Abnormal tumour vasculature has a significant impact on tumour progression and response to therapy. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis and, thus, can be ...delivered to normalize tumour vasculature. However, a NO-delivery system with a prolonged half-life and a sustained release mechanism is currently lacking. Here we report the development of NanoNO, a nanoscale carrier that enables sustained NO release to efficiently deliver NO into hepatocellular carcinoma. Low-dose NanoNO normalizes tumour vessels and improves the delivery and effectiveness of chemotherapeutics and tumour necrosis factor-related, apoptosis-inducing, ligand-based therapy in both primary tumours and metastases. Furthermore, low-dose NanoNO reprogrammes the immunosuppressive tumour microenvironment toward an immunostimulatory phenotype, thereby improving the efficacy of cancer vaccine immunotherapy. Our findings demonstrate the ability of nanoscale NO delivery to efficiently reprogramme tumour vasculature and immune microenvironments to overcome resistance to cancer therapy, resulting in a therapeutic benefit.
Iron, the most abundant transition metal ion in humans, participates in the biosynthesis, translocation, signal transduction, and transformation of nitric oxide through its encapsulation in the form ...of heme, Fe-S, and Fe(NO)
2
cofactors within a variety of enzymes and proteins. After the review on nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC) for the biosynthesis and detection of NO, in this report, we discuss the natural utilization of the Fe(NO)
2
motif for translocation of endogenous NO and the translational development of synthetic dinitrosyl iron complexes (DNICs) for biomedical applications. A mechanistic study of NO-release and NO-transfer reactivity of structure-characterized DNICs promoted the discovery of cell-penetrating and
in vivo
NO-delivery reactivity for treatment of cancer and wound healing in diabetes. Beyond activation of sGC and vasodilation, phase I/II clinical trials of glutathione-bound DNICs (Oxacom®) against hypertension encourage bioinorganic engineering of DNICs into scaffolds for tissue regeneration and repair relying on anti-bacterial, anti-inflammation, cytoprotective, and proliferative effects of NO.
The ubiquitous physiology of nitric oxide enables the bioinorganic engineering of Fe(NO)
2
-containing and NO-delivery scaffolds for tissue engineering.
Continued efforts are made for the utilization of CO2 as a C1 feedstock for regeneration of valuable chemicals and fuels. Mechanistic study of molecular (electro‐/photo‐)catalysts disclosed that ...initial step for CO2 activation involves either nucleophilic insertion or direct reduction of CO2. In this study, nucleophilic activation of CO2 by complex (NO)2Fe(μ‐MePyr)2Fe(NO)22− (2, MePyr=3‐methylpyrazolate) results in the formation of CO2‐captured complex (NO)2Fe(MePyrCO2)− (2‐CO2, MePyrCO2=3‐methyl‐pyrazole‐1‐carboxylate). Single‐crystal structure, spectroscopic, reactivity, and computational study unravels 2‐CO2 as a unique intermediate for reductive transformation of CO2 promoted by Ca2+. Moreover, sequential reaction of 2 with CO2, Ca(OTf)2, and KC8 established a synthetic cycle, 2 → 2‐CO2 → (NO)2Fe(μ‐MePyr)2Fe(NO)2 (1) → 2, for selective conversion of CO2 into oxalate. Presumably, characterization of the unprecedented intermediate 2‐CO2 may open an avenue for systematic evaluation of the effects of alternative Lewis acids on reduction of CO2.
In anionic 2, a nucleophilic pyrazolate ligand, the neutral {Fe(NO)2}10 unit, and the K‐18‐crown‐6‐ether+ countercation work in concert to promote the capture and nucleophilic activation of CO2 through the assembly of stable 2‐CO2. Relying on the one‐electron reduction power of the {Fe(NO)2}10 core in the anionic complex (NO)2Fe(MePyrCO2)−, addition of dicationic Ca2+ further initiates the C−C coupling of activated/reduced CO2 and yields precipitated calcium oxalate.
Abstract
Background
We aimed to evaluate the prognostic significance of preoperative neutrophil‐to‐albumin ratio (NAR) in oral squamous cell carcinoma (OSCC).
Methods
A total of 622 patients with ...surgically treated OSCC were enrolled. NAR was defined as the absolute neutrophil count divided by the serum albumin level in peripheral blood before the radical surgery. Cox proportional hazards model were used to discover survival outcome‐associated factors.
Results
The optimal cut‐off of NAR to predict overall survival (OS) was determined to be 0.1. In Cox model, high NAR was identified as an independent negative prognosticator of OS, cancer‐specific survival, and recurrence‐free survival (adjusted hazard ratio: 1.503, 1.958, and 1.727, respectively; all
p
< 0.05). The NAR‐based nomogram accurately predicted OS (concordance index: 0.750).
Conclusion
Our study suggests that preoperative NAR is a convenient and effective prognostic marker for OSCC and NAR‐based nomogram can be a promising prognostic tool in clinical setting.
After the discovery of endogenous dinitrosyl iron complexes (DNICs) as a potential biological equivalent of nitric oxide (NO), bioinorganic engineering of Fe(NO)2 unit has emerged to develop ...biomimetic DNICs (NO)2Fe(L)2 as a chemical biology tool for controlled delivery of NO. For example, water-soluble DNIC Fe2(μ-SCH2CH2OH)2(NO)4 (DNIC-1) was explored for oral delivery of NO to the brain and for the activation of hippocampal neurogenesis. However, the kinetics and mechanism for cellular uptake and intracellular release of NO, as well as the biocompatibility of synthetic DNICs, remain elusive. Prompted by the potential application of NO to dermato-physiological regulations, in this study, cellular uptake and intracellular delivery of DNIC Fe2(μ-SCH2CH2COOH)2(NO)4 (DNIC-2) and its regulatory effect/biocompatibility toward epidermal cells were investigated. Upon the treatment of DNIC-2 to human fibroblast cells, cellular uptake of DNIC-2 followed by transformation into protein-bound DNICs occur to trigger the intracellular release of NO with a half-life of 1.8 ± 0.2 h. As opposed to the burst release of extracellular NO from diethylamine NONOate (DEANO), the cell-penetrating nature of DNIC-2 rationalizes its overwhelming efficacy for intracellular delivery of NO. Moreover, NO-delivery DNIC-2 can regulate cell proliferation, accelerate wound healing, and enhance the deposition of collagen in human fibroblast cells. Based on the in vitro and in vivo biocompatibility evaluation, biocompatible DNIC-2 holds the potential to be a novel active ingredient for skincare products.
After the first structural characterization of dinuclear dinitrosyl iron complex (DNIC) in 1958 and discovery of natural dinitrosyl iron unit (DNIU) Fe(NO)
2
in 1964–1965, continued investigations ...on natural and synthetic DNICs explored their ubiquitous functions as (1) a product for nitrosylation of non-heme Fe proteins and chelatable iron pool, (2) a biological vehicle for iron and nitric oxide, (3) a novel redox-active unit for stabilization and activation of small molecules, (4) an electrocatalyst for water splitting, and (5) a precursor for electrodeposition of Fe-containing hybrid material. From a synthetic chemistry perspective, herein, we summarize four synthetic methodologies for preparation of structure-characterized DNICs in the attempt to attract continued development of unexplored DNICs featuring novel functions. As collected from CCDC database, structure-characterized DNICs can be classified into (1) tetrahedral {Fe(NO)
2
}
9
DNICs with C/N/P/O/S/Se/Cl/Br/I ligation modes, (2) five-/six-coordinate {Fe(NO)
2
}
9
DNICs with N/O ligation modes, (3) tetrahedral {Fe(NO)
2
}
10
DNICs with C/Sn/N/P/O/S/H ligation modes, (4) metallothiolate-bound {Fe(NO)
2
}
9
/{Fe(NO)
2
}
10
DNICs, and (5) dinuclear {Fe(NO)
2
}
9
–{Fe(NO)
2
}
9
, {Fe(NO)
2
}
9
–{Fe(NO)
2
}
10
, and {Fe(NO)
2
}
10
–{Fe(NO)
2
}
10
DNICs with thiolate/alkoxide/pyrazolate/CO bridging ligands. After buildup of the DNIU Fe(NO)
2
using NO, NO
+
, and NO
2
−
as alternative sources of nitrosyl ligands, ligand substitution and modification reaction of DNICs, redox interconversion between {Fe(NO)
2
}
9
and {Fe(NO)
2
}
10
cores, and transformation between mononuclear and dinuclear DNICs establish the comprehensive pathways to bridge alternative types of DNICs in the chemical library of structure-characterized DNICs. This review on the synthetic methodology for preparation of DNICs will facilitate the incorporation of DNIU Fe(NO)
2
into (bio)materials for potential applications of DNICs in chemistry, catalysis, biology, and biomedicine.
Graphical abstract
Stromal barriers, such as the abundant desmoplastic stroma that is characteristic of pancreatic ductal adenocarcinoma (PDAC), can block the delivery and decrease the tumour-penetrating ability of ...therapeutics such as tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), which can selectively induce cancer cell apoptosis. This study aimed to develop a TRAIL-based nanotherapy that not only eliminated the extracellular matrix barrier to increase TRAIL delivery into tumours but also blocked antiapoptotic mechanisms to overcome TRAIL resistance in PDAC.
Nitric oxide (NO) plays a role in preventing tissue desmoplasia and could thus be delivered to disrupt the stromal barrier and improve TRAIL delivery in PDAC. We applied an
combinatorial phage display technique to identify novel peptide ligands to target the desmoplastic stroma in both murine and human orthotopic PDAC. We then constructed a stroma-targeted nanogel modified with phage display-identified tumour stroma-targeting peptides to co-deliver NO and TRAIL to PDAC and examined the anticancer effect in three-dimensional spheroid cultures
and in orthotopic PDAC models
.
The delivery of NO to the PDAC tumour stroma resulted in reprogramming of activated pancreatic stellate cells, alleviation of tumour desmoplasia and downregulation of antiapoptotic BCL-2 protein expression, thereby facilitating tumour penetration by TRAIL and substantially enhancing the antitumour efficacy of TRAIL therapy.
The co-delivery of TRAIL and NO by a stroma-targeted nanogel that remodels the fibrotic tumour microenvironment and suppresses tumour growth has the potential to be translated into a safe and promising treatment for PDAC.
The ubiquitous function of nitric oxide (NO) guided the biological discovery of the natural dinitrosyliron unit (DNIU) Fe(NO)2 as an intermediate/end product after Fe nitrosylation of nonheme ...cofactors. Because of the natural utilization of this cofactor for the biological storage and delivery of NO, a bioinorganic study of synthetic dinitrosyliron complexes (DNICs) has been extensively explored in the last 2 decades. The bioinorganic study of DNICs involved the development of synthetic methodology, spectroscopic discrimination, biological application of NO-delivery reactivity, and translational application to the (catalytic) transformation of small molecules. In this Forum Article, we aim to provide a systematic review of spectroscopic and computational insights into the bonding nature within the DNIU Fe(NO)2 and the electronic structure of different types of DNICs, which highlights the synchronized advance in synthetic methodology and spectroscopic tools. With regard to the noninnocent nature of a NO ligand, spectroscopic and computational tools were utilized to provide qualitative/quantitative assignment of oxidation states of Fe and NO in DNICs with different redox levels and ligation modes as well as to probe the Fe–NO bonding interaction modulated by supporting ligands. Besides the strong antiferromagnetic coupling between high-spin Fe and paramagnetic NO ligands within the covalent DNIU Fe(NO)2, in polynuclear DNICs, the effects of the Fe···Fe distance, nature of the bridging ligands, and type of bridging modes on the regulation of the magnetic coupling among paramagnetic DNIU Fe(NO)2 are further reviewed. In the last part of this Forum Article, the sequential reaction of {Fe(NO)2}10 DNIC (NO)2Fe(AMP) (1-red) with NO(g), HBF4, and KC8 establishes a synthetic cycle, {Fe(NO)2}9-{Fe(NO)2}9 DNIC (NO)2Fe(μ-dAMP)2Fe(NO)2 (1) → {Fe(NO)2}9 DNIC (NO2)Fe(AMP)BF4 (1-H) → {Fe(NO)2}10 DNIC 1-red → DNIC 1, for the transformation of NO into HNO/N2O. Of importance, the NO-induced transformation of {Fe(NO)2}10 DNIC 1-red and (NO)2Fe(DTA) (2-red; DTA = diethylenetriamine) unravels a synthetic strategy for preparation of the {Fe(NO)2}9-{Fe(NO)2}9 DNICs (NO)2Fe(μ-NHR)2Fe(NO)2 containing amido-bridging ligands, which hold the potential to feature distinctive physical properties, chemical reactivities, and biological applications.
Objectives/Hypothesis
To examine the pathogenic bacterial spectra and prognosis of deep neck infection (DNI) in end‐stage renal disease (ESRD) patients.
Study Design
Retrospective study.
Methods
...Patients diagnosed with DNI between 2004 and 2015 in Chang Gung Memorial Hospital were enrolled and divided into three groups, namely ESRD‐DNI, chronic kidney disease (CKD)‐DNI, and non‐CKD‐DNI. Differences in pathogenic bacteria, treatment, and prognosis were compared across the three groups.
Results
The bacterial spectra differed among the three groups. The main three facultative anaerobic or aerobic bacteria causing ESRD‐DNIs were methicillin‐resistant Staphylococcus aureus (MRSA; 25.4%), methicillin‐susceptible S. aureus (MSSA; 14.1%), and Klebsiella pneumoniae (KP; 12.7%). For CKD‐DNIs, they were KP (23.5%), Viridans streptococci (VS; 23.5%), and MSSA (14.7%). For non‐CKD‐DNIs, they were VS (31.7%), KP (17.2%), and coagulase‐negative staphylococci (8.0%). Compared with the other groups, the ESRD‐DNI group had higher white blood cell and C‐reactive protein levels, longer hospital stays, more frequent admissions to the intensive care unit, more mediastinal complications, and a significantly higher mortality rate.
Conclusions
The ESRD‐DNI group exhibited more severe disease activity and higher mortality compared with those of the CKD‐DNI and non‐CKD‐DNI groups. MRSA was the leading pathogen for patients with ESRD‐DNI. Physicians must implement strategies for the early detection of MRSA to accurately prescribe antibiotics and prevent nosocomial transmission.
Level of Evidence
4 Laryngoscope, 132:1403–1409, 2022
Despite extensive efforts, the electrocatalytic reduction of water using homogeneous/heterogeneous Fe, Co, Ni, Cu, W, and Mo complexes remains challenging because of issues involving the development ...of efficient, recyclable, stable, and aqueous‐compatible catalysts. In this study, evolution of the de novo designed dinitrosyl iron complex DNIC‐PMDTA from a molecular catalyst into a solid‐state hydrogen evolution cathode, considering all the parameters to fulfill the electronic and structural requirements of each step of the catalytic cycle, is demonstrated. DNIC‐PMDTA reveals electrocatalytic reduction of water at neutral and basic media, whereas its deposit on electrode preserves exceptional longevity, 139 h. This discovery will initiate a systematic study on the assembly of Fe(NO)2 motif into current collector for mass production of H2, whereas the efficiency remains tailored by its molecular precursor (L)Fe(NO)2.
From complex to cathode: Dinitrosyl iron complex‐deposited electrodes feature smaller Tafel slope than platinum electrodes in 1 M KCl, as well as exceptional longevity for electrocatalytic H2‐generation. This approach opens the door for adapting other molecular catalysts into solid‐state cathodes.
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