Cells最新文献

Epilepsy is a chronic neurological disorder marked by recurrent seizures, significantly impacting individuals worldwide. Current treatments are often ineffective for a third of patients and can cause severe side effects, necessitating new therapeutic approaches. Glial cells, particularly astrocytes, microglia, and oligodendrocytes, are emerging as crucial targets in epilepsy management. Astrocytes regulate neuronal homeostasis, excitability, and synaptic plasticity, playing key roles in maintaining the blood-brain barrier (BBB) and mediating neuroinflammatory responses. Dysregulated astrocyte functions, such as reactive astrogliosis, can lead to abnormal neuronal activity and seizure generation. They release gliotransmitters, cytokines, and chemokines that may exacerbate or mitigate seizures. Microglia, the innate immune cells of the CNS, contribute to neuroinflammation, glutamate excitotoxicity, and the balance between excitatory and inhibitory neurotransmission, underscoring their dual role in seizure promotion and protection. Meanwhile, oligodendrocytes, primarily involved in myelination, also modulate axonal excitability and contribute to the neuron-glia network underlying seizure pathogenesis. Understanding the dynamic interactions of glial cells with neurons provides promising avenues for novel epilepsy therapies. Targeting these cells may lead to improved seizure control and better clinical outcomes, offering hope for patients with refractory epilepsy.

Arsenic (As) is a risk factor for non-melanoma skin cancer (NMSC). From a six-year follow-up study on 7000 adults exposed to As, we reported the associations of single-nucleotide variation in tumor tissue and gene expression. Here, we identify the associations of small deletions (DELs) and transcriptomic profiles in NMSC. Comparing the (a) NMSC tissue (n = 32) and corresponding blood samples from each patient, and (b) an independent set of non-lesional, healthy skin (n = 16) and paired blood, we identified NMSC-associated DELs. Differential expressions of certain gene pathways (TGF-β signaling pathway, IL-17 pathway, PD-L1 pathway, etc.) showed significant interactions with these somatic DELs and As exposure. In low-As-exposure cases, the DELs in APC were associated with the up-regulation of inflamed T-Cell-associated genes by a fold change (FC) of 8.9 (95% CI 4.5-17.6), compared to 5.7 (95% CI 2.9-10.8) without APC DELs; in high-As-exposure cases, the APC DELs were associated with an FC of 5.8 (95% CI 3.5-9.8) compared to 1.2 (95% CI -1.3 to 1.8) without APC DELs. We report, for the first time, the significant associations of somatic DELs (many in STR regions) in NMSC tissue and As exposure with many dysregulated gene pathways. These findings may help in selecting groups of patients for potential targeted therapy like PD-L1 inhibitors, IL-17 inhibitors, and TGF-β inhibitors in the future.

Amyloid-β peptide (Aβ) is a critical cause of Alzheimer's disease (AD). It is generated from amyloid precursor protein (APP) through cleavages by β-secretase and γ-secretase. γ-Secretase, which includes presenilin, is regulated by several stimuli. Tau protein has also been identified as a significant factor in AD. In particular, Tau phosphorylation is crucial for neuronal impairment, as phosphorylated Tau detaches from microtubules, leading to the formation of neurofibrillary tangles and the destabilization of the microtubule structure. This instability in microtubules damages axons and dendrites, resulting in neuronal impairment. Notably, Aβ is linked to Tau phosphorylation. Another crucial factor in AD is neuroinflammation, primarily occurring in the microglia. Microglia possess several receptors that bind with Aβ, triggering the expression and release of an inflammatory factor, although their main physiological function is to phagocytose debris and pathogens in the brain. NF-κB activation plays a major role in neuroinflammation. Additionally, the production of reactive oxygen species (ROS) in the microglia contributes to this neuroinflammation. In microglia, superoxide is produced through NADPH oxidase, specifically NOX2. Rho GTPases play an essential role in regulating various cellular processes, including cytoskeletal rearrangement, morphology changes, migration, and transcription. The typical function of Rho GTPases involves regulating actin filament formation. Neurons, with their complex processes and synapse connections, rely on cytoskeletal dynamics for structural support. Other brain cells, such as astrocytes, microglia, and oligodendrocytes, also depend on specific cytoskeletal structures to maintain their unique cellular architectures. Thus, the aberrant regulation of Rho GTPases activity can disrupt actin filaments, leading to altered cell morphology, including changes in neuronal processes and synapses, and potentially contributing to brain diseases such as AD.

Traumatic brain injury (TBI) is one of the major causes of severe neurological disorders and long-term dysfunction in the nervous system. Besides inducing neurodegeneration, TBI alters stem cell activity and neurogenesis within primary neurogenic niches. However, the fate of dividing cells in other brain regions remains unclear despite offering potential targets for therapeutic intervention. Here, we investigated cell division and differentiation in non-neurogenic brain regions during the acute and delayed phases of TBI-induced neurodegeneration. We subjected mice to lateral fluid percussion injury (LFPI) to model TBI and analyzed them 1 or 7 weeks later. To assess cellular proliferation and differentiation, we administered 5-ethinyl-2'-deoxyuridine (EdU) and determined the number and identity of dividing cells 2 h later using markers of neuronal precursors and astro-, micro-, and oligodendroglia. Our results demonstrated a significant proliferative response in several brain regions at one week post-injury that notably diminished by seven weeks, except in the optic tract. In addition to active astro- and microgliosis, we detected oligodendrogenesis in the striatum and optic tract. Furthermore, we observed trauma-induced neurogenesis in the striatum. These findings suggest that subcortical structures, particularly the striatum and optic tract, may possess a potential for self-repair through neuronal regeneration and axon remyelination.

Oral squamous cell carcinoma (OSCC) is a highly aggressive malignancy with poor prognosis, mainly due to the presence of cancer stem cells (CSCs), a small subpopulation of cells that contribute to therapy resistance and tumor progression. The principal objective of this study was to investigate the role of miRNA-21 in the maintenance of cancer cell stemness and the possibility of altering it. The CD44 antigen was used as a marker for CSC isolation from oral cancer cell cultures. CD44+ and CD44- populations were sorted via magnetic separation. miRNA-21 inhibition was performed in CD44+ cells via transfection. CD44+ cells possessed a significantly higher migration and invasion potential compared to CD44- cells, higher levels of miRNA-21 (p = 0.004) and β-catenin (p = 0.005), and lower levels of BAX (p = 0.015). miRNA-21 inhibition in CD44+ cells reduced migration, invasion, and colony formation while increasing apoptosis. Stemness markers were significantly downregulated following miRNA-21 inhibition: OCT4 (p = 0.013), SOX2 (p = 0.008), and NANOG (p = 0.0001), as well as β-catenin gene (CTNNB1) (p < 0.05), an important member of WNT signaling pathway. Apoptotic activity was enhanced, with a significant downregulation of the antiapoptotic Bcl-2 (p = 0.008) gene. In conclusion, miRNA-21 plays a critical role in the regulation of oral cancer CD44+ cells properties. Targeting and inhibiting miRNA-21 in CD44+ cells could represent a promising novel strategy in OSCC treatment.

We demonstrate that natural killer (NK) cells induce a higher cytotoxicity against lung cancer stem-like cells (hA549) compared to differentiated lung cancer cell lines (H292). The supernatants from split-anergized NK cells (IL-2 and anti-CD16 mAb-treated NK cells) induced differentiation in hA549. Differentiated lung cancer cell line (H292) and NK cells differentiated hA549 expressed reduced NK cell-mediated cytotoxicity but expressed higher sensitivity to chemotherapeutic drugs. This finding validated our previous reports demonstrating that the levels of tumor killing by NK cells and by chemotherapeutic drugs correlate directly and indirectly, respectively, with the stage and levels of tumor differentiation. We also demonstrate the role of IFN-γ and TNF-α in inducing tumor differentiation. NK cells' supernatants or IFN-γ and TNF-α-induced tumor differentiation was blocked when we used antibodies against IFN-γ and TNF-α. Therefore, IFN-γ and TNF-α released from NK cells play a significant role in differentiating tumors, resulting in increased susceptibility of tumors to chemotherapeutic drugs. We also observed the different effects of MHC-class I antibodies in CSCs vs. differentiated tumors. Treatment with anti-MHC-class I decreased NK cell-mediated cytotoxicity in hA549 tumors, whereas it increased NK cell-mediated cytotoxicity when differentiated tumors were treated with antibodies against MHC-class I.

Macrophages play important roles in metabolic dysfunction-associated steatohepatitis (MASH), an advanced and inflammatory stage of metabolic dysfunction-associated steatotic liver disease (MASLD). In humans and mice, the cellular heterogeneity and diverse function of hepatic macrophages in MASH have been investigated by single cell RNA sequencing (scRNA-seq). However, little is known about their roles in rats. Here, we collected liver tissues at the postnatal week 16, when our previously characterized Lep^{∆I14/∆I14} rats developed MASH phenotypes. By scRNA-seq, we found an increase in the number of macrophages and endothelial cells and a decrease in that of NK and B cells. Hepatic macrophages in rats underwent a unique M1 to M2 transition without expression of the classical markers such as Arg1 and Nos2, except for Cd163. Lipid-associated macrophages (LAMs) were increased, which could be detected by the antibody against Cd63. In the microenvironment, macrophages had an increased number of interactions with hepatocytes, myofibroblasts, T cells, neutrophils, and dendritic cells, while their interaction strengths remained unchanged. Finally, the macrophage migration inhibitory factor (MIF) pathway was identified as the top upregulated cell-communication pathway in MASH. In conclusion, we dissected hepatic macrophage dynamics during MASH at single cell resolution and provided fundamental tools for the investigation of MASH in rat models.

Pregnancy failure in the first trimester of cows significantly impacts the efficiency of the dairy industry. As a type I interferon exclusively to ruminants, IFN-τ plays a key role in maternal recognition and immune tolerance of fetuses. Macrophages are the most common immune cells within the ruminant endometrium. Nevertheless, deeply analyzing the mechanisms of IFN-τ regulating macrophage polarization still needs further study. In this study, a notable decline of bta-miR-30b-5p expression via the increase of SOCS1 was observed in uterine tissues of pregnant cows. We then confirmed that the 3'UTR of SOCS1 was to be directly targeted by bta-miR-30b-5p. After that, we demonstrated that this obviously promoted the bovine macrophages (BoMac) polarized to M2 through enhancing SOCS1 expression with the treatment of IFN-τ. Furthermore, we found that SOCS1 restrained the expression of the key proteins p65 and p-P65 in the NF-κB pathway. Causing, the wide range of cross-species activities of IFN-τ, therefore we established a pregnant mouse model for the future confirmation of the above mechanism. The results verified that IFN-τ significantly improved this mechanism and maintained normal pregnancy status in mice, but miR-30b-5p significantly reduced the M2 polarization by inhibiting SOCS1, which activated the NF-κB signaling pathway, and then leading to the failure of embryo implantation. All these results indicated that IFN-τ can regulate immune tolerance during pregnancy by promoting M2 macrophage polarization through inhibiting bta-miR-30b-5p targeting SOCS1 to deactivate the NF-κB signaling pathway.

Background: The wide variability in clinical responses to anti-tumor immunotherapy drives the search for personalized strategies. One of the promising approaches is drug screening using patient-derived models composed of tumor and immune cells. In this regard, the selection of an appropriate in vitro model and the choice of cellular response assay are critical for reliable predictions. Fluorescence lifetime imaging microscopy (FLIM) is a powerful, non-destructive tool that enables direct monitoring of cellular metabolism on a label-free basis with a potential to resolve metabolic rearrangements in immune cells associated with their reactivity.

Objective: The aim of the study was to develop a patient-derived glioma explant model enriched by autologous peripheral lymphocytes and explore FLIM of the redox-cofactor NAD(P)H in living lymphocytes to measure the responses of the model to immune checkpoint inhibitors.

Methods: The light microscopy, FLIM of NAD(P)H and flow cytometry were used.

Results: The results demonstrate that the responsive models displayed a significant increase in the free NAD(P)H fraction α₁ after treatment, associated with a shift towards glycolysis due to lymphocyte activation. The non-responsive models exhibited no alterations or a decrease in the NAD(P)H α₁ after treatment. The FLIM data correlated well with the standard assays of immunotherapy drug response in vitro, including morphological changes, the T-cells activation marker CD69, and the tumor cell proliferation index Ki67.

Conclusions: The proposed platform that includes tumor explants co-cultured with lymphocytes and the NAD(P)H FLIM assay represents a promising solution for the patient-specific immunotherapeutic drug screening.

Alpha-1 antitrypsin (AAT) is a key serine protease inhibitor for regulating proteases such as neutrophil elastase. AAT restrains the pulmonary matrix from enzymatic degradation, and a deficiency in AAT leads to inflammatory tissue damage in the lungs, resulting in chronic obstructive pulmonary disease. Due to the crucial biological function of AAT, the emerging research interest in this protein has shifted to its role in cancer-associated inflammation and the dynamics of the tumor microenvironment. However, the lack of comprehensive reviews in this field hinders our understanding of AAT as an essential immune modulator with great potential in cancer immunotherapy. Therefore, in this review, we have elucidated the pivotal roles of AAT in inflammation and the tumor microenvironment, including the structure and molecular properties of AAT, its molecular functions in the regulation of the inflammatory response and tumor microenvironment, and its clinical implications in cancer including its diagnosis, prognosis, and therapeutic intervention. This review seeks to bridge the gap in the understanding of AAT between inflammatory diseases and cancer, and to foster deeper investigations into its translational potential in cancer immunotherapy in the future.