Browsing by Author "Lu, Tsai-Te"

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Activation of Angiogenesis and Wound Healing in Diabetic Mice Using NO-Delivery Dinitrosyl Iron Complexes
(2019-10-01)
Chen, Yu-Jen
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Wu, Shou-Cheng
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Wang, Hsiang-Ching
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Wu, Tung-Ho
;
Yuan, Shyng-Shiou F.
In diabetes, abnormal angiogenesis due to hyperglycemia and endothelial dysfunction impairs wound healing and results in high risks of diabetic foot ulcers and mortality. Alternative therapeutic methods were attempted to prevent diabetic complications through the activation of endothelial nitric oxide synthase. In this study, direct application of nitric oxide using dinitrosyl iron complexes (DNICs) to promote angiogenesis and wound healing under physiological conditions and in diabetic mice is investigated. Based on in vitro and in vivo studies, DNIC [Fe-2(mu-SCH2CH2OH)(2)(NO)(4)] (DNIC-1) with a sustainable NO-release reactivity (t(1/2) = 27.4 +/- 0.5 h at 25 degrees C and 16.8 +/- 1.8 h at 37 degrees C) activates the NO-sGC-cGMP pathway and displays the best proangiogenesis activity overwhelming other NO donors and the vascular endothelial growth factor. Moreover, this pro-angiogenesis effect of DNIC-1 restores the impaired angiogenesis in the ischemic hind limb and accelerates the recovery rate of wound closure in diabetic mice. This study translates synthetic DNIC-1 into a novel therapeutic agent for the treatment of diabetes and highlights its sustainable (NO)-N-center dot-release reactivity on the activation of angiogenesis and wound healing.
Bioinorganic Chemistry of the Natural [Fe(NO)(2)] Motif: Evolution of a Functional Model for NO-Related Biomedical Application and Revolutionary Development of a Translational Model!
(2018-10-15)
Lu, Tsai-Te
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Wang, Yun-Ming
;
Hung, Chen-Hsiung
;
Chiou, Show-Jen
;
Liaw, Wen-Feng
Identification of the distinctive electron paramagnetic resonance signal at g = 2.03 in the yeast cells and liver of mice treated with carcinogens opened the discovery and investigation of the natural [Fe(NO)(2)] motif in the form of dinitrosyliron complexes (DNICs). In this Viewpoint, a chronological collection of the benchmark for the study of DNIC demonstrates that the preceding study of its biological synthesis, storage, transport, transformation, and function related to NO physiology inspires the biomimetic study of structural and functional models supported by thiolate ligands to provide mechanistic insight at a molecular level. During the synthetic, spectroscopic, and theoretical investigations on the structure-to-reactivity relationship within DNICs, control of the Fe-NO bonding interaction and of the delivery of NO+/(NO)-N-center dot/HNO/NO- by the supporting ligands and nuclearity evolves into the "redesign of the natural [Fe(NO)(2)] motif" as a strategy to develop DNICs for NO-related biomedical application and therapeutic approach. The revolutionary transformation of covalent a [Fe(NO)(2)] motif into a translational model for hydrogenase, triggered by the discovery of redox interconversion among [{Fe(NO)(2)}(9)-L-center dot] <-> {Fe(NO)(2)}(9) <-> {Fe(NO)(2)}(10) <-> [{Fe(NO)(2)}(10)-L-center dot](-) echoes the preceding research journey on [Fe]/[NiFe]-hydrogenase and completes the development of an electrodeposited-film electrode for electrocatalytic water splitting. Through the 50-year journey, bioinorganic chemistry of DNIC containing the covalent [Fe(NO)(2)] motif and noninnocent/labile NO ligands highlights itself as a unique metallocofactor to join the longitudinal study between biology/chemistry/biomedical application and the lateral study toward multielectron (photo/electro)catalysis for industrial application. This Viewpoint discloses the potential [Fe(NO)(2)] motif awaiting continued contribution in order to emerge as a novel application in the next 50 years, whereas the parallel development of bioinorganic chemistry, guided by inspirational Nature, moves the science forward to the next stage in order to benefit the immediate needs for human activity.
Dinitrosyliron Complex [(PMDTA)Fe(NO)(2)]: Intermediate for Nitric Oxide Monooxygenation Activity in Nonheme Iron Complex
(2020-06-15)
Lu, Shan
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Chiou, Tzung-Wen
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Li, Wei-Liang
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Wang, Chun-Chieh
;
Wang, Yun-Ming
Despite a comprehensive study on the biosynthesis and function of nitric oxide, biological metabolism of nitric oxide, especially when its concentration exceeds the cytotoxic level, remains elusive. Oxidation of nitric oxide by O-2 in aqueous solution has been known to yield NO2. On the other hand, a biomimetic study on the metal-mediated conversion of NO to NO2/NO3- via O-2 reactivity disclosed a conceivable pathway for aerobic metabolism of NO. During the NO-to-NO2-/NO3- conversion, transient formation of metal-bound peroxynitrite and subsequent release of (NO2)-N-center dot via O-O bond cleavage were evidenced by nitration of tyrosine residue or 2,4-di-tert-butylphenol (DTBP). However, the synthetic/catalytic/enzymatic cycle for conversion of nitric oxide into a nitrite pool is not reported. In this study, sequential reaction of the ferrous complex [(PMDTA)Fe(kappa(2) -O,O'- NO2)(kappa(1) -O-NO2)] (3; PMDTA = pentamethyldiethylenetriamine) with NO(g), KC8, and O-2 established a synthetic cycle, complex 3 -> {Fe(NO)(2)}(9) DNIC [(PMDTA)Fe(NO)(2)][NO2] (4) -> {Fe(NO)(2)}(10) DNIC [(PMDTA)Fe(NO)(2)] (1) -> [(PMDTA)(NO)- Fe(kappa(2)-O,N-ONOO)] (2) -> complex 3, for the transformation of nitric oxide into nitrite. In contrast to the reported reactivity of metal-bound peroxynitrite toward nitration of DTBP, peroxynitrite-bound MNIC 2 lacks phenol nitration reactivity toward DTBP. Presumably, the [(PMDTA)Fe] core in {Fe(NO)}(8) MNIC 2 provides a mononuclear template for intramolecular interaction between Fe-bound peroxynitrite and Fe-bound NO , yielding Fe-bound nitrite stabilized in the form of complex 3. This [(PMDTA)Fe]-core-mediated concerted peroxynitrite homolytic O-O bond cleavage and combination of the O atom with Fe- bound NO - reveals a novel and effective pathway for NO-to-NO2- transformation. Regarding the reported assembly of the dinitrosyliron unit (DNIU) [Fe(NO)(2)] in the biological system, this synthetic cycle highlights DNIU as a potential intermediate for nitric oxide monooxygenation activity in a nonheme iron system.
Enhanced Oral Bioavailability of the Pharmacologically Active Lignin Magnolol via Zr-Based Metal Organic Framework Impregnation
(2020-05-01)
Santos, Joshua H.
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Quimque, Mark Tristan J.
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Macabeo, Allan Patrick G.
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Corpuz, Mary Jho-Anne T.
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Wang, Yun-Ming
Bioavailability plays an important role in drug activity in the human body, as certain drug amounts should be present to elicit activity. However, low bioavailability of drugs leads to negligible use for human benefit. In this study, the diversely active neolignan, magnolol, was impregnated onto a Zr-based organometallic framework [Uio-66(Zr)] to increase its low bioavailability (4-5%) and to test its potential acute oral toxicity. Synthesis of Uio-66(Zr) was done through the solvothermal method while simple impregnation at different time points was used to incorporate magnolol. The loading capacity of Uio-66(Zr) at 36 h was found to be significantly higher at 72.16 +/- 2.15% magnolol than in other incubation time. Based on the OECD 425 (limit test), toxicity was not observed at 2000 mg kg(-1) dose of mag@Uio-66(Zr) in female Sprague Dawley rats. The area under the curve (AUC) at 0-720 min of mag@Uio-66(Zr) was significantly higher than the AUC of free magnolol. Moreover, relative bioavailability increased almost two-folds using Uio-66(Zr). Unconjugated magnolol was found in the liver, kidney, and brain of rats in all treatment groups. Collectively, Uio-66(Zr) provided a higher magnolol bioavailability when used as drug carrier. Thus, utilization of Uio-66(Zr) as drug carrier is of importance for maximal use for poorly soluble and lowly bioavailable drugs.
Extension of C-elegans lifespan using the center dot NO-delivery dinitrosyl iron complexes
(2018-07-01)
Huang, Hsiao-Wen
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Lin, Yen-Hung
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Lin, Min-Hsuan
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Huang, Ya-Rong
;
Chou, Chih-Hung
The ubiquitous and emerging physiology function of endogenous nitric oxide in vascular, myocardial, immune, and neuronal systems prompts chemists to develop a prodrug for the controlled delivery of center dot NO in vivo and for the translational biomedical application. Inspired by the discovery of natural [Fe(NO)(2)] motif, herein, we develop the synthetic dinitrosyl iron complexes (DNICs) [Fe-2(mu-SR)(2)(NO)(4)] (1) as a universal platform for the O-2-triggered release of center dot NO, for the regulation of center dot NO-release kinetics (half-life = 0.6-27.4 h), and for the activation of physiological function of center dot NO. Using C. elegans as a model organism, the center dot NO-delivery DNIC 1 regulates IIS signaling pathway, AMPK signaling pathway, and mitochondrial function pathway to extend the lifespan and to delay the aging process based on the lifespan analysis, SA-beta gal activity assay, and next-generation RNA sequencing analysis. This study unveils the anti-aging effect of center dot NO and develops DNICs as a chemical biology probe for the continued discovery of unprecedented NO physiology. [GRAPHICS] .