect in vivo . One of the dual agonists, GLP-1-Fc-FGF21 D1, provided potent and sustained glucose lowering effect in diabetic mice models. It also demonstrated superior weight loss effect to GLP-1 or FGF21 alone. Moreover, GLP-1-Fc-FGF21 D1 exhibited strong anti-NASH effect in the high-fat diet-induced ob/ob model as it improved liver function, serum and hepatic lipid profile and reduced NAFLD activity score with an efficacy superior to either FGF21 or GLP-1 analogs alone. Interpretation This novel GLP-1/FGF21 dual agonist is worth clinical development for the treatment of T2D, obesity and NASH. Funding HEC Pharm R&D Co., Ltd, National natural science fund of China.
研究领域:
药理学
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代谢性疾病
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内分泌学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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