Impaired olfactory identification in dementia-free individuals is associated with the functional abnormality of the precuneus.

OBJECTIVE: Olfactory dysfunction indicates a higher risk of developing dementia. However, the potential structural and functional changes are still largely unknown. METHODS: A total of 236 participants were enrolled, including 45 Alzheimer's disease (AD) individuals and 191dementia-free individuals. Detailed study methods, comprising neuropsychological assessment and olfactory identification test (University of Pennsylvania smell identification test, UPSIT), as well as structural and functional magnetic resonance imaging (MRI) were applied in this research. The dementia-free individuals were divided into two sub-groups based on olfactory score: dementia-free with olfactory dysfunction (DF-OD) sub-group and dementia-free without olfactory dysfunction (DF-NOD) sub-group. The results were analyzed for subsequent intergroup comparisons and correlations. The cognitive assessment was conducted again three years later. RESULTS: (i) At dementia-free stage, there was a positive correlation between olfactory score and cognitive function. (ii) In dementia-free group, the volume of crucial brain structures involved in olfactory recognition and processing (such as amygdala, entorhinal cortex and basal forebrain volumes) are positively associated with olfactory score. (iii) Compared to the DF-NOD group, the DF-OD group showed a significant reduction in olfactory network (ON) function. (iv) Compared to DF-NOD group, there were significant functional connectivity (FC) decline between PCun_L(R)_4_1 in the precuneus of posterior default mode network (pDMN) and the salience network (SN) in DF-OD group, and the FC values decreased with falling olfactory scores. Moreover, in DF-OD group, the noteworthy reduction in FC were observed between PCun_L(R)_4_1 and amygdala, which was a crucial component of ON. (v) The AD conversion rate of DF-OD was 29.41%, while the DF-NOD group was 12.50%. The structural and functional changes in the precuneus were also observed in AD and were more severe. CONCLUSIONS: In addition to the olfactory circuit, the precuneus is a critical structure in the odor identification process, whose abnormal function underlies the olfactory identification impairment of dementia-free individuals.

Near-Infrared Fluorescence Probe with a New Recognition Moiety for Specific Detection and Imaging of Aldehyde Dehydrogenase Expecting the Identification and Isolation of Cancer Stem Cells.

Aldehyde dehydrogenase (ALDH) is a vital enzyme that converts aldehyde to acetic acid during alcohol metabolism. ALDH is also a cellular marker of cancer stem cells (CSCs), which plays an important role in cancer diagnosis and prognosis assessment. Therefore, there is a need to explore convenient, selective, and sensitive methods for the detection and imaging of ALDH. Because of the low background fluorescence and high penetration, near-infrared (NIR) fluorescent probes are powerful tools for the detection of ALDH. Until now, only one NIR fluorescent probe has been reported for detecting ALDH. Hence, we synthesized a novel NIR fluorescent probe, Probe-ALDH, by linking the new specific recognition moiety 4-hydroxymethyl benzaldehyde with NIR fluorophore AXPI. Compared with the existing ALDH fluorescent probes, Probe-ALDH has excellent properties, such as a new specific recognition moiety without the substitution of benzaldehyde, a simple synthesis method, emission wavelength in the NIR region, reaction time of only 30 min, and a detection limit as low as 0.03 U·mL-1, which is better than those of the previously reported probes. The probe effectively eliminates the interference from reactive oxygen species (ROS), amino acids, and amines. More importantly, the flow cytometry results showed that Probe-ALDH has great potential applications in the identification and isolation of CSCs. Ultimately, it was successfully applied to the imaging analysis of endogenous ALDH in HepG2 cells by the addition of inhibitor disulfiram. The excellent performance of Probe-ALDH makes it a promising candidate for drug discovery, cancer diagnosis, and so forth.

New Insights into lncRNAs in Aß Cascade Hypothesis of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of dementia, but its pathogenesis is not fully understood, and effective drugs to treat or reverse the progression of the disease are lacking. Long noncoding RNAs (lncRNAs) are abnormally expressed and deregulated in AD and are closely related to the occurrence and development of AD. In addition, the high tissue specificity and spatiotemporal specificity make lncRNAs particularly attractive as diagnostic biomarkers and specific therapeutic targets. Therefore, an in-depth understanding of the regulatory mechanisms of lncRNAs in AD is essential for developing new treatment strategies. In this review, we discuss the unique regulatory functions of lncRNAs in AD, ranging from Aß production to clearance, with a focus on their interaction with critical molecules. Additionally, we highlight the advantages and challenges of using lncRNAs as biomarkers for diagnosis or therapeutic targets in AD and present future perspectives in clinical practice.

Design of a New Hydrazine Moiety-Based Near-Infrared Fluorescence Probe for Detection and Imaging of Endogenous Formaldehyde In Vivo.

Formaldehyde (FA), the smallest molecular aldehyde with strong reducing properties, could regulate body homeostasis endogenously during physiological and pathological processes. The effective near-infrared (NIR) fluorescent probe is needed as a visualizer of FA in biologic organisms. In this work, a novel NIR fluorescent Probe-NHNH2 was designed on the basis of Probe-NH2 via introducing a strong nucleophilic hydrazine group, which can be used as a quenching and recognizing moiety for the detection of FA. With the treatment of FA, the hydrazine group of Probe-NHNH2 undergoes condensation and achieves a turn-on NIR fluorescence signal at a wavelength of 706 nm. The spectroscopic performance of Probe-NHNH2 for FA was evaluated, and it exhibited high sensitivity and selectivity for the detection of FA in solution. Moreover, compared to the amine moiety-based Probe-NH2, which our group reported, we found that hydrazine moiety-based Probe-NHNH2, exhibited a better reaction time of within 10 min and a lower detection limit of 0.68 µM, reflecting that the reaction of FA with hydrazine moiety is faster and more sensitive than that of FA with the amino group. More importantly, Probe-NHNH2 was successfully applied to real-time imaging of endogenous FA by reacting with effective stimulant tetrahydrofolate and scavenger sodium bisulfite in zebrafish and mice. It is expected that we can provide a new rapid, sensitive NIR fluorescence theoretical basis for FA detection and in vivo imaging applications.

A new amine moiety-based near-infrared fluorescence probe for detection of formaldehyde in real food samples and mice.

A new amine moiety-based near-infrared fluorescent probe (Probe-NH2) is developed for detection of formaldehyde in food samples and mice. Probe-NH2 is constructed and synthesized from the IR-780 via two-step reactions as a hemicyanine skeleton bearing an amino moiety. The response mechanism is based on Schiff base reaction that formaldehyde reacts with amine group to form the corresponding imines. Probe-NH2 for detection of formaldehyde exhibits excellent analytical performance, including near-infrared fluorescence emission at 708 nm, high selectivity and sensitivity, also provides a response time as low as 30 min with a detection limit of 1.87 µmolL-1. Notably, we constructed a simple, rapid and visual formaldehyde detection platform based on paper chips in the near-infrared region for the first time. The accurate detection of formaldehyde in real food samples is of great significance, Probe-NH2 was detected in dried beancurd sticks, endive sprout, frozen shrimp and squid, with good recoveries of 99.60%-112.72%, indicating the reliability of Probe-NH2 for spiked determination of formaldehyde in contaminated foods. More importantly, Probe-NH2 has been successfully applied to the detection of endogenous formaldehyde in mice.

A new near-infrared fluorescence probe synthesized from IR-783 for detection and bioimaging of hydrogen peroxide in vitro and in vivo.

A new near-infrared fluorescence probe was developed and synthesized for detection of hydrogen peroxide (H2O2) in vitro and in vivo. Synthesized from IR-783, the probe DBIS was designed to connect 4-(Bromomethyl)benzeneboronic acid pinacol ester as the recognizing moiety to the stable hemicyanine skeleton. Reaction of probe DBIS with H2O2 would result in the oxidation of phenylboronic acid pinacol ester, and thereby release the near-infrared fluorophore HXIS. The background signal of probe DBIS is very low, which is necessary for sensitive detection. Compared with the existing probes for detecting H2O2, the proposed probe DBIS shows excellent optical performance in vitro and in vivo, high selectivity, high sensitivity and good water solubility, as well as near-infrared fluorescence emission 708 nm, with a low detection limit of 0.12 µM. Furthermore, probe DBIS is low cytotoxic, cell membrane permeable, and its applicability has been shown to visualize endogenous H2O2 in mice. In addition, it is the first time that paper chips have been used as carrier to detect H2O2 through fluorescence signals instead of the traditional liquid phase detection mode of fluorescent probes. These superior characteristics of the probe make it have great application potential in biological systems or in vivo related research.

Application of Antibody Fragments Against Aß With Emphasis on Combined Application With Nanoparticles in Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and accumulating evidences suggest a key role of amyloid-ß (Aß) peptide in the pathogenesis of AD. According to the amyloid cascade hypothesis, the imbalance of producing and clearing Aß is the beginning of neurodegeneration and dementia. Consequently, immunotherapy becomes popular through using antibodies against Aß. However, many studies of monoclonal antibodies were stopped because adverse effects appeared or there were no evident benefits observed. Some antibody fragments have many advantages over monoclonal antibodies, such as small sizes, lack of the crystallizable fraction (Fc) and so on. There are three main antibody fragments, including single chain variable fragments (scFvs), Fab fragments and single-domain antibody fragments. Nanoparticles can facilitate the entry of drug molecules across the blood-brain barrier, making them become excellent carriers. Various kinds of nanoparticles have been applied in the treatment of AD. The combination of nanoparticles and antibody fragments against amyloid-ß can be used in the diagnosis and treatment of Alzheimer's disease. In this review, we summarize the progress of antibody fragments against amyloid-ß in AD, focusing on the combined application with nanoparticles in the diagnosis and treatment of AD.

Detection of Tyrosinase in Real Food Samples and Living Cells by a Novel Near-Infrared Fluorescence Probe.

A new near-infrared fluorescence probe was developed and applied to the fluorescence detection of tyrosinase in real food samples and living cells. The probe (E)-2-(2-(6-((3-hydroxybenzyloxy)carbonylamino)-2,3-dihydro-1H-xanthen-4-yl)vinyl)-3,3-dimethyl-1-propyl-3H-indolium (1) was designed and synthesized by coupling 3-hydroxybenzyl alcohol via carbamate bond with an amino hemicyanine skeleton, based on the high anti-interference ability of 3-hydroxybenzyl alcohol to reactive oxygen species and its binding affinity to tyrosinase. Compared with the existing tyrosinase probes, the proposed probe exhibits superior analytical performance, such as high selectivity, high sensitivity, superior spatiotemporal sampling ability, fluorescence signal switching at 706 nm, and low detection limit of 0.36 U mL-1. More importantly, the probe has been successfully used to monitor tyrosinase in the browning of apple slices for the first time, and the results indicated that the strongest fluorescence intensity could be achieved at 2.5 h to realize precise visual recognition of tyrosinase. Notably, the probe determined tyrosinase in real food samples (apple, banana, cheese, and red wine) with a stable average recovery range of 95.7-108.3% and has been successfully used to monitor tyrosinase in the living B16 cells. The superior properties of the probe make it of great potential use in food nutritional value evaluation and clinical diagnosis of melanin-related diseases.

Exhaustive-exercise-induced oxidative stress alteration of erythrocyte oxygen release capacity.

The aim of the present study was to explore the effect of exhaustive running exercise in the oxygen release capacity of rat erythrocytes. Rats were divided into sedentary control, moderate running exercise, and exhaustive running exercise groups. The thermodynamic and kinetic properties of the erythrocyte oxygen release process of the different groups were tested. We also determined the degree of band-3 oxidation and phosphorylation, anion transport activity, and carbonic anhydrase isoform II activity. Biochemical studies suggested that exhaustive running significantly increased oxidative injury parameters in thiobarbituric acid reactive substances and methaemoglobin levels. Furthermore, exhaustive running significantly decreased anion transport activity and carbonic anhydrase isoform II activity. Thermodynamic analysis indicated that erythrocytes oxygen release ability also significantly increased due to elevated 2,3-DPG level after exhaustive running. Kinetic analysis indicated that exhaustive running resulted in significantly decreased T50 value. We presented evidence that exhaustive running remarkably impacted thermodynamic and kinetic properties of RBC oxygen release. In addition, changes in 2,3-DPG levels and band-3 oxidation and phosphorylation could be the driving force for exhaustive-running-induced alterations in erythrocyte oxygen release thermodynamic and kinetic properties.