T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3), a potential immunotherapeutic target for cancer, has been shown to display diverse characteristics in a context-dependent manner. ...Thus, it would be useful to delineate the precise functional features of TIM-3 in a given situation. Here, we report that glial TIM-3 shows distinctive properties in the brain tumor microenvironment. TIM-3 was expressed on both growing tumor cells and their surrounding cells including glia and T cells in an orthotopic mouse glioma model. The expression pattern of TIM-3 was distinct from those of other immune checkpoint molecules in tumor-exposed and tumor-infiltrating glia. Comparison of cells from tumor-bearing and contralateral hemispheres of a glioma model showed that TIM-3 expression was lower in tumor-infiltrating CD11b
CD45
glial cells but higher in tumor-infiltrating CD8
T cells. In TIM-3 mutant mice with intracellular signaling defects and Cre-inducible TIM-3 mice, TIM-3 affected the expression of several immune-associated molecules including iNOS and PD-L1 in primary glia-exposed conditioned media (CM) from brain tumors. Further, TIM-3 was cross-regulated by TLR2, but not by TLR4, in brain tumor CM- or Pam
CSK
-exposed glia. In addition, following exposure to tumor CM, IFNγ production was lower in T cells cocultured with TIM-3-defective glia than with normal glia. Collectively, these findings suggest that glial TIM-3 actively and distinctively responds to brain tumor, and plays specific intracellular and intercellular immunoregulatory roles that might be different from TIM-3 on T cells in the brain tumor microenvironment. SIGNIFICANCE: TIM-3 is typically thought of as a T-cell checkpoint receptor. This study demonstrates a role for TIM-3 in mediating myeloid cell responses in glioblastoma.
We investigated the role of cytokines in trimethyltin (TMT)-induced convulsive neurotoxicity. Evaluation of TNF-α, interferon-γ, and interleukin (IL)-6 knockout (−/−) mice showed that the IL-6−/− ...mice had the greatest susceptibility to TMT-induced seizures. In both wild-type and IL-6−/− mice, TMT treatment increased glutathione oxidation, lipid peroxidation, protein oxidation, and levels of reactive oxygen species in the hippocampus. These effects were more pronounced in the IL-6−/− mice than in wild-type controls. In addition, the ability of TMT to induce nuclear translocation of Nrf2 and upregulation of heme oxygenase-1 and γ-glutamylcysteine ligase was significantly decreased in IL-6−/− mice. Treatment of IL-6−/− mice with recombinant IL-6 protein (rIL-6) restored these effects of TMT. Treatment with rIL-6 also significantly attenuated the TMT-induced inhibition of phosphoinositol 3-kinase (PI3K)/Akt signaling, thereby increasing phosphorylation of Bad (Bcl-xL/Bcl-2-associated death promoter protein), expression of Bcl-xL and Bcl-2, and the interaction between p-Bad and 14-3-3 protein and decreasing Bax expression and caspase-3 cleavage. Furthermore, in IL-6−/− mice, rIL-6 provided significant protection against TMT-induced neuronal degeneration; this effect of rIL-6 was counteracted by the PI3K inhibitor LY294002. These results suggest that activation of Nrf2-dependent glutathione homeostasis and PI3K/Akt signaling is required for the neuroprotective effects of IL-6 against TMT.
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► We observed that IL-6 is an endogenous neuroprotectant in response to trimethyltin (TMT) toxicity. ► IL-6 KO mice are more susceptible to TMT seizures than either TNF-α or IFN-γ KO mice. ► Recombinant IL-6 attenuates oxidative burden and neurodegeneration in TMT-treated IL-6 KO mice. ► We suggest that IL-6 activates Nrf2/PI3K-dependent signaling for neuroprotection.
Abstract Lipopolysaccharide (LPS)-induced microglial activation causes degeneration of nigral dopaminergic (DA) neurons. Here, we examined whether fluoxetine prevents LPS-induced degeneration of DA ...in the rat substantia nigra (SN) in vivo . Seven days after LPS injection into the SN, immunostaining for tyrosine hydroxylase (TH) revealed a significant loss of nigral DA neurons. Parallel activation of microglia (visualized by OX-42 and ED1 immunohistochemistry), production of reactive oxygen species (ROS) (assessed by hydroethidine histochemistry), and degeneration of nigral DA neurons were also observed in the SN. Western blot analyses and double-label immunohistochemistry showed an increase in the expression of inducible nitric oxide synthase (iNOS) within activated microglia. LPS also induced translocation of p67phox , the cytosolic component of NADPH oxidase, to the membrane of SN microglia, indicating activation of NADPH oxidase. The LPS-induced loss of nigral DA neurons was partially inhibited by fluoxetine, and the observed neuroprotective effects were associated with fluoxetine-mediated suppression of microglial NADPH oxidase activation and iNOS upregulation, and decreased ROS generation and oxidative stress. These results suggest that fluoxetine and analogs thereof may be beneficial for the treatment of neurodegenerative diseases, such as PD, that are associated with microglia-derived oxidative damage.
Porous silicon (pSi) materials have gained a great deal of attention from various research fields, and their surface-functionalization is one of the critical points for their applications. In this ...study, a new surface modification method of Si-H-terminated pSi materials via microwave-induced Si-S bond formation is disclosed. The silicon hydride (Si−H) functionality on the pSi surface could react with the 5-membered cyclic disulfide (S-S) compound (DL-α-lipoic acid in this study) by microwave-induced in situ S-S bond cleavage and Si-S bond formation. This surface chemistry is fast responsive (<10 min) and more efficient than other methods such as vortexing, heating stirring, or ultrasonication. The reaction maintains the primary porous structure of pSi materials including pSi wafer, pSi rugate filer, and pSi nanoparticles. An additional functional group such as carboxylic acid is demonstrated to be readily introducible on the pSi surface for further applications. Overall, this study has successfully demonstrated the porous silicon surface modification via a microwave-induced in situ cyclic disulfide (S-S) cleavage and Si-S bond formation.
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•A new surface modification method of porous silicon materials is disclosed.•Microwave induces 1,2-dithiolane ring-opening and Si-S bond formation.•This new method is fast responsive, efficient, and user-friendly.•Additional functional group is readily introducible for further applications.
The aim of this study was to evaluate the findings of CT scans in patients with pathologically confirmed primary colorectal squamous-cell carcinoma (SCC). The clinical presentation and CT findings in ...eight patients with pathologically confirmed primary colorectal squamous-cell carcinoma were retrospectively reviewed by two gastrointestinal radiologists. Hematochezia was the most common symptom (n = 5). The tumors were located in the rectum (n = 7) and sigmoid colon (n = 1). The tumors showed circumferential wall thickening (n = 4), bulky mass (n = 3), or eccentric wall thickening (n = 1). The mean maximal wall thickness of the involved segment was 29.1 mm ± 13.4 mm. The degree of tumoral enhancement observed via CT was well enhanced (n = 4) or moderately enhanced (n = 4). Necrosis within the tumor was found in five patients. The mean total number of metastatic lymph nodes was 3.1 ± 3.3, and the mean short diameter of the largest metastatic lymph node was 16.6 ± 5.7 mm. Necrosis within the metastatic node was observed in six patients. Invasions to adjacent organs were identified in five patients (62.5%). Distant metastasis was detected in only one patient. In summary, primary SCCs that arise from the colorectum commonly present as marked invasive wall thickening or a bulky mass with heterogeneous well-defined enhancement, internal necrosis, and large metastatic lymphadenopathies.
Atopic dermatitis (AD) is an inflammatory skin disease caused by an imbalance between Th1 and Th2 cells. AD patients suffer from pruritus, excessive dryness, red or inflamed skin, and complications ...such as sleep disturbances and depression. Although there are currently many AD treatments available there are insufficient data on their long-term stability and comparative effects. Moreover, they have limitations due to various side effects. Multipotent mesenchymal stem cells (M-MSCs) might have potential for next-generation AD therapies. MSCs are capable of immune function regulation and local inflammatory response inhibition. M-MSCs, derived from human embryonic stem cells (hESC), additionally have a stable supply. In L507 antibody array, M-MSCs generally showed similar tendencies to bone marrow-derived mesenchymal stem cells (BM-MSCs), although the immunoregulatory function of M-MSCs seemed to be superior to BM-MSCs. Based on the characteristics of M-MSCs on immunoregulatory functions, we tested a M-MSC conditioned media concentrate (MCMC) in mice with AD lesions on their dorsal skin. MCMC significantly decreased RNA expression levels of inflammatory cytokines in the mouse dorsal skin. It also suppressed serum IgE levels. In addition, significant histopathologic alleviation was identified. In conclusion, secretions of M-MSCs have the potential to effectively improve AD-related inflammatory lesions. M-MSCs showed potential for use in next-generation AD treatment.
Internet gaming disorder (IGD) has attracted considerable attention as a serious mental and public health issue worldwide. Currently, there are no established treatment guidelines for IGD. Herein, we ...review the latest findings on the efficacy and related neural effects of pharmacological and psychosocial treatments for individuals with IGD.
A database search of relevant studies published between 2007 and 2020 was conducted using PubMed and Google Scholar. Twenty-seven studies were reviewed for current evidence related to the efficacy and neural effects of pharmacological and psychosocial IGD treatments.
Pharmacological studies suggest that bupropion may play a significant role in IGD. Additionally, nuclear imaging studies on IGD have demonstrated functional impairment of the dopamine system, providing a neurobiological basis for the efficacy of dopamineenhancing drugs. Among the various psychosocial interventions, current evidence suggests that cognitive behavioral therapy may be an effective intervention for IGD. Cognitive behavioral therapy and bupropion were found to influence resting-state functional connectivity within the cortico-subcortical circuit and default mode network, suggesting a possible neural mechanism. Innovative approaches, including virtual reality treatment, residential camps, voluntary abstinence, and transcranial direct current stimulation, have shown promising results. However, methodological limitations, such as the absence of proper controls, small sample sizes, short duration, inconsistency of inclusion criteria across studies, and self-report measures of outcome, hamper conclusions regarding the efficacy of treatments.
Ongoing basic research and clinical trials overcoming these limitations could add to the existing knowledge on IGD and contribute to the development of evidence-based treatments.
The ultraviolent irradiation resistance-associated gene (UVRAG), a component of the Beclin 1/autophagy-related 6 complex, regulates the autophagy initiation step and functions in the DNA-damage ...response. UVRAG is frequently mutated in various cancer types, and mutations of UVRAG increase sensitivity to chemotherapy by impairing DNA-damage repair. In this study, we addressed the epigenetic regulation of UVRAG in colorectal cancer cells. UVRAG expression was increased in cells treated with histone deacetylase (HDAC) inhibitors, such as valproic acid and suberoylanilide hydroxamic acid. Down-regulation of HDAC1 enhanced UVRAG expression in colorectal cancer cells. In addition, both chemical and genetic inhibition of HDAC1 reduced the activation of caspase-3 and cytotoxicity in 5-fluorouracil (5FU)-treated cancer cells. In contrast, UVRAG overexpression inhibited caspase activation and cell death in 5FU-treated cells. Taken together, our findings suggest that up-regulation of UVRAG by HDAC1 inhibition potentiates DNA-damage-mediated cell death in colorectal cancer cells.
Hyponatraemia predicts poor prognosis in patients hospitalised for acute heart failure (AHF). Yet, the association of hyponatraemia improvement with better postdischarge outcome has not been ...elucidated. Here, we determined the clinical impact of hyponatraemia improvement during hospitalisation on postdischarge outcome in patients admitted for AHF.
Prospective cohort study.
Nation-wide twenty-four academic hospitals in Korea (mean follow-up of 1.7 years after discharge).
2888 patients hospitalised for AHF.
Primary endpoints were composite of death or rehospitalisation due to heart failure.
Hyponatraemia was present in 575 of total 2888 patients hospitalised for AHF at admission. Hyponatraemia was normalised in 274 patients (47.7%) at discharge. During mean follow-up of 1.7 years total 735 rehospitalisations and 397 deaths were documented. Persistent hyponatraemia during hospitalisation was significantly associated with increased incidence of composite endpoint of death or rehospitalisation in multivariate analysis compared with normonatraemia at admission (HR 1.345, 95% CI 1.075 to 1.683, p=0.010). However, improvement of hyponatraemia during hospitalisation was not significantly associated with lower incidence of composite endpoint of death or rehospitalisation in multivariate analysis (HR 1.084, 95% CI 0.709 to 1.659, p=0.709). Improved hyponatraemia was not associated with better prognosis in analysis with propensity score matching, either (HR 1.111, 95% CI 0.588 to 2.100, p=0.746).
In patients hospitalised for AHF, hyponatraemia on admission is associated with a worse prognosis compared with normonatraemia, irrespective of whether hyponatraemia improves during hospitalisation.
Core needle biopsy (CNB) has been suggested as a complementary diagnostic method to fine-needle aspiration in patients with thyroid nodules. Many recent CNB studies have suggested a more advanced ...role for CNB, but there are still no guidelines on its use. Therefore, the Task Force Committee of the Korean Society of Thyroid Radiology has developed the present consensus statement and recommendations for the role of CNB in the diagnosis of thyroid nodules. These recommendations are based on evidence from the current literature and expert consensus.
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