Structure-Based Specific Detection and Inhibition of Monoamine Oxidases and Their Applications in Central Nervous System Diseases.

Monoamine oxidases (MAOs) are the enzymes that catalyze the oxidation of monoamines, such as dopamine, norepinephrine, and serotonin, which serve as key neurotransmitters in the central nervous system (CNS). MAOs play important roles in maintaining the homeostasis of monoamines, and the aberrant expression or activation of MAOs underlies the pathogenesis of monoamine neurotransmitter disorders, including neuropsychiatric and neurodegenerative diseases. Clearly, detecting and inhibiting the activities of MAOs is of great value for the diagnosis and therapeutics of these diseases. Accordingly, many specific detection probes and inhibitors have been developed and substantially contributed to basic and clinical studies of these diseases. In this review, progress in the detecting and inhibiting of MAOs and their applications in mechanism exploration and treatment of neurotransmitter-related disorders is summarized. Notably, how the detection probes and inhibitors of MAOs were developed has been specifically addressed. It is hoped that this review will benefit the design of more effective and sensitive probes and inhibitors for MAOs, and eventually the treatment of monoamine neurotransmitter disorders.

Ligand-displacement-based two-photon fluorogenic probe for visualizing mercapto biomolecules in live cells, Drosophila brains and zebrafish.

Investigating the change in expression level of mercapto biomolecules (GSH/Cys/Hcy) necessitates a rapid detection method for a series of physiological and pathological processes. Herein, we present a ligand-displacement-based two-photon fluorogenic probe based on an Fe(iii) complex, TPFeS, which is a GSH/Cys/Hcy rapid detection fluorogenic probe for in vitro analysis and live cell/tissue/in vivo imaging. The "in situ" probe is non-fluorescent and was prepared from a 1 : 2 ratio of Fe(iii) and TPS, a novel two-photon (TP) fluorophore with excellent one-photon (OP) and TP properties under physiological conditions, as a fluorescent ligand. This probe shows a rapid and remarkable fluorescence restoration (OFF-ON) property due to the ligand-displacement reaction of mercapto biomolecules in a recyclable manner in vitro. A significant two-photon action cross-section, good selectivity for biothiols, low cytotoxicity, and insensitivity to pH over the biologically relevant pH range allowed the direct visualization of mercapto biomolecules at different levels between normal/drug-treated live cells, as well as in Drosophila brain tissues/zebrafish based on the use of two-photon fluorescence microscopy.

Identification of telomere-associated gene signatures to predict prognosis and drug sensitivity in glioma.

OBJECTIVE: Gliomas are a heterogeneous group of brain tumors with distinct biological and clinical properties, leading to significant mortality and morbidity. Emerging evidence shows telomere maintenance has implicated in glioma susceptibility and prognosis. In this study, we comprehensively analyzed gene signatures related to telomere maintenance in glioma and their predictive values for predicting the prognosis and drug sensitivity in glioma. METHODS: We initially identified telomere-related genes differentially expressed between low-grade glioma (LGG) and glioblastoma (GBM) and accordingly developed a risk model by univariate and multivariate Cox analysis to assess the expressions of telomere-related genes across the risk groups. Finally, to assess these genes in immune function the anti-tumor medications often used in the clinical treatment of glioma, we computed immune cell infiltration analysis and drug sensitivity analysis. RESULTS: The consensus clustering analysis identified 20 telomere-related genes which split LGG patients into two distinct subtypes. The patient survival, the expressions of key telomere-related DEGs, and immune cell infiltration significantly differed between Cluster 1 and Cluster 2. The LASSO risk model [riskScore=(0.086)*HOXA7+(0.242)*WEE1+(0.247)*IGF2BP3+(0.052)*DUSP10] showed significant differences regarding the 1-, 3-, 5-year overall survival, immune cell infiltration, and drug sensitivity between high- and low-risk groups. The predictive nomogram constructed to quantify the survival probability of each sample at 1, 3, and 5 years was consistent with the actual patient survival. CONCLUSION: Our comprehensive characterization of telomere-associated gene signatures in glioma reveals their possible roles in the development, tumor microenvironment, and prognosis. The study provides some suggestive relationships between four telomere-related genes (HOXA7, WEE1, IGF2BP3, and DUSP10) and glioma prognosis.

Simultaneous detection of human norovirus GI, GII and SARS-CoV-2 by a quantitative one-step triplex RT-qPCR.

Background: There are many similarities in the clinical manifestations of human norovirus and SARS-CoV-2 infections, and nucleic acid detection is the gold standard for diagnosing both diseases. In order to expedite the identification of norovirus and SARS-CoV-2, a quantitative one-step triplex reverse transcription PCR (RT-qPCR) method was designed in this paper. Methods: A one-step triplex RT-qPCR assay was developed for simultaneous detection and differentiation of human norovirus GI (NoV-GI), GII (NoV-GII) and SARS-CoV-2 from fecal specimens. Results: The triplex RT-qPCR assay had high detection reproducibility (CV < 1%) and sensitivity. The lower limits of detection (LLOD95) of the triplex RT-qPCR assay for each target site were 128.5-172.8 copies/mL, and LLOD95 of the singleplex RT-qPCR assay were 110.3-142.0 copies/mL. Meanwhile, among the detection of clinical oropharyngeal swabs and fecal specimens, the results of the singleplex and triplex RT-qPCR assay showed high agreement. Conclusion: The triplex RT-qPCR assay for simultaneous detection of NoV-GI, NoV-GII and SARS-CoV-2 from fecal specimens has high clinical application value.

Vitamin B12 Ameliorates the Pathological Phenotypes of Multiple Parkinson's Disease Models by Alleviating Oxidative Stress.

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the substantia nigra of the midbrain. The etiology of PD has yet to be elucidated, and the disease remains incurable. Increasing evidence suggests that oxidative stress is the key causative factor of PD. Due to their capacity to alleviate oxidative stress, antioxidants hold great potential for the treatment of PD. Vitamins are essential organic substances for maintaining the life of organisms. Vitamin deficiency is implicated in the pathogenesis of various diseases, such as PD. In the present study, we investigated whether administration of vitamin B12 (VB12) could ameliorate PD phenotypes in vitro and in vivo. Our results showed that VB12 significantly reduced the generation of reactive oxygen species (ROS) in the rotenone-induced SH-SY5Y cellular PD model. In a Parkin gene knockout C. elegans PD model, VB12 mitigated motor dysfunction. Moreover, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse PD model, VB12 also displayed protective effects, including the rescue of mitochondrial function, dopaminergic neuron loss, and movement disorder. In summary, our results suggest that vitamin supplementation may be a novel method for the intervention of PD, which is safer and more feasible than chemical drug treatment.

GIPC2 interacts with Fzd7 to promote prostate cancer metastasis by activating WNT signaling.

Prostate cancer (PCa) causes significant mortality and morbidity, with advanced metastasis. WNT signaling is a promising therapeutic target for metastatic PCa. GIPC2 is a GIPC1 paralog involved in WNT signaling pathways associated with tumor progression, but its role in PCa metastasis remains unclear. Herein, we demonstrated that high GIPC2 expression in PCa tissues was significantly associated with distant metastasis and poor prognosis. Functional studies demonstrated that high GIPC2 expression due to CpG-island demethylation promoted increased metastatic capabilities of PCa cells. Conversely, silencing GIPC2 expression significantly inhibited PCa metastasis in vitro and in vivo. Furthermore, GIPC2 directly bound the WNT co-receptor Fzd7 through its PDZ domain, which enabled activation of WNT-ß-catenin cascades, thereby stimulating PCa metastasis. Interestingly, GIPC2 protein was also identified as a component of exosomes and that it robustly stimulated PCa adhesion, invasion, and migration. The presence of GIPC2 in tumor-derived exosomes and ability to impact the behavior of tumor cells suggest that GIPC2 is a novel epigenetic oncogene involved in PCa metastasis. Our findings identified GIPC2 as a novel exosomal molecule associated with WNT signaling and may represent a potential therapeutic target and biomarker for metastatic PCa.

Polydatin protects SH-SY5Y in models of Parkinson's disease by promoting Atg5-mediated but parkin-independent autophagy.

Parkinson's disease (PD), the second most common chronic neurodegenerative disorder, broadly remains incurable. Both genetic susceptibility and exposure to deleterious environmental stimuli contribute to dopaminergic neuron degeneration in the substantia nigra. Hence, reagents that can ameliorate the phenotypes rendered by genetic or environmental factors should be considered in PD therapy. In this study, we found that polydatin (Pol), a natural compound extracted from grapes and red wines, significantly attenuated rotenone- (Rot) or Parkin deficiency-induced mitochondrial dysfunction and cell death in SH-SY5Y, a human dopaminergic neuronal cell line. We showed that Pol significantly attenuated the Rot-induced decrease in cell viability, mitochondrial membrane potential (MMP), and Sirt 1 expression and increase in cell death, reactive oxygen species (ROS) and DJ1 expression. Rot resulted in a decrease in mTOR/Ulk-involved autophagy and an increase in PGC1ß/mfn2-involved mitochondrial fusion, which was inhibited by Pol. We further demonstrated that the protective effects of Pol are partially blocked when autophagy-related gene 5 (Atg5) is genetically inactivated, suggesting that Pol-mediated neuroprotection requires Atg5. Moreover, Pol rescued Parkin knockdown-induced oxidative stress, mitochondrial dysfunction, autophagy impairment, and mitochondrial fusion enhancement. Interestingly, Pol treatment could also rescue the mitochondrial morphological abnormality and motorial dysfunction of a Drosophila PD model induced by Parkin deficiency. Thus, Pol could represent a useful therapeutic strategy as a disease-modifier in PD by decreasing oxidative stress and regulating autophagic processes and mitochondrial fusion.

α-Arbutin Protects Against Parkinson's Disease-Associated Mitochondrial Dysfunction In Vitro and In Vivo.

Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by the progressive loss of dopaminergic neurons in substantia nigra. The underlying mechanisms of PD pathogenesis have not been fully illustrated and currently PD remains incurable. Accumulating evidences suggest that mitochondrial dysfunction plays pivotal role in the dopaminergic neuronal death. Therefore, discovery of novel and safe agent for rescuing mitochondrial dysfunction would benefit PD treatment. Here we demonstrated for the first time that α-Arbutin (Arb), a natural polyphenol extracted from Ericaceae species, displayed significant protective effect on the rotenone (Rot)-induced mitochondrial dysfunction and apoptosis of human neuroblastoma cell (SH-SY5Y). We further found that the neuroprotective effect of Arb was associated with ameliorating oxidative stress, stabilizing of mitochondrial membrane potential, and enhancing adenosine triphosphate production. To investigate the underlying mechanism, we checked the AMP-activated protein kinase and autophagy pathway and we found that both were involved in the neuroprotection of Arb. Moreover, we explored the protective effect of Arb in drosophila PD model and found that Arb rescued parkin deficiency-induced motor function disability and mitochondrial abnormality of drosophila. Taken together, our study demonstrated that Arb got excellent neuroprotective effect on PD models both in vitro and in vivo and Arb might serve as a potent therapeutic agent for the treatment of PD.

Thinning shell thickness of CuInS2@ZnS quantum dots to boost detection sensitivity.

Quantum dots (QDs), drawing large attention during the past three decades, have been extensively applied in lighting, display, and biodetection. However, the mechanism for their ability in biodetection, especially in recognizing toxic metal ions, has scarcely been explored. In this work, three sets of CuInS2@ZnS QDs systems with inert shell thickness varying from 1.1 to 4.1 nm have been performed. As the shrinkage of inert shell, QDs not only show red-shift emission but also demonstrate more sensitive and higher response to the added Cd2+. The thin-shell CuInS2@ZnS QDs could detect 0.91 nM Cd2+, and could further detect 4.36 nM Cd2+ when integrated with paper-based platform. Importantly, thin-shell CuInS2@ZnS QDs combined with paper-based platform can detect 105.86 nM Cd2+ even just applying mobile phone as detector and hand-held UV lamp as excitation resource. The mechanism is further proposed based on the energy transfer routes. The thin inert shell can not completely protect the emissive core away from the surface defects, but it can neither exclude the energy transfer from the surface to the emissive core. The added Cd2+ would facilitate the formation of CdS on the surface of QDs, which not only can alleviate the surface defects but also can transfer energy to emissive CuInS2, thus thinning the thickness of inert shell greatly boost the detection sensitivity.

A novel pyrimidine based deep-red fluorogenic probe for detecting hydrogen peroxide in Parkinson's disease models.

Parkinson's disease (PD) severely affects life quality of patients and has brought huge economic burden to health system worldwide. Previous studies have shown that the abnormal expression of hydrogen peroxide (H2O2) in the brain is closely related to the development of neurodegenerative diseases such as PD. Herein, we designed a novel deep-red H2O2 fluorogenic probe PB1 to detect the level of H2O2in vivo. PB1 showed a highly selectivity response to H2O2 over other reactants such as reactive oxygen/nitrogen species, biothiols and various ions in aqueous solution at physiological pH. We have demonstrated that PB1 possesses an excellent response to H2O2 in the cells and in the brain tissue of drosophila from confocal fluorescence imaging. These results suggested that PB1 holds great potential in the study of the relationship between H2O2 overexpression and PD.

Natural Molecules From Chinese Herbs Protecting Against Parkinson's Disease via Anti-oxidative Stress.

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, affecting about 7-10 million patients worldwide. The major pathological features of PD include loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the midbrain and the presence of α-synuclein-enriched Lewy bodies. Although the mechanism underlying PD pathogenesis remains to be elucidated, oxidative stress induced by the overproduction of reactive oxygen species (ROS) is widely accepted to be a key pathogenic factors. ROS cause oxidative damage to proteins, lipids, and DNA, which subsequently lead to neurodegeneration. Great efforts have been made to slow or stop the progress of PD. Unfortunately there is no effective cure for PD till now. Compounds with good antioxidant activity represent the promising candidates for therapeutics of PD. Some natural molecules from Chinese herbs are found to have good antioxidant activity. Both in vitro and in vivo studies demonstrate that these natural molecules could mitigate the oxidative stress and rescue the neuronal cell death in PD models. In present review, we summarized the reported natural molecules that displayed protective effects in PD. We also addressed the possible signal pathway through which natural molecules achieved their antioxidative effects and mitigate PD phenotypes. Hopefully it will pave the way to better recognize and utilize Chinese herbs for the treatment of PD.

Fast response two-photon fluorogenic probe based on Schiff base derivatives for monitoring nitric oxide levels in living cells and zebrafish.

Numerous excellent fluorogenic probes for NO detection based on NO-mediated reactions have been developed. However, some of them still suffer from limitations such as low selectivity, slow response, and a short excitation wavelength (<500 nm). Herein, a novel two-photon fluorogenic probe (XNO1) based on a Schiff base derivative has been reported for the first time. This new mechanism with a Schiff base structure as the specific response moiety towards NO endows the probe with fast responsibility, high selectivity and pH-independent properties. Furthermore, XNO1 has been demonstrated to be lysosome-targeted and to successfully monitor exogenous/endogenous NO in living cells and zebrafishes with one- and two-photon fluorescence imaging.

A novel flurophore-cyano-carboxylic-Ag microhybrid: Enhanced two photon absorption for two-photon photothermal therapy of HeLa cancer cells by targeting mitochondria.

In this study, a novel two-photon photothermal therapy (TP-PTT) agent based on an organic-metal microhybrid with surface Plasmon resonance (SPR) enhanced two-photon absorption (TPA) characteristic was designed and synthesized using a fluorescent cyano-carboxylic derivative 2-cyano-3-(9-ethyl-9H-carbazol-3-yl) -acrylic acid (abbreviated as CECZA) and silver nanoparticles through self-assembly process induced by the interfacial coordination interactions between the O/N atom of CECZA and Ag+ion at the surface of Ag nanoparticles. The coordination interactions caused electron transfer from the Ag nanoparticles to CECZA molecules at the excited state, resulting in a decreased fluorescence quantum yield. The interfacial coordination interactions also enhanced the nonlinear optical properties, including 13 times increase in the TPA cross-section (δ). The decreased fluorescence quantum yield and increased two photon absorption caused by the SPR effect led excellent two-photon photothermal conversion, which was beneficial for the TP-PTT effect on HeLa cancer cells.

Mitochondrial Specific H2S n Fluorogenic Probe for Live Cell Imaging by Rational Utilization of a Dual-Functional-Photocage Group.

Reactive sulfur species play a very important role in modulating neural signal transmission. Hydrogen polysulfides (H2S n, n > 1) are recently suggested to be the actual signaling molecules. There are still few spatiotemporal controllable-based probes to detect H2S n. In this work, for the first time, we proposed the photocleavage product of the common photoremovable protecting group (2-nitrophenyl moiety) capable of trapping H2S n. Taking advantage of this, we constructed the probe H1 containing a photocontrollable group, a mitochondrial directing unit and a signal reporter fluorescein dye. H1 exhibited excellent fluorescence enhancement (50-fold) in response to H2S n under the aqueous buffer only after UV irradiation. H1 also showed high selectivity and sensitivity for H2S n over other reactive sulfur species, reactive oxygen species, and other analytes, especially biothoils including hydrogen sulfide, cysteine, homocysteine, and glutathione. We showed the utility of H1 to image H2S n in living cells with high spatiotemporal resolution.

A ferrocene∩europium assembly showing phototriggered anticancer activity and fluorescent modality imaging.

Two macrocyclic ferrocenophanes containing a coumarin fluorophore, Se2N[7]ferrocenophane (fc1), and Se4N2[7,7]ferrocenophane (fc2), construct an assembly of fc1-H+ClO4[Eu(C10H21COO)2(H2O)2(ClO4)] (fc1∩Eu) and fc2-2H+{ClO4[Eu(C10H21COO)2(H2O)2(ClO4)]}2 (fc2∩Eu) via a N-HO hydrogen bond and a coordinate bond between EuIII and ClO4-. In fc1∩Eu, UV light irradiation triggers non-covalent bond cleavage to release a ferrocenium and EuII complex, accompanying chromism and luminescence signals. Investigations through the steady-state UV-vis absorption, fluorescence, time-resolved fluorescence, femtosecond transient absorption spectra and electrochemical characterization elucidate a stepwise mechanism: firstly, an effective electron transfer occurs from a ferrocene unit to the singlet state of a coumarin unit; the following proton-coupled electron transfer (PCET) reduces EuIII and results in a non-covalent interaction cleavage. Further in vitro exploration of fc1∩Eu in HepG2 cells demonstrated phototriggered integrated cell cytotoxicity and fluorescent modality imaging.