Nitric oxide (NO),
a pro-neurogenic and antineuroinflammatory gasotransmitter,
features the potential to develop a translational medicine against
neuropathological conditions. Despite the extensive ...efforts made on
the controlled delivery of therapeutic NO, however, an orally active
NO prodrug for a treatment of chronic neuropathy was not reported
yet. Inspired by the natural dinitrosyl iron unit (DNIU) Fe(NO)
2
, in this study, a reversible and dynamic interaction between
the biomimetic (NO)
2
Fe(μ-SCH
2
CH
2
OH)
2
Fe(NO)
2
(
DNIC-1
) and serum
albumin (or gastrointestinal mucin) was explored to discover endogenous
proteins as a vehicle for an oral delivery of NO to the brain after
an oral administration of
DNIC-1
. On the basis of the
in vitro and in vivo study, a rapid binding of
DNIC-1
toward gastrointestinal mucin yielding the mucin-bound dinitrosyl
iron complex (DNIC) discovers the mucoadhesive nature of
DNIC-1
. A reversible interconversion between mucin-bound DNIC and
DNIC-1
facilitates the mucus-penetrating migration of
DNIC-1
shielded in the gastrointestinal tract of the stomach
and small intestine. Moreover, the NO-release reactivity of
DNIC-1
induces the transient opening of the cellular tight
junction and enhances its paracellular permeability across the intestinal
epithelial barrier. During circulation in the bloodstream, a stoichiometric
binding of
DNIC-1
to the serum albumin, as another endogenous
protein vehicle, stabilizes the DNIU Fe(NO)
2
for a subsequent
transfer into the brain. With aging mice under a Western diet as a
disease model for metabolic syndrome and cognitive impairment, an
oral administration of
DNIC-1
in a daily manner for 16
weeks activates the hippocampal neurogenesis and ameliorates the impaired
cognitive ability. Taken together, these findings disclose the synergy
between biomimetic
DNIC-1
and endogenous protein vehicles
for an oral delivery of therapeutic NO to the brain against chronic
neuropathy.
Transformations of dinitrosyl iron complex (DNIC) (NO)2Fe(SEt)2− and the anionic Roussin’s red ester (RRE) (NO)2Fe(μ-SEt)2Fe(NO)2− into 2Fe-2S clusters facilitated by HSCPh3/Me2S3 and Fe(SEt)4−, ...respectively, via an intermediate anionic mixed thiolate−sulfide-bridged RRE (NO)2Fe(μ-SEt)(μ-S)Fe(NO)2− through the reassembling process ((NO)2Fe(SEt)2− (2)/(NO)2Fe(μ-SEt)2Fe(NO)2− (4) → (NO)2Fe(μ-SEt)(μ-S)Fe(NO)2− (3-Et) → (NO)2Fe(μ-S)2Fe(NO)22− (5) → (SEt)2Fe(μ-S)2Fe(SEt)22− (1)) were demonstrated. The anionic mixed thiolate−sulfide-bridged RRE 3-Et was characterized by IR, UV−vis, electron paramagnetic resonance, 1H NMR, cyclic voltammetry, and single-crystal X-ray diffraction. In contrast to the nucleophilicity displayed by complex 2, the inertness of (NO)2Fe(SPh)2− toward HSCPh3 implicates how the reducing ability of the coordinated thiolates of DNICs modulate the release of sulfide from HSCPh3 via reduction and the conversion of DNICs into the anionic mixed sulfide−thiolate-bridged complex. The reversible interconversion between complex 3-Et and complex (NO)2Fe(μ-SPh)(μ-S)Fe(NO)2− (3-Ph) via protonation and a bridged-thiolate exchange reaction, respectively, demonstrates that the {Fe(NO)2}9−{Fe(NO)2}9 motif displays a preference for the stronger electron-donating alkylthiolate-bridged ligand over the phenylthiolate-bridged ligand. This study may signify that the anionic mixed thiolate−sulfide-bridged RREs act as a key intermediate in the transformation of DNICs into 2Fe−2S clusters. Also, the thiolate-coordinate DNICs serve as not only the thiolate/electron carrier activating the incorporation of sulfide of HSCPh3 (Me2S3) to assemble the Fe(μ-S)2Fe core but also the Fe source in the biosynthesis of the 2Fe−2S and 4Fe−4S iron−sulfur clusters.
Background: Peritonsillar abscess (PTA) is an infectious emergency in the head and neck, and patients with end-stage renal disease (ESRD) have an immunocompromised status. However, no relevant ...research has focused on the ESRD–PTA relationship. This study explored PTA in ESRD patients and their prognosis. Methods: We identified 157,026 patients diagnosed as having ESRD over January 1997 to December 2013 from Taiwan’s National Health Insurance Research Database (NHIRD). Each patient with ESRD (hereafter, patients) was matched with one control without chronic kidney disease (CKD; hereafter, controls) by sex, age, urbanization level, and income. Next, PTA incidence until death or the end of 2013 was compared between the two groups, and the relative risk of PTA was analyzed using a multiple logistic regression model. Results: The patients had a significantly higher PTA incidence than did the controls (incidence rate ratio: 2.02, 95% confidence interval CI: 1.40–2.91, p < 0.001). The Kaplan–Meier analysis revealed that the patients had a higher cumulative incidence of PTA than did the controls (p < 0.001). In Cox regression analysis, the patients had nearly twofold higher PTA risk (adjusted hazard ratio HR: 1.98, 95% CI: 1.37–2.86, p < 0.001). The between-group differences in the PTA-related hospital stay length (8.1 ± 10.3 days in patients and 5.7 ± 4.6 days in controls, p = 0.09), consequent deep-neck infection complication (4.2% in patients and 6.3% in controls, p = 0.682), and mortality (0.0% in both groups) were nonsignificant. Conclusions: Although ESRD does not predict a poor prognosis of PTA, it is an independent PTA risk factor.
Candida auris, a multidrug resistant pathogenic yeast, has spread worldwide and caused several outbreaks in healthcare settings. Here, we report the first case of C. auris candidemia in Taiwan in a ...patient with a two-month history of hospitalization in Vietnam. We performed further investigation on the isolate from the present case as well as the previously reported C. auris isolate identified from a wound in 2018 in Taiwan, which was the first case reported in Taiwan. Both C. auris isolates were found to be susceptible to fluconazole, amphotericin B, and echinocandins. Additionally, mutations in ERG11 or FKS1 were not detected in either isolate. Microsatellite genotyping revealed that both isolates belonged to the South Asian clade. In recent years, C. auris has emerged as a global concern, and differences in clades and susceptibility patterns mandate further awareness and systematic surveillance.
Dinitrosyl iron unit (DNIU), Fe(NO)2, is a natural metallocofactor for biological storage, delivery, and metabolism of nitric oxide (NO). In the attempt to gain a biomimetic insight into the natural ...DNIU under biological system, in this study, synthetic dinitrosyl iron complexes (DNICs) (NO)2Fe(μ-SCH2CH2COOH)2Fe(NO)2 (DNIC–COOH) and (NO)2Fe(μ-SCH2CH2COOCH3)2Fe(NO)2 (DNIC–COOMe) were employed to investigate the structure–reactivity relationship of mechanism and kinetics for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective heme oxygenase (HO)-1. After rapid cellular uptake of dinuclear DNIC–COOMe through a thiol-mediated pathway (t max = 0.5 h), intracellular assembly of mononuclear DNIC (NO)2Fe(SR)(SCys) n−/(NO)2Fe(SR)(SCys‑protein) n− occurred, followed by O2-induced release of free NO (t max = 1–2 h) or direct transfer of NO to soluble guanylate cyclase, which triggered the downstream HO-1. In contrast, steady kinetics for cellular uptake of DNIC–COOH via endocytosis (t max = 2–8 h) and for intracellular release of NO (t max = 4–6 h) reflected on the elevated activation of cytoprotective HO-1 (∼50–150-fold change at t = 3–10 h) and on the improved survival of DNIC–COOH-primed mesenchymal stem cell (MSC)/human corneal endothelial cell (HCEC) under stressed conditions. Consequently, this study unravels the bridging thiolate ligands in dinuclear DNIC–COOH/DNIC–COOMe as a switch to control the mechanism, kinetics, and efficacy for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective HO-1, which poses an implication on enhanced survival of postengrafted MSC for advancing the MSC-based regenerative medicine.
The phenolic natural product magnolol exhibits neuroprotective properties through β-amyloid toxicity in PC-12 cells and ameliorative effects against cognitive deficits in a TgCRND8 transgenic mice ...model. Its bioavailability and blood–brain barrier crossing ability have been significantly improved using the metal–organic framework (MOF) UiO-66(Zr) as a drug delivery system (DDS). To investigate the neuroprotective effects of the Zr-based DDS, magnolol and magnolol-loaded-UiO-66(Zr) (Mag@UiO-66(Zr)) were evaluated for inhibitory activity against β-secretase and AlCl3-induced neurotoxicity. Due to the moderate inhibition observed for magnolol in vitro, in silico binding studies were explored against β-secretase along with 11 enzymes known to affect Alzheimer’s disease (AD). Favorable binding energies against CDK2, CKD5, MARK, and phosphodiesterase 3B (PDE3B) and dynamically stable complexes were noted through molecular docking and molecular dynamic simulation experiments, respectively. The magnolol-loaded DDS UiO-66(Zr) also showed enhanced neuroprotective activity against two pathological indices, namely, neutrophil infiltration and apoptotic neurons, in addition to damage reversal compared to magnolol. Thus, MOFs are promising drug delivery platforms for poorly bioavailable drugs.
Streptococcus pneumoniae causes pneumonia and other invasive diseases, and is a leading cause of mortality in the elderly population. The present study aimed to provide current antimicrobial ...resistance and epidemiological profiles of S. pneumoniae infections in Taiwan.
A total of 252 nonduplicate S. pneumoniae isolates were collected from patients admitted to 16 hospitals in Taiwan between January 2017 and December 2019, and were analyzed. The minimum inhibitory concentration of antibiotics was determined using the Vitek 2 automated system for antimicrobial susceptibility testing. Furthermore, epidemiological profiles of S. pneumoniae infections were analyzed.
Among the strains analyzed, 88% were recognized as invasive pneumococcal strains. According to the Clinical and Laboratory Standards Institute criteria for non-meningitis, the prevalence of penicillin-non-susceptible S. pneumoniae demonstrated a declining trend from 43.6% in 2017 to 17.2% in 2019. However, the rate of penicillin-non-susceptible S. pneumoniae was 85.7% based on the criteria for meningitis. Furthermore, the prevalence of ceftriaxone-non-susceptible S. pneumoniae was 62.7% based on the criteria for meningitis. Isolates demonstrated higher susceptibility toward doripenem and ertapenem than toward meropenem and imipenem. An increased rate of non-susceptibility toward levofloxacin was observed in southern Taiwan (15.1%) and elderly patients (≥65 years; 11.4%). Most isolates were susceptible to vancomycin and linezolid.
Empirical treatment with ceftriaxone monotherapy for pneumococcal meningitis should be carefully monitored owing to its high non-susceptibility rate. The susceptibility rates of most isolates to penicillin (used for treating non-meningitis pneumococcal diseases), carbapenems (ertapenem and doripenem), respiratory quinolones (moxifloxacin and levofloxacin), vancomycin, and linezolid suggested the potential of these antibiotics in treating pneumococcal diseases in Taiwan.
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive impairment, memory loss, and behavioral deficits. β-amyloid1–42 (Aβ1–42) aggregation is a significant cause of the ...pathogenesis in AD. Despite the numerous types of research, the current treatment efficacy remains insufficient. Hence, a novel therapeutic strategy is required. Nitric oxide (NO) is a multifunctional gaseous molecule. NO displays a neuroprotective role in the central nervous system by inhibiting the Aβ aggregation and rescuing memory and learning deficit through the NO signaling pathway. Targeting the NO pathway might be a therapeutic option; however, NO has a limited half-life under the biological system. To address this issue, a biomimetic dinitrosyl iron complex (NO)2Fe(μ-SCH2CH2COOH)2Fe(NO)2 (DNIC-COOH) that could stably deliver NO was explored in the current study. To determine whether DNIC-COOH exerts anti-AD efficacy, DNIC-COOH was added to neuron-like cells and primary cortical neurons along with Aβ1–42. This study found that DNIC-COOH protected neuronal cells from Aβ-induced cytotoxicity, potentiated neuronal functions, and facilitated Aβ1–42 degradation through the NO-sGC-cGMP-AKT-GSK3β-CREB/MMP-9 pathway.
Craniofacial/jawbone deformities remain a significant clinical challenge in restoring facial/dental functions and esthetics. Despite the reported therapeutics for clinical bone tissue regeneration, ...the bioavailability issue of autografts and limited regeneration efficacy of xenografts/synthetic bone substitutes, however, inspire continued efforts towards functional conjugation and improvement of bioactive bone graft materials. Regarding the potential of nitric oxide (NO) in tissue engineering, herein, functional conjugation of NO-delivery dinitrosyl iron complex (DNIC) and osteoconductive bone graft materials was performed to optimize the spatiotemporal control over the delivery of NO and to activate synergistic osteogenesis and angiogenesis in rat calvaria bone defects. Among three types of biomimetic DNICs, Fe
2
(μ-SCH
2
CH
2
COOH)
2
(NO)
4
(
DNIC-COOH
) features a steady kinetics for cellular uptake by MC3T3-E1 osteoblast cells followed by intracellular assembly of protein-bound DNICs and release of NO. This steady kinetics for intracellular delivery of NO by
DNIC-COOH
rationalizes its biocompatibility and wide-spectrum cell proliferation effects on MC3T3-E1 osteoblast cells and human umbilical vein endothelial cells (HUVECs). Moreover, the bridging SCH
2
CH
2
COOH
−
thiolate ligands in
DNIC-COOH
facilitate its chemisorption to deproteinized bovine bone mineral (DBBM) and physisorption onto TCP (β-tricalcium phosphate), respectively, which provides a mechanism to control the kinetics for the local release of loaded
DNIC-COOH
. Using rats with calvaria bone defects as an
in vivo
model, DNIC-DBBM/DNIC-TCP promotes the osteogenic and angiogenic activity ascribed to functional conjugation of osteoconductive bone graft materials and NO-delivery
DNIC-COOH
. Of importance, the therapeutic efficacy of DNIC-DBBM/DNIC-TCP on enhanced compact bone formation after treatment for 4 and 12 weeks supports the potential for clinical application to regenerative medicine.
Through conjugation of osteoconductive bone graft materials with biomimetic dinitrosyl iron complexes (DNICs), spatiotemporal control over NO delivery activates synergistic osteogenesis and angiogenesis for the treatment of rat calvaria bone defects.
Obstructive sleep apnea (OSA) is a common disease in adults, which influences human relations, quality of life and associates with major complications. Continuous positive airway pressure (CPAP) is ...the gold standard treatment modality in OSA patients. For patients incompliant or unwilling to CPAP therapy, surgery is an alternative treatment. Sleep surgery for OSA include intrapharyngeal surgery, extrapharyngeal surgery and bariatric surgery addressing upper airway soft tissue, maxillofacial bone, and obesity, respectively. Among sleep surgeries, intrapharyngeal surgery (soft tissue surgery) is widespread used and serves overwhelming majority in OSA surgical patients. Despite the popularity of intrapharyngeal surgery, its outcomes can be influenced by multiple factors and consequently need conjunctive remedy to enhance at the short-term and sustain in the long-term. In this article, we introduce updated indications for treating OSA, practical principle in decision-making between CPAP and surgery, hybrid procedures in treating obstruction at the nose, palate, tongue and epiglottis, and postoperative integrated treatment including oropharyngeal myofunctional therapy (local), positional therapy (regional), and body weight reduction (systemic), and circadian rhythm (central). In summary, intrapharyngeal surgery is a target-oriented procedure that needs to be performed precisely and combines with integrated treatment as a holistic care for OSA patients.
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