Cathepsins and SARS-CoV-2 infection: From pathogenic factors to potential therapeutic targets.

Coronavirus disease-19 (COVID-19) is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. The COVID-19 pandemic began in March 2020 and has wrought havoc on health and economic systems worldwide. Efficacious treatment for COVID-19 is lacking: Only preventive measures as well as symptomatic and supportive care are available. Preclinical and clinical studies have indicated that lysosomal cathepsins might contribute to the pathogenesis and disease outcome of COVID-19. Here, we discuss cutting-edge evidence on the pathological roles of cathepsins in SARS-CoV-2 infection, host immune dysregulations, and the possible underlying mechanisms. Cathepsins are attractive drug targets because of their defined substrate-binding pockets, which can be exploited as binding sites for pharmaceutical enzyme inhibitors. Accordingly, the potential modulatory strategies of cathepsin activity are discussed. These insights could shed light on the development of cathepsin-based interventions for COVID-19.

Zinc finger protein 335 mediates lipopolysaccharide-induced neurodegeneration and memory loss as a transcriptional factor in microglia.

Zinc finger protein 335 (Zfp335) is a transcription factor that regulates mammalian neurogenesis and neuronal differentiation. It is a causative factor for severe microcephaly, small somatic size, and neonatal death. Here, we evaluated the effects of Zfp335 in the adult mouse brain after lipopolysaccharide (LPS) challenge. We used wild-type (WT) and Zfp335 knock-down (Zfp335+/- ) mice with LPS administered in the intracerebral ventricle in vivo and cultured microglia treated with LPS in vitro. The impact of Zfp335 was evaluated by RT-PCR, RNA-sequencing, western blotting, immunocytochemistry, ELISA, and the memory behavior tests. Knockdown of Zfp335 expression ameliorated microglia activation significantly, including reduced mRNA and protein expression of Iba1, reduced numbers of microglia, reduced cell diameter, and increased branch length, in the brains of 2-month-old mice after LPS treatment. Zfp335 was expressed in microglia and neurons, but increased in microglia, not neurons, in the brain of mice after LPS administration. LPS-induced microglia-mediated neurodegeneration was dependent upon microglial Zfp335 controlled by nuclear factor-kappa B. Microglial Zfp335 affected neuronal activity through transcriptional regulation of lymphocyte antigen-6M (Ly6M). Our data suggest that Zfp335 is a key transcription factor that exacerbates microglia-mediated neurodegeneration through upregulation of Ly6M expression. Inhibition of microglial Zfp335 may be a new strategy for preventing brain disease induced by microglia activation.

Cathepsin H: Molecular characteristics and clues to function and mechanism.

Cathepsin H (CatH) is a lysosomal cysteine protease with a unique aminopeptidase activity that is extensively expressed in the lung, pancreas, thymus, kidney, liver, skin, and brain. Owing to its specific enzymatic activity, CatH has critical effects on the regulation of biological behaviours of cancer cells and pathological processes in brain diseases. Moreover, a neutral pH level is optimal for CatH activity, so it is expected to be active in the extra-lysosomal and extracellular space. In the present review, we describe the expression, maturation, and enzymatic properties of CatH, and summarize the available experimental evidence that mechanistically links CatH to various physiological and pathological processes. Finally, we discuss the challenges and potentials of CatH inhibitors in CatH-induced disease therapy.

Cathepsin B in programmed cell death machinery: mechanisms of execution and regulatory pathways.

Cathepsin B (CatB), a cysteine protease, is primarily localized within subcellular endosomal and lysosomal compartments. It is involved in the turnover of intracellular and extracellular proteins. Interest is growing in CatB due to its diverse roles in physiological and pathological processes. In functional defective tissues, programmed cell death (PCD) is one of the regulable fundamental mechanisms mediated by CatB, including apoptosis, pyroptosis, ferroptosis, necroptosis, and autophagic cell death. However, CatB-mediated PCD is responsible for disease progression under pathological conditions. In this review, we provide an overview of the critical roles and regulatory pathways of CatB in different types of PCD, and discuss the possibility of CatB as an attractive target in multiple diseases. We also summarize current gaps in the understanding of the involvement of CatB in PCD to highlight future avenues for research.

Hierarchical deconvolution dehazing method based on transmission map segmentation.

Images captured in fog are often affected by scattering. Due to the absorption and scattering of light by aerosols and water droplets, the image quality will be seriously degraded. The specific manifests are brightness decrease, contrast decrease, image blur, and noise increase. In the single-image dehazing method, the image degradation model is essential. In this paper, an effective image degradation model is proposed, in which the hierarchical deconvolution strategy based on transmission map segmentation can effectively improve the accuracy of image restoration. Specifically, the transmission map is obtained by using the dark channel prior (DCP) method, then the transmission histogram is fitted. The next step is to divide the image region according to the fitting results. Furthermore, to more accurately recover images of complex objects with a large depth of field, different levels of inverse convolution are adopted for different regions. Finally, the sub-images of different regions are fused to get the dehazing image. We tested the proposed method using synthetic fog images and natural fog images respectively. The proposed method is compared with eight advanced image dehazing methods on quantitative rating indexes such as peak signal-to-noise ratio (PSNR), structural similarity (SSIM), image entropy, natural image quality evaluator (NIQE), and blind/referenceless image spatial quality evaluator (BRISQUE). Both subjective and objective evaluations show that the proposed method achieves competitive results.

Regioselective Difluoromethane sulfonylation and Triflylation of Resorufin Derivatives.

Reported herein is a regioselective difluoromethane sulfonylation or triflylation of resorufin derivatives, which allows easy access to 2-difluoromethane sulfonylated or triflylated resorufin derivatives in good yields. The installation of a difluoromethane sulfonyl group significantly increases the solubility of the chromophore and expands its Stokes shift. A difluoromethane sulfonylated resorufin-based fluorogenic probe proved to be able to image enzyme activity in live cells with a stronger fluorescence signal compared with its resorufin counterpart.

From structure to concepts: The two stages of facial expression recognition.

Facial expressions are the dominant way of human emotional and social communications. However, it remains unclear that how can perceivers extract emotion from the face. In the present study, we adopted a repetition-priming paradigm in combine with event-related potentials (ERP) to examine neurocognitive processing stages of facial expression perception. Results showed that emotional words were recognized faster than emotional faces, when both of which were primed by emotional faces, indicating the involvement of concepts processes in facial expression recognition. ERP results showed that all emotional faces could evoke responses of N170, while there was no significant difference between positive and negative emotional faces, suggesting that geometrical configurations of faces rather than emotional concepts of faces are processed at the stage of N170. In contrast, both emotional words and faces showed larger P2 in response to anger than happiness, which suggests that emotional concepts are extracted from faces at the stage of P2. To examine the underlying dynamic causal connectivity between facial structure and emotional conception, we conducted information flow analysis, which showed significant decreases of information flow from the fusiform gyrus to dorsal anterior cingulate cortex/dorsal medial prefrontal cortex and increases of information flow from the fusiform gyrus to posterior insula. These results revealed neural mechanisms underlying processes from physical structure to emotional concepts. Our findings suggest that facial expression recognition consists of two stages from geometrical structure of faces to emotional concepts of facial expressions, which provides evidence for facial expression processing and has important implications in the diagnosis and treatment of emotion recognition related disorders.

Late-stage difluoromethylation leading to a self-immobilizing fluorogenic probe for the visualization of enzyme activities in live cells.

Reported herein is a novel p-quinone methide-based self-immobilizing fluorogenic probe for the visualization of ß-galactosidase activities in live cells. This easily prepared imaging reagent massively increases the fluorescence intensity and covalently links to the activation site with high efficiency upon enzymatic trigger.