ACS Agricultural Science & Technology
·
2023
·
IF 2.5
Liang Jin,Xiao-Di Zhao,Jun-Ao Liao,Li-Jun Fu,Yi Lin
Cry toxins produced by Bacillus thuringiensis (Bt) are toxic to Lepidoptera, Coleoptera, and Diptera, but display very low activity against aphids. Recently, Cry41-related toxin was found to show moderate toxicity against Myzus persicae with the 50% lethal concentration (LC50) of 32.7 μg/mL, and its mode of action was proposed to be the acceleration of the apoptosis of aphid cells by enhancing Cathepsin B activity. This study focused on constructing Cry41-related mutants against M. persicae based on its interaction with Cathepsin B. First, eight key interacting residues in Cry41-related toxin were identified using alanine scanning and site-directed saturation mutagenesis. Subsequently, the positive mutant Cry41-7M protein (mutations of Gly48, Ile59, Lys364, Gln367, Gln377, Tyr378, and Ser400 to Tyr, Ala, Arg, Lys, Lys, Lys, and Ala in Cry41-related toxin, respectively) and the negative mutant Cry41-6A protein (mutations of Gly48, Lys364, Gln367, Gln377, and Tyr378 to Ala and mutation of Pro453 to Glu in Cry41-related toxin) were constructed, expressed, and purified. We then found that Cry41-7M protein performed slightly stronger than Cry41-related toxin in enhancing the enzymatic activity of Cathepsin B, whereas Cry41-6A protein did not affect Cathepsin B activity. A further bioassay showed that the mortality caused by Cry41-7M protein (LC50 = 19.144 μg/mL) was marginally higher than that of Cry41-related toxin, while Cry41-6A protein caused a decreased mortality (LC50 = 42.478 μg/mL). These results are expected to open new avenues for improving Cry aphidicidal activity.
研究领域:
昆虫学
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分子生物学
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生物技术
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DOI
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2020
·
IF 4.192
Xiao-Di Zhao,Bin-Wu Zhang,Li-Jun Fu,Qi-Lin Li,Yi Lin,Xiao-Qiang Yu
Cry toxins produced by Bacillus thuringiensis are well known for their high insecticidal activities against Lepidoptera, Diptera, and Coleoptera; however, their activities against Aphididae are very low. Recently, it has been reported that a Cry41-related toxin exhibited moderate activity against the aphid Myzus persicae, and thus, it is highly desirable to uncover its unique mechanism. In this paper, we report that Cathepsin B, calcium-transporting ATPase, and symbiotic bacterial-associated protein ATP-dependent-6-phosphofructokinase were pulled down from the homogenate of M. persicae as unique proteins that possibly bound to Cry41-related toxin. Cathepsin B has been reported to cleave and inactivate antiapoptotic proteins and plays a role in caspase-initiated apoptotic cascades. In this study, Cathepsin B was expressed in Escherichia coli and purified, and in vitro interaction between recombinant Cathepsin B and Cry41-related toxin was demonstrated. Interestingly, we found that addition of Cry41-related toxin obviously enhanced Cathepsin B activity. We propose a model for the mechanism of Cry41-related toxin as follows: Cry41-related toxin enters the aphid cells and enhances Cathepsin B activity, resulting in acceleration of apoptosis of aphid cells.
研究领域:
昆虫学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Fang Shi,Yong-Sheng Gao,Shu-Mei Han,Cheng-Suo Huang,Qing-Sheng Hou,Xiao-wen Wen,Ben-Shi Wang,Zhen-Yu Zhu,Lei Zou
Metabolic changes have been linked to the development of inflammatory bowel disease (IBD), which includes colitis. Allulose, an endogenous bioactive monosaccharide, is vital to the synthesis of numerous compounds and metabolic processes within living organisms. Nevertheless, the precise biochemical mechanism by which allulose inhibits colitis remains unknown. Allulose is an essential and intrinsic protector of the intestinal mucosal barrier, as it maintains the integrity of tight junctions in the intestines, according to the current research. It is also important to know that there is a link between the severity of inflammatory bowel disease (IBD) and colorectal cancer (CRC), chemically-induced colitis in rodents, and lower levels of allulose in the blood. Mice with colitis, either caused by dextran sodium sulphate (DSS) or naturally occurring colitis in IL-10 -/- mice, had less damage to their intestinal mucosa after being given allulose. Giving allulose to a colitis model starts a chain of reactions because it stops cathepsin B from ejecting and helps lysosomes stick together. This system effectively stops the activity of myosin light chain kinase (MLCK) when intestinal epithelial damage happens. This stops the breakdown of tight junction integrity and the start of mitochondrial dysfunction. To summarise, the study's findings have presented data that supports the advantageous impact of allulose in reducing the advancement of colitis. Its ability to stop the disruption of the intestinal barrier enables this. Therefore, allulose has potential as a medicinal supplement for treating colitis.
研究领域:
胃肠病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2026
·Vol. 22
·期 4
·1752-1774
·
IF 10
Wu Wentong,Du Jiangxia,Li Jinjin,Zhang Shaoyin,Kang Xingchen,Cao Yashi,Chen Jian,Pan Zengyue,Huang Xiangliang,Xu Zhifei,Yang Bo,He Qiaojun,Yang Xiaochun,Yan Hao,Luo Peihua
Vandetanib, a critical therapy for advanced thyroid and RET-driven cancers, is limited by life-threatening hepato-cardiotoxicity. This study identifies lysosomal protease cathepsin B (CTSB) as the central mediator of vandetanib-induced organ damage through STAT3-driven transcriptional activation. CTSB triggers mitochondrial apoptosis by cleaving the lysosomal calcium channel mucolipin TRP cation channel 1 (MCOLN1), disrupting calcium/AMP-activated protein kinase (AMPK) signaling and autophagy flux. Crucially, the natural compound tannic acid directly binds and inhibits CTSB, completely protecting against hepato-cardiotoxicity without compromising vandetanib's antitumor efficacy in preclinical models. Overall, our findings establish CTSB-mediated lysosomal dysfunction and MCOLN1-calcium-AMPK axis disruption as the core mechanism of vandetanib-induced hepato-cardiotoxicity, and identify tannic acid as a readily translatable adjuvant strategy to prevent this toxicity. These findings redefine CTSB as a druggable target for kinase inhibitor toxicities and position tannic acid as a clinically translatable adjuvant to enhance vandetanib's safety profile. By preserving lysosomal function and calcium homeostasis, this strategy addresses a critical unmet need in precision oncology, enabling prolonged, safer use of vandetanib and related tyrosine kinase inhibitors. The discovery of shared lysosomal injury mechanisms across organs also opens avenues for preventing multi-organ toxicities in broader cancer therapies.
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PubMed
高影响因子
International Journal of Nanomedicine
·
2019
·
IF 4.471
Ning Sun,Dou Wang,Guoqiang Yao,Xiaomei Li,Ting Mei,Xinke Zhou,Kwok-Yin Wong,Baishan Jiang,Zhiyuan Fang
Background: The intraoperative visualization of tumor cells is a powerful modality for surgical treatment of solid tumors. Since the completeness of tumor excision is closely correlated with the survival of patients, probes that can assist in distinguishing tumor cells are highly demanded.Purpose: In the present study, a fluorescent probe JF1 was synthesized for imaging of tumor cells by conjugating a substrate of cathepsin B (quenching moiety) to Oregon Green derivative JF2 using a self-immolative linker.Methods: JF1 was then loaded into the folate-PEG modified CaCO3 nanoparticles. The folate receptor-targeted, pH-dependent, and cathepsin B activable CaCO3 nanoprobe was test in vitro and in vivo for tumor imaging.Results: CaCO3 nanoprobe demonstrated good stability and fast lighting ability in tumors under low pH conditions. It also showed lower fluorescence background than the single cathepsin B dependent fluorescent probe. The pH-dependent and cathepsin B controlled “turn-on” property enables precise and fast indication of tumor in vitro and in vivo.Conclusion: This strategy of controlled drug delivery enables in vivo imaging of tumor nodules with a high signal-to-noise ratio, which has great potential in surgical tumor treatment.
研究领域:
生物医学工程
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肿瘤学
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分子影像学
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产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2020
·
IF 7.097
Hao Cai,Yufan Xiang,Yujun Zeng,Zhiqian Li,Xiuli Zheng,Qiang Luo,Hongyan Zhu,Qiyong Gong,Zhongwei Gu,Yanhui Liu,Hu Zhang,Kui Luo
Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of cancer. Polymeric carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs in response to a tumor specific microenvironment. A theranostic nanomedicine was designed and prepared by complexing a small gadolinium chelate, conjugating a chemotherapeutic drug PTX through a cathepsin B-responsive linker and covalently bonding a fluorescent probe pheophorbide a (Ppa) with a branched glycopolymer. The branched prodrug-based nanosystem was degradable in the tumor microenvironment with overexpressed cathepsin B, and PTX was simultaneously released to exert its therapeutic effect. The theranostic nanomedicine, branched glycopolymer-PTX-DOTA-Gd, had an extended circulation time, enhanced accumulation in tumors, and excellent biocompatibility with significantly reduced gadolinium ion (Gd 3+ ) retention after 96 h post-injection. Enhanced imaging contrast up to 24 h post-injection and excellent antitumor efficacy with a tumor inhibition rate more than 90% were achieved from glycopolymer-PTX-DOTA-Gd without obvious systematic toxicity. This branched polymeric prodrug-based nanomedicine is very promising for safe and effective diagnosis and treatment of cancer.
研究领域:
药学
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纳米技术
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癌症研究
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生物医学工程
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材料科学
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DOI
PubMed
高影响因子
DYES AND PIGMENTS
·
2025
·
IF 4.2
Xin-Tao Chen,Wu-Juan Hao,Jun-Lian Liu,Zhong-Yuan Cheng,Kai Wang
Hepatic ischemia-reperfusion (I-R) injury is a critical clinical condition lacking methods for real-time visualization of its key enzymatic activity. To address this, we developed WK-catB , an activatable optical probe targeting cathepsin B (catB), based on a sulfur-substituted hemicyanine scaffold. This probe exhibits minimal background fluorescence and photoacoustic signal in its native state but undergoes significant enhancement upon catB-mediated cleavage, enabling sensitive and selective detection of enzyme activity. In vitro assays demonstrated high specificity, low detection limit, and excellent biocompatibility. Using a murine I-R model, we successfully visualized upregulated catB activity in injured livers via both fluorescence and photoacoustic imaging, which was corroborated by ex vivo immunofluorescence, histopathology, and serum analysis. These findings highlight WK-catB as a promising tool for non-invasive monitoring of catB-related pathologies.
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DOI
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Gang Wang,Wen Liang,Noshin Afshan,Yuxin Lei,Haoyu Li,Yang Xiang,Jin Jiao
The integration of in vivo detection and liquid biopsy through engineered artificial biomarkers has garnered significant attention. These biomarkers overcome limitations of traditional liquid biopsy, such as low abundance and rapid clearance of endogenous biomarkers, by enabling quantifiable detection of disease-specific targets in body fluids. Herein, we report a spherical peptide nucleic acid (PNA)-based artificial biomarker system (Gold-Peptide-PNA, GPP) for ultrasensitive analysis of tumor-associated Cathepsin B (CB). The GPP system comprises AuNP-loaded tandem peptide-PNA probes, where the peptide serves as a CB-responsive substrate and linker, while the enzymatically stable PNA acts as a shielded reporter. Upon CB-mediated cleavage in tumor tissues, PNA probes are released into circulation, excreted via urine, and detected using an Nb. Bbv CI-assisted DNA walker based electrochemical sensor. The sensor leverages competitive binding between PNA and a locked DNA walker to trigger methylene blue (MB) signal amplification. In vitro and in vivo studies demonstrated that GPP achieves a detection limit of 17.5 pg/ mL for CB, exhibits robust stability under enzymatic and physiological challenges, and enables tumor-specific fluorescence/electrochemical signal readouts within 2–3 h of post-injection. This work pioneers a multi-functional, enzyme-responsive nanoplatform for non-invasive tumor diagnosis, combining the programmability of PNA with the sensitivity of electrochemical sensing.
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高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2019
·
IF 2.983
Baofang Zhang,Zilin Chen
A simple and valid method for rapid screening of cathepsin B inhibitors from traditional Chinese medicines (TCMs) was established by the combination of immobilized enzyme microreactor (IMER) and capillary electrophoresis. Cathepsin B was immobilized on the inner surface of the capillary by glutaraldehyde method. The separation of substrate and product could be finished by baseline within 3 min. The activity of the immobilized cathepsin B remained approximately 90% after 50 runs. The quantification and statistical analysis of the product peak area was used to evaluate the catalytic activity of cathepsin B. The value of Michaelis-Menten constant of cathepsin B was 0.85 mM. The half-maximal inhibitory concentration (IC 50 ) of L -trans-Epoxysuccinyl-leucylamido(4-guanidino)butane (E-64) was measured as 36.08 nM, which indicated that the cathepsin B reactor was successfully developed and was feasible for inhibitorscreening. The raised method was then applied to discover the inhibitory potential of 17 standard compounds from traditional Chinese medicines. Five natural products, including kaempferol, rutaecarpine, evodiamine, theophylline, lycobetaine showed potential inhibition for cathepsin B. Additionally, molecular docking study was investigated for supporting the interaction between enzyme and inhibitors.
研究领域:
药理学
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生物化学
·
药物化学
·
酶学
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DOI
PubMed
高影响因子
POLYMER INTERNATIONAL
·
2021
·Vol. 71
·期 3
·317-327
·
IF 2.99
Wenjie Song,Junwu Wei,Lindong Li,Yangyang Qian,Yujia Wang,Yunmei Bi
In this study, two linear poly( N -vinylcaprolactam)s (PNVCLs) with different molecular weights were first synthesized as polymeric supporters by reversible addition-fragmentation chain transfer polymerization and then were used to prepare cathepsin B and thermal dual-stimuli responsive amphiphilic linear–dendritic block copolymers (LDBCs) PNVCL n - b - d (Phe-Lys) 1–3 ( n = 66, 100) with linear PNVCL and dendritic phenylalanyl-lysine (Phe-Lys) dipeptides via stepwise peptide chemistry. The copolymers were characterized by 1 H NMR spectra and gel permeation chromatography and exhibited a controlled molecular weight and a narrow molecular weight distribution (polydispersity index ≤ 1.27). They self-assemble into stable micelles at relatively low critical micelle concentrations (0.007–0.019 mg mL −1 ) in aqueous solution. These micelles are capable of dissociating to release the encapsulated anticancer drug doxorubicin upon cathepsin B treatment. The doxorubicin release rates from PNVCL n - b - d (Phe-Lys) 1–3 micelles decreased with increasing generation of Phe-Lys dipeptide dendrons and decreasing molecular weight of PNVCL. In addition, the lower critical solution temperatures of the copolymers increased with an extension of the enzyme incubation time. The results of in vitro cytotoxicity and cell uptake experiments showed that LDBCs show no cytotoxicity even at a high LDBC concentration of 0.4 mg mL −1 and the drug-loaded micelles can be enriched in tumor cells. Such smart copolymers could be efficiently used in targeted therapy systems. © 2021 Society of Industrial Chemistry.
研究领域:
生物材料
·
药学
·
肿瘤学
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DOI
高影响因子
ACS Applied Bio Materials
·
2019
·
IF 0
Xiaomin Zhi,Yuqian Jiang,Linlin Xie,Yanbo Li,Chen-Jie Fang
Multidrug resistance (MDR) and adverse effects of chemotherapeutic agents are severe issues in clinical cancer treatment. Due to the dysregulation of enzymes in the cancer cells, enzyme-responsive drug delivery systems (DDSs) have been considered as a viable technology for cancer chemotherapy. In the present work, doxorubicin (DOX) is visible after leaving from AuNR–LAX. After treatment with AuNR–LAX, the drug resistance index of DOX-resistant MCF-7/ADR cells was reduced from extremely high 955.0 to 1.7, implying high potential of AuNR–LAX in the MDR phenotype cancer treatment. In addition, the cellular viability of both MCF-7 and MCF-7/ADR cells decreased from 50% to 80% after treatment with AuNR–LAX along (equivalent DOX concentration = 2.3 μg/mL, Au concentration = 30 μg/mL) to below 10% after AuNR–LAX treatment plus radiation of 808 nm, due to the NIR photothermal effect of AuNRs. Human bronchial epithelial cell line 16HBE was chosen to evaluate the adverse effect of AuNR–LAX on the normal cells. At the low concentration, the cytotoxicity of LAX and AuNR–LAX is comparable for breast cancer cell MCF-7 and normal cell 16HBE. It is noted that, at high concentration (with equivalent DOX concentration = 13.1 μg/mL, Au concentration = 167.7 μg/mL), the cellular viability of 16HBE cells is over 50%, whereas that of MCF-7 cancer cells is close to 0, implying the potential of AuNR–LAX in reducing the adverse effects of DOX against normal cells/tissues. Overall, AuNR–LAX showed high potential in overcoming MDR and alleviating adverse effect on normal cells.
研究领域:
纳米技术
·
药学
·
癌症研究
·
生物医学工程
·
药物递送系统
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产品关联
DOI
PubMed
DYES AND PIGMENTS
·
2025
·
IF 4.2
Ningxi Wu,Sirui Hang,Shuying Chen,Kai Wang,Yue Zheng
We report the design and synthesis of CatP, a sulfur-substituted hemicyanine-based activatable probe, for the sensitive detection of cathepsin B (CatB) activity. This probe was applied to study the dynamic changes of hepatic CatB in diabetic mellitus (DM), a prevalent metabolic disease. The probe incorporates a Val-Cit linker specifically cleaved by CatB, triggering an intramolecular charge transfer (ICT) mechanism that generates strong near-infrared (750 nm) fluorescence and photoacoustic signals. Structural optimization through sulfur substitution significantly enhanced photoacoustic signal intensity compared to conventional oxygen-substituted analogs. In diabetic mouse models, CatP revealed significantly elevated hepatic CatB activity, which was normalized by metformin treatment as confirmed by both in vivo imaging and ex vivo immunofluorescence. Comprehensive biosafety evaluation demonstrated excellent biocompatibility with >90 % cell viability and no observable organ toxicity. These findings establish sulfur-modified hemicyanine as a promising scaffold for developing high-performance activatable probes, and demonstrate the value of CatP as a functional dye for studying protease activity in biomedical research.
研究领域:
分子影像学
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生物医学工程
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糖尿病研究
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蛋白酶生物学
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光学成像
·
诊疗一体化
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DOI
高影响因子
危险品化学品经营许可证（带存储）