In the adult hippocampus, synapses are constantly formed and eliminated
. However, the exact function of synapse elimination in the adult brain, and how it is regulated, are largely unknown. Here we ...show that astrocytic phagocytosis
is important for maintaining proper hippocampal synaptic connectivity and plasticity. By using fluorescent phagocytosis reporters, we find that excitatory and inhibitory synapses are eliminated by glial phagocytosis in the CA1 region of the adult mouse hippocampus. Unexpectedly, we found that astrocytes have a major role in the neuronal activity-dependent elimination of excitatory synapses. Furthermore, mice in which astrocytes lack the phagocytic receptor MEGF10 show a reduction in the elimination of excitatory synapses; as a result, excessive but functionally impaired synapses accumulate. Finally, Megf10-knockout mice show defective long-term synaptic plasticity and impaired formation of hippocampal memories. Together, our data provide strong evidence that astrocytes eliminate unnecessary excitatory synaptic connections in the adult hippocampus through MEGF10, and that this astrocytic function is crucial for maintaining circuit connectivity and thereby supporting cognitive function.
The previous outbreaks of SARS-CoV and MERS-CoV have led researchers to study the role of diagnostics in impediment of further spread and transmission. With the recent emergence of the novel ...SARS-CoV-2, the availability of rapid, sensitive, and reliable diagnostic methods is essential for disease control. Hence, we have developed a reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay for the specific detection of SARS-CoV-2. The primer sets for RT-LAMP assay were designed to target the nucleocapsid gene of the viral RNA, and displayed a detection limit of 10
2
RNA copies close to that of qRT-PCR
.
Notably, the assay has exhibited a rapid detection span of 30 min combined with the colorimetric visualization. This test can detect specifically viral RNAs of the SARS-CoV-2 with no cross-reactivity to related coronaviruses, such as HCoV-229E, HCoV-NL63, HCoV-OC43, and MERS-CoV as well as human infectious influenza viruses (type B, H1N1pdm, H3N2, H5N1, H5N6, H5N8, and H7N9), and other respiratory disease-causing viruses (RSVA, RSVB, ADV, PIV, MPV, and HRV). Furthermore, the developed RT-LAMP assay has been evaluated using specimens collected from COVID-19 patients that exhibited high agreement to the qRT-PCR. Our RT-LAMP assay is simple to perform, less expensive, time-efficient, and can be used in clinical laboratories for preliminary detection of SARS-CoV-2 in suspected patients. In addition to the high sensitivity and specificity, this isothermal amplification conjugated with a single-tube colorimetric detection method may contribute to the public health responses and disease control, especially in the areas with limited laboratory capacities.
Radiotherapy (RT) is a highly effective multimodal nonsurgical treatment that is essential for patients with advanced colorectal cancer (CRC). Nevertheless, cell subpopulations displaying intrinsic ...radioresistance survive after RT. The reactivation of their proliferation and successful colonization at local or distant sites may increase the risk of poor clinical outcomes. Recently, radioresistant cancer cells surviving RT were reported to exhibit a more aggressive phenotype than parental cells, although the underlying mechanisms remain unclear.
By investigating public databases containing CRC patient data, we explored potential radioresistance-associated signaling pathways. Then, their mechanistic roles in radioresistance were investigated through multiple validation steps using patient-derived primary CRC cells, human CRC cell lines, and CRC xenografts.
Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling was activated in radioresistant CRC tissues in correlation with local and distant metastases. JAK2 was preferentially overexpressed in the CRC stem cell subpopulation, which was accompanied by the phosphorylation of STAT proteins, especially STAT3. JAK2/STAT3 signaling played an essential role in promoting tumor initiation and radioresistance by limiting apoptosis and enhancing clonogenic potential. Mechanistically, the direct binding of STAT3 to the cyclin D2 (CCND2) promoter increased CCND2 transcription. CCND2 expression was required for persistent cancer stem cell (CSC) growth via the maintenance of an intact cell cycle and proliferation with low levels of DNA damage accumulation.
Herein, we first identified JAK2/STAT3/CCND2 signaling as a resistance mechanism for the persistent growth of CSCs after RT, suggesting potential biomarkers and regimens for improving outcomes among CRC patients.
Chemotherapy, one of the principal approaches for cancer patients, plays a crucial role in controlling tumor progression. Clinically, tumors reveal a satisfactory response following the first ...exposure to the chemotherapeutic drugs in treatment. However, most tumors sooner or later become resistant to even chemically unrelated anticancer agents after repeated treatment. The reduced drug accumulation in tumor cells is considered one of the significant mechanisms by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell membrane. The mechanisms of treatment failure of chemotherapeutic drugs have been investigated, including drug efflux, which is mediated by extracellular vesicles (EVs). Exosomes, a subset of EVs with a size range of 40–150 nm and a lipid bilayer membrane, can be released by all cell types. They mediate specific cell‐to‐cell interactions and activate signaling pathways in cells they either fuse with or interact with, including cancer cells. Exosomal RNAs are heterogeneous in size but enriched in small RNAs, such as miRNAs. In the primary tumor microenvironment, cancer‐secreted exosomes and miRNAs can be internalized by other cell types. MiRNAs loaded in these exosomes might be transferred to recipient niche cells to exert genome‐wide regulation of gene expression. How exosomal miRNAs contribute to the development of drug resistance in the context of the tumor microenvironment has not been fully described. In this review, we will highlight recent studies regarding EV‐mediated microRNA delivery in formatting drug resistance. We also suggest the use of EVs as an advancing method in antiresistance treatment.
The dermis is primarily composed of the extracellular matrix (ECM) and fibroblasts. During the aging process, the dermis undergoes significant changes. Collagen, which is a major component of ECM, ...becomes fragmented and coarsely distributed, and its total amount decreases. This is mainly due to increased activity of matrix metalloproteinases, and impaired transforming growth factor-β signaling induced by reactive oxygen species generated during aging. The reduction in the amount of collagen hinders the mechanical interaction between fibroblasts and the ECM, and consequently leads to the deterioration of fibroblast function and further decrease in the amount of dermal collagen. Other ECM components, including elastic fibers, glycosaminglycans (GAGs), and proteoglycans (PGs), also change during aging, ultimately leading to a reduction in the amount of functional components. Elastic fibers decrease in intrinsically aged skin, but accumulate abnormally in photoaged skin. The changes in the levels of GAGs and PGs are highly diverse, and previous studies have reported conflicting results. A reduction in the levels of functional dermal components results in the emergence of clinical aging features, such as wrinkles and reduced elasticity. Various antiaging approaches, including topicals, energy-based procedures, and dermal fillers, can restore the molecular features of dermal aging with clinical efficacy. This review summarizes the current understanding of skin aging at the molecular level, and associated treatments, to put some of the new antiaging technology that has emerged in this rapidly expanding field into molecular context.
In this study, we engineered liposomal indocyanine green (ICG) to maximize its photothermal effects while maintaining the fluorescence intensity. Various liposomal formulations of ICG were prepared ...by varying the lipid composition and the molar ratio between total lipid and ICG, and their photothermal characteristics were evaluated under near-infrared irradiation. We showed that the ICG dispersity in the liposomal membrane and its physical interaction with phospholipids were the main factors determining the photothermal conversion efficiency. In phototherapeutic studies, the optimized formulation of liposomal ICG showed greater anticancer effects in a mouse tumor model compared with other liposomal formulations and the free form of ICG. Furthermore, we utilized liposomal ICG to visualize the metastatic lymph node around the primary tumor under fluorescence imaging guidance and ablate the lymph node with the enhanced photothermal effect, indicating the potential for selective treatment of metastatic lymph node.
It has been established that nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) members promote survival by upregulating antiapoptotic genes and that genetic and pharmacological ...inhibition of NF‐κB is required for tumor necrosis factor (TNF)‐induced hepatocyte apoptosis. In this study, we demonstrate that this pro‐survival pathway is switched to pro‐apoptosis under pyruvate dehydrogenase kinase 4 (PDK4)‐deficient conditions. PDK4‐deficiency triggered hepatic apoptosis concomitantly with increased numbers of aberrant mitochondria, reactive oxygen species (ROS) production, sustained c‐Jun N‐terminal Kinase (JNK) activation, and reduction of glutathione (GSH). Interestingly, PDK4 retained p65 in cytoplasm via a direct protein‐protein interaction. Disruption of PDK4‐p65 association promoted p65 nuclear translocation. This, in turn, facilitated p65 binding to the TNF promoter to activate TNF‐TNFR1 apoptotic pathway. Pdk4−/− livers were sensitized to Jo2 and D‐(+)‐Galactosamine /Lipopolysaccharide (GalN/LPS)‐mediated apoptotic injury which was prevented by the inhibition of p65 or TNFR1. The pro‐survival activity of TNF was shifted, which was switched to a pro‐apoptotic activity in Pdk4−/− hepatocytes as a result of impaired activation of pro‐survival NF‐κB targets. Conclusion: PDK4 is indispensable to dictate the fate of TNF/NF‐κB‐mediated hepatocyte apoptosis. (Hepatology 2018).
To evaluate the association between thyroid echogenicity and heterogeneity seen on ultrasonography (US) and thyroid function in pediatric and adolescent populations with autoimmune diffuse thyroid ...diseases (AITD). From 2000 to 2020, we reviewed thyroid ultrasound (US) images and thyroid function statuses in 133 children and adolescent AITD patients. Our review of the images focused on decreased echogenicity and heterogeneity, which were classified into four grades. Among patients with overt hypothyroidism or overt hyperthyroidism, 94.2% (65/69) showed a US grade of 3 or 4. In patients with subclinical hyper/hypothyroidism or euthyroidism, 45.3% (29/64) showed grades 1 or 2. There were no overt hyper/hypothyroidism patients with US grade 1. When we compared US grades according to thyroid status, more severe thyroid dysfunction was significantly associated with higher US grade (p = 0.047). Thyroid stimulating hormone (TSH) level differed significantly according to US grades when we evaluated hyperthyroid (p = 0.035) and hypothyroid (p = 0.027) states independently. 11 patients showed both US grade and thyroid function status changes on follow-up US. In children and adolescent AITD patients, there was an association between decreased echogenicity and heterogeneity on US and thyroid dysfunction.
The current study was designed to assess the inhibitory activity of Broussonetia papyrifera-derived polyphenols against 3-chymotrypsin-like and papain-like coronavirus cysteine proteases. The ...isolated compounds were broussochalcone B (1), broussochalcone A (2), 4-hydroxyisolonchocarpin (3), papyriflavonol A (4), 3′-(3-methylbut-2-enyl)-3′,4,7-trihydroxyflavane (5), kazinol A (6), kazinol B (7), broussoflavan A (8), kazinol F (9), and kazinol J (10). All polyphenols were more potent against papain-like protease (PL
pro
) than against 3-chymotripsin-like protease (3CL
pro
); therefore, we investigated their structural features that were responsible for this selectivity. Compound 4 was the most potent inhibitor of PL
pro
with an IC
50
value of 3.7 μM. The active compounds displayed kinetic behaviors, and the binding constants of their interaction with PL
pro
were determined from surface plasmon resonance analysis. Our results suggest B. papyrifera constituents as promising candidates for development into potential anti-coronaviral agents.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Fucoxanthin is a xanthophyll carotenoid abundant in macroalgae, such as brown seaweeds. When fucoxanthin is consumed, it can be esterified or hydrolyzed to fucoxanthinol in the gastrointestinal tract ...and further converted into amarouciaxanthin A in the liver. It has a unique chemical structure that confers its biological effects. Fucoxanthin has a strong antioxidant capacity by scavenging singlet molecular oxygen and free radicals. Also, it exerts an anti-inflammatory effect. Studies have demonstrated potential health benefits of fucoxanthin for the prevention of chronic diseases, such as cancer, obesity, diabetes mellitus, and liver disease. Animal studies have shown that fucoxanthin supplementation has no adverse effects. However, investigation of the safety of fucoxanthin consumption in humans is lacking. Clinical trials are required to assess the safety of fucoxanthin in conjunction with the study of mechanisms by which fucoxanthin exhibits its health benefits. This review focuses on current knowledge of metabolism and functions of fucoxanthin with its potential health benefits.
This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.
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