Biochemical and biophysical research communications最新文献

Antimicrobial peptides (AMPs) are essential components of the innate immune system, demonstrating their antimicrobial effects primarily through the creation of transmembrane pores that result in membrane disruption. Cholesterol within the membrane can significantly affect the interaction between AMPs and the membrane, as it is known to alter both the permeability and elastic properties of the membrane. In this study, we have investigated the influence of cholesterol on the interaction of the AMP, NK-2 with phospholipid vesicles. We prepared giant unilamellar vesicles (GUVs) composed of DOPC-DOPG and Egg PC, varying the cholesterol concentrations, and analyzed them using phase contrast microscopy. The aggregation of vesicles is evident in the phase contrast microscopy observations of GUVs. The aggregation of GUVs with cholesterol ultimately leads to a collapse state, a condition not typically seen in GUVs lacking cholesterol. Furthermore, the aggregation kinetics were determined from the analysis of phase contrast micrographs. This biophysical investigation offers valuable insights into how cholesterol affects the interactions between membranes induced by antimicrobial peptides.

Metabolic-associated fatty liver disease (MAFLD) is an important public health problem, and the gut microbiota has become a new treatment target for MAFLD. Previously, A. indistinctus, a core gut bacterium, was shown to potentially contribute to the prevention of MAFLD. However, the effect and mechanism of A. indistinctus on MAFLD are still unclear and need to be investigated. This study primarily evaluated whether A. indistinctus can improve gut microbiota disorders and prevent the progression from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) in mice fed a high-fat diet (HFD). First, we observed that A. indistinctus significantly improved lipid metabolism disorders and reduced hepatic inflammation induced by HFD consumption in mice. We found that A. indistinctus improved gut barrier function and inhibited the LPS/TLR4/NF-κB pathway, thereby reducing hepatic inflammation. Moreover, 16S rRNA V3-V4 analyses revealed that A. indistinctus could significantly change the structure of the gut microbiota and increase the abundance of L. johnsonii by promoting its growth. Finally, we showed that L. johnsonii administration significantly improved lipid metabolism disorders and reduced hepatic lipid accumulation induced by HFD consumption in mice. In summary, A. indistinctus administration significantly reduces hepatic inflammation by improving gut barrier function and improves lipid metabolism disorders by promoting the growth of L. johnsonii. Our research improves the understanding of the gut microbiota and provides a basis for future therapeutic use of A. indistinctus.

Microproteins synthesized through non-canonical translation pathways are frequently found within mitochondria. However, the functional significance of these mitochondria-localized microproteins in energy-intensive organs such as the heart remains largely unexplored. In this study, we demonstrate that the long non-coding RNA CD63-AS1 encodes a mitochondrial microprotein. Notably, in ribosome profiling data of human hearts, there is a positive correlation between the expression of CD63-AS1 and genes associated with cardiomyopathy. We have termed this microprotein CEAM (CD63-AS1 encoded amyloid-like motif containing microprotein), reflecting its sequence characteristics. Our biochemical assays show that CEAM forms protease-resistant aggregates within mitochondria, whereas deletion of the amyloid-like motif transforms CEAM into a soluble cytosolic protein. Overexpression of CEAM triggers mitochondrial stress responses and adversely affect mitochondrial bioenergetics in cultured cardiomyocytes. In turn, the expression of CEAM is reciprocally inhibited by the activation of mitochondrial stresses induced by oligomycin. When expressed in mouse hearts via adeno-associated virus, CEAM impairs cardiac function. However, under conditions of pressure overload-induced cardiac hypertrophy, CEAM expression appears to offer a protective benefit and mitigates the expression of genes associated with cardiac remodeling, presumably through a mechanism that suppresses stress-induced translation reprogramming. Collectively, our study uncovers a hitherto unexplored amyloid-like microprotein expressed in the human cardiomyocytes, offering novel insights into myocardial hypertrophy pathophysiology.

The dynamic and versatile group of enzymes referred to as glutathione S-transferases (GSTs) play diverse roles in cellular detoxification, safeguarding hosts from oxidative damage, and performing various other functions. This review explores different classes of GST, existence of polymorphisms in GST, functions of GST and utilizations of GST inhibitors in treatment of human diseases. The study indicates that the cytosolic GSTs, mitochondrial GSTs, microsomal GSTs, and bacterial proteins that provide resistance to Fosfomycin are the major classes. Given a GST, variation in its expression and function among individuals is due to the presence of polymorphic alleles that encode it. Genetic polymorphism might result in the modification of GST activity, thereby increasing individuals' vulnerability to harmful chemical compounds. GSTs have been demonstrated to play a regulatory function in cellular signalling pathways through kinases, S-Glutathionylation, and in detoxification processes. Various applications of bacterial GSTs and their potential roles in plants were examined. Targeting GSTs, especially GSTP1-1, is considered a potential therapeutic strategy for treating cancer and diseases linked to abnormal cell proliferation. Their role in cancer cell growth, differentiation, and resistance to anticancer agents makes them promising targets for drug development, offering prospects for the future.

Although natural killer (NK) cell responses to tumor and viral infection have been studied, the mechanisms underlying NK cell homeostasis in vivo remain unclear. In this study, we demonstrate the pharmacological action of cytostatin, a protein phosphatase 2A (PP2A) specific inhibitor (PP2Ai), on NK cells in regulating NK cell homeostasis in the peripheral tissues. We found that PP2Ai treatment decreased NK cell percentages in the bone marrow and secondary lymphoid tissues while increasing NK cell percentages in peripheral tissues such as the lung and liver. In the peripheral tissues of PP2Ai-treated mice, Ki-67 expression and BrdU uptake in NK cells were upregulated, and an initial increase in the pre-mature CD11b^hiCD27^hi NK subset was observed, followed by an increase in the terminally differentiated mature CD11b^hiCD27^lo NK subset. In addition, bone marrow Ki-67⁺ NK cells predominantly expressed CX3CR1 in the PP2Ai-treated mice and were further mobilized to the peripheral tissues. Among various target molecules of PP2A, we found that the upregulation of c-Myc pathway and its phosphorylation, along with its downstream cyclin E expression and G1/S cell cycle transition in PP2Ai-treated mice NK cells. Our results suggest that PP2Ai modulates NK cell proliferation through c-Myc and cyclin E, leading to their maturation and trafficking from the bone marrow to the peripheral tissues.

Reinforcement learning algorithms often struggle to learn in partially observable environments, where different states of the environment may appear identical. However, not all partially observable environments pose the same level of difficulty for learning. This work introduces the concept of dissonance distance, a metric that can estimate the difficulty of learning in such environments. We demonstrate that self-information, such as internal oscillations or memory of previous actions, can increase the dissonance distance and make learning easier in partially observable environments. Additionally, sensory occlusion may occur after learning was completed, leading to a lack of sufficient information and catastrophic failure. To address this, we propose a spatially layered architecture (SLA) inspired by the brain, which trains multiple policies in parallel for the same task. SLA can change the amount of external information processed at each timestep, providing an adaptive approach to handle the changing information in the environment state-space. We evaluate the effectiveness of our SLA method showing learnability and robustness against realistic noise and occlusion in sensory inputs for the partially observable Continuous Mountain Car environment. We hypothesize that multi-policy approaches like SLA might explain the complex dopamine dynamics in the brain that cannot be explained with the state of the art scalar Temporal Difference error.

Chemotherapy-induced neurodegeneration represents a significant challenge in cancer survivorship, manifesting in cognitive impairments that severely affect patients' quality of life. Emerging neuroregenerative therapies offer promise in mitigating these adverse effects, with miRNA-124 playing a pivotal role due to its critical functions in neural differentiation, neurogenesis, and neuroprotection. This review article delves into the innovative approach of using miRNA-124-loaded extracellular vesicles (EVs) encapsulated within hydrogel matrices as a targeted strategy for combating chemotherapy-induced neurodegeneration. We explore the biological underpinnings of miR-124 in neuroregeneration, detailing its mechanisms of action and therapeutic potential. The article further examines the roles and advantages of EVs as natural delivery systems for miRNAs and the application of hydrogel matrices in creating a sustained release environment conducive to neural tissue regeneration. By integrating these advanced materials and biological agents, we highlight a synergistic therapeutic strategy that leverages the bioactive properties of miR-124, the targeting capabilities of EVs, and the supportive framework of hydrogels. Preclinical studies and potential pathways to clinical translation are discussed, alongside the challenges, ethical considerations, and future directions in the field. This comprehensive review underscores the transformative potential of miR-124-loaded EVs in hydrogel matrices, offering insights into their development as a novel and integrative approach for addressing the complexities of chemotherapy-induced neurodegeneration.

Stroke is a major global cause of death and disability, with ischemic stroke being the most common type. The disruption of the blood-brain barrier (BBB) is a key factor in the pathophysiology of ischemic stroke, allowing immune cells to infiltrate and worsening neuroinflammation. This study uses single-cell RNA sequencing (scRNA-seq) to examine the transcriptional changes in neutrophils, endothelial cells, and T cells during ischemic stroke. Our findings indicate a significant increase in neutrophil and lymphocyte infiltration, along with a notable decrease in endothelial cell populations, demonstrating severe BBB disruption. Differential gene expression analysis shows that endothelial cells lose important characteristics post-stroke, while lymphocytes activate cytotoxic pathways that may lead to neuronal damage. Additionally, we reveal the contrasting roles of CXCR2 and CXCR4 in neutrophil movement and identify neutrophil-derived damage-associated molecular patterns (DAMPs) and matrix metalloproteinases (MMPs) as key drivers of endothelial cell apoptosis. Notably, the S100A8/A9 inhibitor paquinimod significantly protects neurons and reduces lymphocyte infiltration, suggesting that targeting S100A8/A9 could be a promising therapeutic strategy for reducing neurological deficits after ischemic stroke. Overall, these results enhance our understanding of the complex interactions between immune cells and the BBB in ischemic stroke, paving the way for innovative therapeutic approaches aimed at maintaining brain integrity and improving patient outcomes.

The tumor microenvironment features dynamic biomechanical interactions between extracellular matrix physics and tumor progression. Tumor growth compresses the supportive matrix, and the stiffness-gradient guides tumor invasion. From the mechanical perspective, the complexity of the matrix topology involving durotaxis-driven metastasis remains lacking in a comprehensive description. In this study, A549 adenocarcinoma spheroids were exposed to a stiffness-and fiber-adjusted collagen matrix to examine the influence of collective motility. Centrifugated compression on the collagen constructs was adopted to mimic the matrix deformation in response to solid tumor development. Centrifugated compression physically stiffened and condensed collagen constructs simultaneously. Cultured with A549 spheroids for 7 days, compressed collagen constructs disadvantaged spheroid expansion without the effect of tumor proliferation potency but promoted matrix metalloproteinase activity corresponding to softened rigidity. Results suggested that the fibrous structure may counterbalance the matrix stiffness-induced motility.

The physiological actions of a gut hormone, glucagon-like peptide-1 (GLP-1), in Alzheimer's disease (AD) brain remain poorly understood, although GLP-1 receptor (GLP-1R) expression in this organ has been shown in several experimental studies. Therefore, we explored whether the GLP-1R signaling promotes the clearance of amyloid β (Aβ) (1-42) which is a core pathological hallmark of AD, focusing on the water channel protein aquaporin 4 (AQP4) localized to astrocyte endfeet perivascular membranes in intact brain. First, we confirmed that Glp1r mRNA is predominantly expressed at perivascular site of astrocytes in normal mouse cerebral cortex through in situ hybridization analysis. Next, we observed that 20-week subcutaneous administration of a GLP-1R agonist (GLP-1RA) liraglutide significantly reduced Aβ (1-42) accumulation in the cerebral cortex and improved spatial working memory in an AD mouse model, App^{NL-G-F/NL-G-F} mice. Furthermore, our current data revealed that the 4-week liraglutide treatment relocalized subcellular AQP4 in morphologically injured reactive astrocytes of App^{NL-G-F/NL-G-F} mice to the cell surface perivascular site through PKA-mediated AQP4 phosphorylation. Such translocation of phosphorylated AQP4 to astrocyte cell surface following incubation with liraglutide was observed also in the present in vitro study using the cell line in which AQP4 cDNA was introduced into immortalized human astrocyte. These results suggest that enhanced intracerebral GLP-1R signaling following peripheral administration of GLP-1RA restores AQP4 subcellular polarization in reactive astrocytes and would promote Aβ excretion possibly through increasing AQP4-mediated intracerebral water flux in the brain in AD.