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Article: Editorial: Small molecule inhibitors targeting mammalian selenoprotein thioredoxin reductases (TXNRDs): Interactions, mechanisms, and applications.

Xu, Jianqiang / Vlamis-Gardikas, Alexios / Fang, Jianguo

2023 Volume 10, Page(s) 1141772

Language	English
Publishing date	2023-02-02
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2023.1141772
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Article ; Online: Assay of selenol species in biological samples by the fluorescent probe Sel-green.

Zhang, Baoxin / Fang, Jianguo

Methods in enzymology

2021 Volume 662, Page(s) 259–273

Abstract: Selenium (Se) is an essential trace element for diverse cellular functions. The biological significance of Se is predominantly dependent on its incorporation into the selenocysteine (Sec) for synthesis of selenoproteins (SePs), such as thioredoxin ... ...

Abstract	Selenium (Se) is an essential trace element for diverse cellular functions. The biological significance of Se is predominantly dependent on its incorporation into the selenocysteine (Sec) for synthesis of selenoproteins (SePs), such as thioredoxin reductase family enzymes and glutathione peroxidase family enzymes. In general, the hyperactivity of the selenol group in Sec confers the Sec residue critical for functions of SePs. The Sec is much less abundant than its sulfur analog cysteine (Cys), and it remains a high challenge to detect Sec, especially in complex biological samples. We recently reported a selective fluorescent probe Sel-green for selenols and summarized the principles for design of selenol (and thiophenol) probes. Sel-green discriminates selenols from other biological species, especially thiols, under physiological conditions, and has been applied to detect both endogenous and exogenous selenol species in live cells. In this chapter, we describe a protocol and guideline for the selective detection of Sec by applying the Sel-green. This protocol is also suitable for detection of other selenol species. This practical and convenient assay would assist scientists to better understand the pivotal roles of Sec as well as SePs.
MeSH term(s)	Fluorescent Dyes/chemistry ; Selenium ; Selenium Compounds/chemistry ; Selenocysteine/chemistry ; Selenocysteine/metabolism ; Selenoproteins/metabolism
Chemical Substances	Fluorescent Dyes ; Selenium Compounds ; Selenoproteins ; selenol ; Selenocysteine (0CH9049VIS) ; Selenium (H6241UJ22B)
Language	English
Publishing date	2021-11-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1557-7988
ISSN (online)	1557-7988
DOI	10.1016/bs.mie.2021.10.021
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Article ; Online: Aloe-emodin alleviates doxorubicin-induced cardiotoxicity via inhibition of ferroptosis.

He, Ying / Xi, Junmin / Fang, Jianguo / Zhang, Baoxin / Cai, Wenqing

Free radical biology & medicine

2023 Volume 206, Page(s) 13–21

Abstract: Aloe-emodin (AE), a novel ferroptosis inhibitor, alleviates the doxorubicin (DOX)-induced cardiotoxicity in H9c2 rat cardiomyocytes. The inhibition of ferroptosis and the protective effect against cardiotoxicity were evaluated via MTT assay in H9c2 cells. ...

Abstract	Aloe-emodin (AE), a novel ferroptosis inhibitor, alleviates the doxorubicin (DOX)-induced cardiotoxicity in H9c2 rat cardiomyocytes. The inhibition of ferroptosis and the protective effect against cardiotoxicity were evaluated via MTT assay in H9c2 cells. The molecular mechanism of action (MOA) of nuclear factor erythroid 2-related factor 2 (Nrf2) activation, including transactivation of multiple downstream cytoprotective genes, were further assessed by Western blot, luciferase reporter assay and qRT-PCR analyses. Fluorescent imaging was performed to detect the change of intracellular reactive oxygen species, mitochondrial membrane potential and lipid peroxidation. In addition, an infrared spectroscopy was employed to detect the AE-Fe (II) complex. AE, alleviates oxidative stress in DOX-induced H9c2 cells by activating Nrf2 and increasing the expression of Nrf2 downstream antioxidant genes, SLC7A11 and GPX4. Furthermore, AE complexes bivalent iron and regulates the intracellular iron-related genes. In conclusion, the discovery of AE as a novel ferroptosis inhibitor and its MOA provides a new perspective for further exploration of cardio-protective agents in cancer patients during chemotherapy.
MeSH term(s)	Rats ; Animals ; Cardiotoxicity/drug therapy ; Emodin/metabolism ; Emodin/pharmacology ; Emodin/therapeutic use ; Aloe/metabolism ; Ferroptosis ; NF-E2-Related Factor 2/genetics ; NF-E2-Related Factor 2/metabolism ; Signal Transduction ; Cell Line ; Doxorubicin/pharmacology ; Oxidative Stress ; Myocytes, Cardiac/metabolism
Chemical Substances	Emodin (KA46RNI6HN) ; NF-E2-Related Factor 2 ; Doxorubicin (80168379AG)
Language	English
Publishing date	2023-06-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	807032-5
ISSN	1873-4596 ; 0891-5849
ISSN (online)	1873-4596
ISSN	0891-5849
DOI	10.1016/j.freeradbiomed.2023.06.025
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Article ; Online: Recent Progress on NIR Fluorescent Probes for Enzymes.

Zhao, Jintao / Ma, Tao / Chang, Bingbing / Fang, Jianguo

Molecules (Basel, Switzerland)

2022 Volume 27, Issue 18

Abstract: The majority of diseases' biomarkers are enzymes, and the regulation of enzymes is fundamental but crucial. Biological system disorders and diseases can result from abnormal enzymatic activity. Given the biological significance of enzymes, researchers ... ...

Abstract	The majority of diseases' biomarkers are enzymes, and the regulation of enzymes is fundamental but crucial. Biological system disorders and diseases can result from abnormal enzymatic activity. Given the biological significance of enzymes, researchers have devised a plethora of tools to map the activity of particular enzymes in order to gain insight regarding their function and distribution. Near-infrared (NIR) fluorescence imaging studies on enzymes may help to better understand their roles in living systems due to their natural imaging advantages. We review the NIR fluorescent probe design strategies that have been attempted by researchers to develop NIR fluorescent sensors of enzymes, and these works have provided deep and intuitive insights into the study of enzymes in biological systems. The recent enzyme-activated NIR fluorescent probes and their applications in imaging are summarized, and the prospects and challenges of developing enzyme-activated NIR fluorescent probes are discussed.
MeSH term(s)	Biomarkers ; Fluorescent Dyes ; Optical Imaging/methods
Chemical Substances	Biomarkers ; Fluorescent Dyes
Language	English
Publishing date	2022-09-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules27185922
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Article: The biological activities of quinolizidine alkaloids.

Zhang, Junmin / Liu, Ying-Qian / Fang, Jianguo

The Alkaloids. Chemistry and biology

2022 Volume 89, Page(s) 1–37

Abstract: Quinolizidine alkaloids isolated from various marine and terrestrial animals and plants are primarily composed of lupinine-, matrine-, and sparteine-type alkaloids. Matrine, phenanthroquinolizidines, bis-quinolizidines, and small molecules from amphibian ...

Abstract	Quinolizidine alkaloids isolated from various marine and terrestrial animals and plants are primarily composed of lupinine-, matrine-, and sparteine-type alkaloids. Matrine, phenanthroquinolizidines, bis-quinolizidines, and small molecules from amphibian skins are representative compounds of such alkaloids. Quinolizidine alkaloids harbor anticancer, antibacterial, antiinflammatory, antifibrosis, antiviral, and anti-arrhythmia. In this chapter, we comprehensively outline the biological activity and pharmacological action of quinolizidine alkaloids and discuss new avenues toward the discovery of novel and more efficient drugs based on these naturally occurring compounds. It is urgent for basic research and clinical practice to conduct more targeted comprehensive research based on the lead drugs of quinolizidine alkaloids with significant pharmacological activity.
MeSH term(s)	Animals ; Quinolizidine Alkaloids ; Alkaloids/pharmacology ; Quinolizidines/pharmacology ; Sparteine ; Anti-Inflammatory Agents ; Matrines
Chemical Substances	Quinolizidine Alkaloids ; Alkaloids ; Quinolizidines ; Sparteine (298897D62S) ; Anti-Inflammatory Agents ; Matrines
Language	English
Publishing date	2022-08-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	7577-2
ISSN	1099-4831 ; 0099-9598
ISSN	1099-4831 ; 0099-9598
DOI	10.1016/bs.alkal.2022.06.001
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Article ; Online: Targeting thioredoxin reductase by micheliolide contributes to radiosensitizing and inducing apoptosis of HeLa cells.

Zhang, Junmin / Chen, Yaxiong / Fang, Jianguo

Free radical biology & medicine

2022 Volume 186, Page(s) 99–109

Abstract: Inhibition of thioredoxin reductase (TrxR) is a crucial strategy for the discovery of antineoplastic drugs and radiosensitizers. As an anticancer candidate derived from Michelia, micheliolide (MCL) is converted readily from parthenolide (PTL), and has ... ...

Abstract	Inhibition of thioredoxin reductase (TrxR) is a crucial strategy for the discovery of antineoplastic drugs and radiosensitizers. As an anticancer candidate derived from Michelia, micheliolide (MCL) is converted readily from parthenolide (PTL), and has better stability and solubility than PTL. However, the anticancer mechanism of MCL has not been fully dissected. We present here for the first time that MCL-targeted inhibition of TrxR not only promotes oxidative stress-mediated HeLa cell apoptosis but also sensitizes ionizing radiation (IR) treatment. Further mechanistic studies demonstrate that MCL covalently binds to Sec at position 498 of TrxR to restrain the biological function of TrxR. It exhibits the inhibition of TrxR activity, enhancement of oxidized Trx, and sensitization of IR in the cellular environment, accompanied by the accumulation of reactive oxygen species (ROS) and the collapse of the intracellular redox balance. In addition, HeLa-shTrxR1 cells with knockdown of TrxR were more sensitive than the HeLa-shNT cells to either MCL-treated or IR-induced cytotoxicity, ROS, and apoptosis, suggesting that inhibition of TrxR by MCL is likely responsible for increased cytotoxicity and enhanced radiation response. These findings further establish the mechanistic understanding and preclinical data to support the further investigation of MCL's potential as a prospective radiosensitizer and cancer chemotherapeutic agent.
MeSH term(s)	Adult ; Antineoplastic Agents/pharmacology ; Apoptosis ; HeLa Cells ; Humans ; Prospective Studies ; Reactive Oxygen Species/metabolism ; Sesquiterpenes, Guaiane ; Thioredoxin-Disulfide Reductase/metabolism
Chemical Substances	Antineoplastic Agents ; Reactive Oxygen Species ; Sesquiterpenes, Guaiane ; micheliolide ; Thioredoxin-Disulfide Reductase (EC 1.8.1.9)
Language	English
Publishing date	2022-05-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	807032-5
ISSN	1873-4596 ; 0891-5849
ISSN (online)	1873-4596
ISSN	0891-5849
DOI	10.1016/j.freeradbiomed.2022.05.007
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Article ; Online: How can we improve the design of small molecules to target thioredoxin reductase for treating cancer?

Xu, Jianqiang / Fang, Jianguo

Expert opinion on drug discovery

2020 Volume 16, Issue 4, Page(s) 331–333

MeSH term(s)	Antineoplastic Agents/pharmacology ; Drug Design ; Enzyme Inhibitors/pharmacology ; Humans ; Neoplasms/drug therapy ; Neoplasms/enzymology ; Thioredoxin-Disulfide Reductase/antagonists & inhibitors ; Thioredoxin-Disulfide Reductase/metabolism
Chemical Substances	Antineoplastic Agents ; Enzyme Inhibitors ; Thioredoxin-Disulfide Reductase (EC 1.8.1.9)
Language	English
Publishing date	2020-12-14
Publishing country	England
Document type	Editorial ; Research Support, Non-U.S. Gov't
ZDB-ID	2259618-5
ISSN	1746-045X ; 1746-0441
ISSN (online)	1746-045X
ISSN	1746-0441
DOI	10.1080/17460441.2021.1854220
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Article ; Online: Association between magnesium, copper, and potassium intakes with risk of rheumatoid arthritis: a cross-sectional study from National Health and Nutrition Examination Survey (NHANES).

Fang, Jianguo / Cao, Tingwei / Liu, Cai / Wang, Duojun / Zhang, Hui / Tong, Jinyu / Lin, Zaijun

BMC public health

2023 Volume 23, Issue 1, Page(s) 2085

Abstract: Background: The relationship between Mg (magnesium), Cu (copper), and K (potassium) intakes and the risk of rheumatoid arthritis (RA) remains limited. The aim of present study was to examine the associations between Mg, Cu and K intakes with RA.: ... ...

Abstract	Background: The relationship between Mg (magnesium), Cu (copper), and K (potassium) intakes and the risk of rheumatoid arthritis (RA) remains limited. The aim of present study was to examine the associations between Mg, Cu and K intakes with RA. Methods: Using data from the National Health and Nutrition Examination Survey (NHANES) 2003-2018, we examined the association between Mg, Cu and K intakes and the risk of RA among US adults. After adjustment for age, sex, race, BMI, educational level, smoking history, alcohol consumption, family Poverty Income Ratio (PIR), diabetes and total daily energy intake, logistic regression models and smooth curve fitting were applied to examine the associations of Mg, Cu and K intakes with RA. Results: A total of 18,338 participants were included (1,008 participants with RA). The multivariate adjusted ORs (95% CI) of RA were [0.66 (0.51, 0.84)], [0.76 (0.60, 0.97)], and [0.75 (0.58, 0.97)] in the highest versus lowest quartile of magnesium intakes, respectively. A nonlinear association between Cu intakes and RA was found. When Cu intake (ln) was between 0.6-2.2 mg, the risk of RA reduced by 26% for every 1 mg increase of intake in Cu [0.74 (0.58, 0.96)]. Conclusions: Higher Mg, Cu and K intakes may be inversely associated with the risk of RA among US adults, and an inverse L-shaped association between dietary Cu and RA was found.
MeSH term(s)	Adult ; Humans ; Magnesium ; Nutrition Surveys ; Copper ; Cross-Sectional Studies ; Diet ; Arthritis, Rheumatoid/epidemiology ; Potassium
Chemical Substances	Magnesium (I38ZP9992A) ; Copper (789U1901C5) ; Potassium (RWP5GA015D)
Language	English
Publishing date	2023-10-24
Publishing country	England
Document type	Journal Article
ZDB-ID	2041338-5
ISSN	1471-2458 ; 1471-2458
ISSN (online)	1471-2458
ISSN	1471-2458
DOI	10.1186/s12889-023-16906-y
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Article ; Online: Glutathione-triggered prodrugs: Design strategies, potential applications, and perspectives.

Zhao, Jintao / Li, Xinming / Ma, Tao / Chang, Bingbing / Zhang, Baoxin / Fang, Jianguo

Medicinal research reviews

2023 Volume 44, Issue 3, Page(s) 1013–1054

Abstract: The burgeoning prodrug strategy offers a promising avenue toward improving the efficacy and specificity of cytotoxic drugs. Elevated intracellular levels of glutathione (GSH) have been regarded as a hallmark of tumor cells and characteristic feature of ... ...

Abstract	The burgeoning prodrug strategy offers a promising avenue toward improving the efficacy and specificity of cytotoxic drugs. Elevated intracellular levels of glutathione (GSH) have been regarded as a hallmark of tumor cells and characteristic feature of the tumor microenvironment. Considering the pivotal involvement of elevated GSH in the tumorigenic process, a diverse repertoire of GSH-triggered prodrugs has been developed for cancer therapy, facilitating the attenuation of deleterious side effects associated with conventional chemotherapeutic agents and/or the attainment of more efficacious therapeutic outcomes. These prodrug formulations encompass a spectrum of architectures, spanning from small molecules to polymer-based and organic-inorganic nanomaterial constructs. Although the GSH-triggered prodrugs have been gaining increasing interests, a comprehensive review of the advancements made in the field is still lacking. To fill the existing lacuna, this review undertakes a retrospective analysis of noteworthy research endeavors, based on a categorization of these molecules by their diverse recognition units (i.e., disulfides, diselenides, Michael acceptors, and sulfonamides/sulfonates). This review also focuses on explaining the distinct benefits of employing various chemical architecture strategies in the design of these prodrug agents. Furthermore, we highlight the potential for synergistic functionality by incorporating multiple-targeting conjugates, theranostic entities, and combinational treatment modalities, all of which rely on the GSH-triggering. Overall, an extensive overview of the emerging field is presented in this review, highlighting the obstacles and opportunities that lie ahead. Our overarching goal is to furnish methodological guidance for the development of more efficacious GSH-triggered prodrugs in the future. By assessing the pros and cons of current GSH-triggered prodrugs, we expect that this review will be a handful reference for prodrug design, and would provide a guidance for improving the properties of prodrugs and discovering novel trigger scaffolds for constructing GSH-triggered prodrugs.
MeSH term(s)	Humans ; Prodrugs/pharmacology ; Prodrugs/chemistry ; Retrospective Studies ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/chemistry ; Glutathione/chemistry ; Cell Line, Tumor
Chemical Substances	Prodrugs ; Antineoplastic Agents ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2023-12-23
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	603210-2
ISSN	1098-1128 ; 0198-6325
ISSN (online)	1098-1128
ISSN	0198-6325
DOI	10.1002/med.22007
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Zs.A 1764: Show issues

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Article ; Online: Synthesis and discovery of Baylis-Hillman adducts as potent and selective thioredoxin reductase inhibitors for cancer treatment.

He, Yi-Lin / Zhong, Miao / Song, Zi-Long / Shen, Yu-Kai / Zhao, Lanning / Fang, Jianguo

Bioorganic & medicinal chemistry

2023 Volume 79, Page(s) 117169

Abstract: The selenoprotein thioredoxin reductase (TrxR) is of paramount importance in maintaining cellular redox homeostasis, and aberrant upregulation of TrxR is frequently observed in various cancers due to their elevated oxidative stress in cells. Thus, it ... ...

Abstract	The selenoprotein thioredoxin reductase (TrxR) is of paramount importance in maintaining cellular redox homeostasis, and aberrant upregulation of TrxR is frequently observed in various cancers due to their elevated oxidative stress in cells. Thus, it seems promising and feasible to target the ablation of intracellular TrxR for the treatment of cancers. We report herein the design and synthesis of a series of Baylis-Hillman adducts, and identified a typical adduct that possesses the superior cytotoxicity against HepG2 cells over other types of cancer cells. The biological investigation shows the selected typical adduct selectively targets TrxR in HepG2 cells, which thereafter results in the collapse of intracellular redox homeostasis. Further mechanistic studies reveal that the selected typical adduct arrests the cell cycle in G1/G0 phase. Importantly, the malignant metastasis of HepG2 cells is significantly restrained by the selected typical adduct. With well-defined molecular target and mechanism of action, the selected typical adduct, even other Baylis-Hillman skeleton-bearing compounds, merits further development as candidate or ancillary agent for the treatment of various cancers.
MeSH term(s)	Humans ; Thioredoxin-Disulfide Reductase/metabolism ; Oxidative Stress ; Neoplasms/drug therapy ; Oxidation-Reduction
Chemical Substances	Thioredoxin-Disulfide Reductase (EC 1.8.1.9)
Language	English
Publishing date	2023-01-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1161284-8
ISSN	1464-3391 ; 0968-0896
ISSN (online)	1464-3391
ISSN	0968-0896
DOI	10.1016/j.bmc.2023.117169
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