Mitochondrial quality control plays an important role in maintaining mitochondrial homeostasis and function. Disruption of mitochondrial quality control degrades brain function. We found that flunarizine (FNZ), a drug whose chronic use causes parkinsonism, led to a parkinsonism-like motor dysfunction in mice. FNZ induced mitochondrial dysfunction and decreased mitochondrial mass specifically in the brain. FNZ decreased mitochondrial content in both neurons and astrocytes, without affecting the number of nigral dopaminergic neurons. In human neural progenitor cells, FNZ also induced mitochondrial depletion. Mechanistically, independent of ATG5- or RAB9-mediated mitophagy, mitochondria were engulfed by lysosomes, followed by a vesicle-associated membrane protein 2– and syntaxin-4–dependent extracellular secretion. A genome-wide CRISPR knockout screen identified genes required for FNZ-induced mitochondrial elimination. These results reveal not only a previously unidentified lysosome-associated exocytosis process of mitochondrial quality control that may participate in the FNZ-induced parkinsonism but also a drug-based method for generating mitochondria-depleted mammal cells.
Aging is an inevitable process that all individuals experience, of which the extent differs among individuals. It has been recognized as the risk factor of neurodegenerative diseases by affecting gut microbiota compositions, microglia, and cognition abilities. Aging‐induced changes in gut microbiota compositions have a critical role in orchestrating the morphology and functions of microglia through the gut‐brain axis. Gut microbiota communicates with microglia by its secreted metabolites and neurotransmitters. This is highly associated with age‐related cognitive declines. Here, we review the main composition of microbiota in the aged individuals, outline the changes of the brain in age‐related cognitive decline from a neuroinflammation perspective, especially the changes of morphology and functions of microglia, discuss the crosstalk between microbiota and microglia in the aged brain and further highlight the role of microbiota‐microglia connections in neurodegenerative diseases (Alzheimer's disease and Parkinson's disease).
Submicron-sized iron oxide particles can influence the activity of bacteria, but the exact mechanisms of oxide toxicity toward bacteria remain elusive. By using atomic force microscopy (AFM), soft X-ray tomography (Nano-CT), and Fourier transform infrared (FTIR) spectrometry, we show how the size-dependent interfacial interactions between hematite particles and bacteria in the absence of any ligands contribute to the antimicrobial properties against Gram-positive and Gram-negative bacterial strains. We found that surface adhesion between hematite particles and bacterial cells is initially dominated by Lifshitz van der Waals and electrostatic forces. Subsequently, the rapid formation of P–O–Fe bonds occurs, followed by changes in the structures of membrane proteins in 2 h, resulting in the loss of the structural integrity of the membrane within 10 h. Thus, particles can migrate into the cells. After contact with bacterial cells, reactive oxygen species are generated on the surface of hematite particles, leading to cell permeabilization. G– bacteria appear to be more susceptible to this process than G+ bacteria because the latter exhibit weaker adhesion forces toward hematite and benefit from the protective effects of the peptidoglycan layers. Our work revealed that hematite nanoparticles are more toxic to bacteria than microscaled particles due to their strong interfacial physicochemical interactions with the cells.
Positron emission tomography (PET) represents molecular imaging for non-invasive phenotyping of physiological and biochemical processes in various oncological diseases. PET imaging with 18 F-fluorodeoxyglucose ( 18 F-FDG) for glucose metabolism evaluation is the standard imaging modality for the clinical management of lymphoma. One of the 18 F-FDG PET applications is the detection and pre-treatment staging of lymphoma, which is highly sensitive. 18 F-FDG PET is also applied during treatment to evaluate the individual chemo-sensitivity and accordingly guide the response-adapted therapy. At the end of the therapy regiment, a negative PET scan is indicative of a good prognosis in patients with advanced Hodgkin's lymphoma and diffuse large B-cell lymphoma. Thus, adjuvant radiotherapy may be alleviated. Future PET studies using non-18 F-FDG radiotracers, such as 68 Ga-labeled pentixafor (a cyclic pentapeptide that enables sensitive and high-contrast imaging of C-X-C motif chemokine receptor 4), 68 Ga-labeled fibroblast activation protein inhibitor (FAPI) that reflects the tumor microenvironment, and 89 Zr-labeled atezolizumab that targets the programmed cell death-ligand 1 (PD-L1), may complement 18 F-FDG and offer essential tools to decode lymphoma phenotypes further and identify the mechanisms of lymphoma therapy.
A lack of efficient diagnostic tools for early and noninvasive diagnosis of breast cancer has restricted the clinical treatment effect. This problem might be addressed by the combination of aggregation‐induced emission (AIE) fluorescence imaging and positron emission tomography (PET) with the dual advantages of high resolution and easy operation, and unlimited penetration and high sensitivity. Here, a mitochondria‐targeted AIE luminogen (AIEgen) radiolabeled with 18F was developed through a two‐step radiochemical reaction by virtue of a prosthetic group. The obtained 18/19F‐Bz‐CP imaging probe was examined by in vitro cell uptake and cell proliferation inhibition in two breast cancer cell lines, showing that the probe can efficiently target and locate in the mitochondria through the analysis of fluorescence imaging and PET simultaneously. Additionally, the probe can induce cancer cell apoptosis with the half maximal inhibitory concentration (IC50) of 4.8 μM for MCF‐7 cells and 7.2 μM for T47D cells, indicating its potential application for breast cancer therapy.
Coronavirus disease 2019 (COVID-19) has become a major public health problem worldwide since its outbreak in 2019. Currently, the spread of COVID-19 is far from over, and various complications have roused increasing awareness of the public, calling for novel techniques to aid at diagnosis and treatment. Based on the principle of molecular imaging, positron emission tomography (PET) is expected to offer pathophysiological alternations of COVID-19 in the molecular/cellular perspectives and facilitate the clinical management of patients. A number of PET-related cases and research have been reported on COVID-19 over the past one year. This article reviews the current studies of PET in the diagnosis and treatment of COVID-19, and discusses potential applications of PET in the development of management strategy for COVID-19 patients in the pandemic era.
Recent BOLD-fMRI studies have revealed spatial distinction between variability- and mean-based between-condition differences, suggesting that BOLD variability could offer complementary and even orthogonal views of brain function with traditional activation. However, these findings were mainly observed in block-designed fMRI studies. As block design may not be appreciate for characterizing the low-frequency dynamics of BOLD signal, the evidences suggesting the distinction between BOLD variability and mean are less convincing. Based on the high reproducibility of signal variability modulation between continuous eyes-open (EO) and eyes-closed (EC) states, here we employed EO/EC paradigm and BOLD-fMRI to compare variability- and mean-based EO/EC differences while the subjects were in light. The comparisons were made both on block-designed and continuous EO/EC data. Our results demonstrated that the spatial patterns of variability- and mean-based EO/EC differences were largely distinct with each other, both for block-designed and continuous data. For continuous data, increases of BOLD variability were found in secondary visual cortex and decreases were mainly in primary auditory cortex, primary sensorimotor cortex and medial nuclei of thalamus, whereas no significant mean-based differences were observed. For the block-designed data, the pattern of increased variability resembled that of continuous data and the negative regions were restricted to medial thalamus and a few clusters in auditory and sensorimotor networks, whereas activation regions were mainly located in primary visual cortex and lateral nuclei of thalamus. Furthermore, with the expanding window analyses we found variability results of continuous data exhibited a rather slower dynamical process than typically considered for task activation, suggesting block design is less optimal than continuous design in characterizing BOLD variability. In sum, we provided more solid evidences that variability-based modulation could represent orthogonal views of brain function with traditional mean-based activation.
The amplitude of low-frequency fluctuation (ALFF) describes the regional intensity of spontaneous blood-oxygen-level-dependent signal in resting-state functional magnetic resonance imaging (fMRI). How the fMRI–ALFF relates to the amplitude in electrophysiological signals remains unclear. We here aimed to investigate the neural correlates of fMRI–ALFF by comparing the spatial difference of amplitude between the eyes-closed (EC) and eyes-open (EO) states from fMRI and magnetoencephalography (MEG), respectively. By synthesizing MEG signal into amplitude-based envelope time course, we first investigated 2 types of amplitude in MEG, meaning the amplitude of neural activities from delta to gamma (i.e. MEG–amplitude) and the amplitude of their low-frequency modulation at the fMRI range (i.e. MEG–ALFF). We observed that the MEG–ALFF in EC was increased at parietal sensors, ranging from alpha to beta; whereas the MEG–amplitude in EC was increased at the occipital sensors in alpha. Source-level analysis revealed that the increased MEG–ALFF in the sensorimotor cortex overlapped with the most reliable EC–EO differences observed in fMRI at slow-3 (0.073–0.198 Hz), and these differences were more significant after global mean standardization. Taken together, our results support that (i) the amplitude at 2 timescales in MEG reflect distinct physiological information and that (ii) the fMRI–ALFF may relate to the ALFF in neural activity.
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