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The transition from the family home to a nursing home can be an emotionally stressful experience for older adults. This study aimed to examine the feasibility and effects of a narrative therapy combined with a solution focus (NTCSF) program on the psychological adjustment, depression, and self-efficacy of nursing home residents. A non-random concurrent controlled trial was conducted in Fujian, China that involved 81 participants (intervention = 41, comparison = 40) from four separate nursing homes. The control group received routine institutional care, while the intervention group underwent a three-week NTCSF program in addition to receiving routine care. In the variance analyses, significant differences were found in "psychological adjustment" (T = 4.007, P < 0.001) and "self-efficacy" (T = 3.204, P = 0.002), compared to the control group. There was no significant difference in "depression" (t = -1.550, P = 0.125) between the groups at the baseline, but the experimental group showed a significant decrease in depression (t = -2.204, P = 0.033) after the intervention. The NTCSF program was found to be effective in improving the psychological adjustment of nursing home residents. Trial registration This study was registered on the Chinese Clinical Trial Registry (Registration No: ChiCTR-2100042767).
Subject(s)
Depression , Nursing Homes , Humans , Male , Female , Aged , Depression/therapy , Narrative Therapy/methods , Self Efficacy , China , Aged, 80 and over , Adaptation, PsychologicalABSTRACT
Adenosine (Ado) is significantly elevated in the tumor microenvironment (TME) compared to normal tissues. It binds to adenosine receptors (AdoRs), suppressing tumor antigen presentation and immune cell activation, thereby inhibiting tumor adaptive immunity. Ado downregulates major histocompatibility complex II (MHC II) and co-stimulatory factors on dendritic cells (DCs) and macrophages, inhibiting antigen presentation. It suppresses anti-tumor cytokine secretion and T cell activation by disrupting T cell receptor (TCR) binding and signal transduction. Ado also inhibits chemokine secretion and KCa3.1 channel activity, impeding effector T cell trafficking and infiltration into the tumor site. Furthermore, Ado diminishes T cell cytotoxicity against tumor cells by promoting immune-suppressive cytokine secretion, upregulating immune checkpoint proteins, and enhancing immune-suppressive cell activity. Reducing Ado production in the TME can significantly enhance anti-tumor immune responses and improve the efficacy of other immunotherapies. Preclinical and clinical development of inhibitors targeting Ado generation or AdoRs is underway. Therefore, this article will summarize and analyze the inhibitory effects and molecular mechanisms of Ado on tumor adaptive immunity, as well as provide an overview of the latest advancements in targeting Ado pathways in anti-tumor immune responses.
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AIM: Our study aims to identify novel non-coding RNA-mRNA regulatory networks associated with ß-cell dysfunction and compensatory responses in obesity-related diabetes. METHODS: Glucose metabolism, islet architecture and secretion, and insulin sensitivity were characterized in C57BL/6J mice fed on a 60% high-fat diet (HFD) or control for 24 weeks. Islets were isolated for whole transcriptome sequencing to identify differentially expressed (DE) mRNAs, miRNAs, IncRNAs, and circRNAs. Regulatory networks involving miRNA-mRNA, lncRNA-mRNA, and lncRNA-miRNA-mRNA were constructed and functions were assessed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. RESULTS: Despite compensatory hyperinsulinemia and a significant increase in ß-cell mass with a slow rate of proliferation, HFD mice exhibited impaired glucose tolerance. In isolated islets, insulin secretion in response to glucose and palmitic acid deteriorated after 24 weeks of HFD. Whole transcriptomic sequencing identified a total of 1324 DE mRNAs, 14 DE miRNAs, 179 DE lncRNAs, and 680 DE circRNAs. Our transcriptomic dataset unveiled several core regulatory axes involved in the impaired insulin secretion in HFD mice, such as miR-6948-5p/Cacna1c, miR-6964-3p/Cacna1b, miR-3572-5p/Hk2, miR-3572-5p/Cckar and miR-677-5p/Camk2d. Additionally, proliferative and apoptotic targets, including miR-216a-3p/FKBP5, miR-670-3p/Foxo3, miR-677-5p/RIPK1, miR-802-3p/Smad2 and ENSMUST00000176781/Caspase9 possibly contribute to the increased ß-cell mass in HFD islets. Furthermore, competing endogenous RNAs (ceRNA) regulatory network involving 7 DE miRNAs, 15 DE lncRNAs and 38 DE mRNAs might also participate in the development of HFD-induced diabetes. CONCLUSIONS: The comprehensive whole transcriptomic sequencing revealed novel non-coding RNA-mRNA regulatory networks associated with impaired insulin secretion and increased ß-cell mass in obesity-related diabetes.
Subject(s)
Diabetes Mellitus , MicroRNAs , RNA, Long Noncoding , Mice , Animals , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Diet, High-Fat/adverse effects , RNA, Circular/metabolism , Insulin Secretion , Exome Sequencing , Mice, Inbred C57BL , MicroRNAs/genetics , MicroRNAs/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Obesity/genetics , Gene Regulatory Networks , Calcium Channels, N-Type/metabolismABSTRACT
Prorocentrum shikokuense (formerly P. donghaiense) is a pivotal dinoflagellate species associating with the HABs in the East China Sea. The complexity of its large nuclear genome hindered us from understanding its genomic characteristics. Full-length transcriptome sequencing offers a practical solution to decipher the physiological mechanisms of a species without the reference genome. In this study, we employed single-molecule real-time (SMRT) sequencing technology to sequence the full-length transcriptome of Prorocentrum shikokuense. We successfully generated 41.73 Gb of clean SMRT sequencing reads and isolated 105,249 non-redundant full-length non-chimeric reads. Our trial has led to the identification of 11,917 long non-coding RNA transcripts, 514 alternative splicing events, 437 putative transcription factor genes from 17 TF gene families, and 34,723 simple sequence repeats. Additionally, a total of 78,265 open reading frames were identified, of them 15,501 were the protein coding sequences. This dataset is valuable for annotating P. shikokuense genome, and will contribute significantly to the in-depth studies on the molecular mechanisms underlining the dinoflagellate bloom formation.
Subject(s)
Dinoflagellida , Transcriptome , Alternative Splicing , China , Dinoflagellida/genetics , Gene Expression Profiling , Open Reading Frames , Transcription Factors/genetics , EutrophicationABSTRACT
Cisplatin remains the most widely used chemotherapeutic agent in cancer treatment; however, its inherent drawbacks have fueled the development of novel metalloanticancer drugs. In this study, two novel Cu(II) complexes (Cu1 and Cu2) were designed and synthesized. Notably, these Cu(II) complexes showed higher cytotoxicity against HL-7402 cells than cisplatin. Moreover, Cu(II) complexes significantly inhibited liver cancer growth in a xenograft model. A mechanism study revealed that the Cu(II) complexes reduced the mitochondrial membrane potential of cancer cells, produced excessive reactive oxygen species (ROS), induced mitochondrial DNA (mtDNA) damage, and ultimately facilitated cancer cell apoptosis.
Subject(s)
Antineoplastic Agents , Apoptosis , Coordination Complexes , Copper , DNA Damage , DNA, Mitochondrial , Liver Neoplasms , Mitochondria , Reactive Oxygen Species , Humans , Copper/chemistry , Copper/pharmacology , Apoptosis/drug effects , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Animals , DNA Damage/drug effects , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Mice , Mitochondria/drug effects , Mitochondria/metabolism , DNA, Mitochondrial/metabolism , DNA, Mitochondrial/genetics , Reactive Oxygen Species/metabolism , Membrane Potential, Mitochondrial/drug effects , Cell Line, Tumor , Hydrazones/pharmacology , Hydrazones/chemistry , Hydrazones/chemical synthesis , Xenograft Model Antitumor Assays , Mice, Nude , Mice, Inbred BALB CABSTRACT
BACKGROUND: Older adults do not always adapt successfully to nursing homes. Learning resourcefulness and instrumental reminiscence may contribute to the psychological adjustment made by nursing home residents. How both attributes can be combined to enhance residents' adjustment remains unclear. OBJECTIVES: This study examined the effects of resourcefulness-based instrumental reminiscence therapy (RBIRT) on psychological adjustment, learned resourcefulness, self-efficacy, social support and quality of life (QoL) of nursing home residents. METHODS: A randomised, controlled, assessor-blinded, parallel-arm trial was conducted between January 2022 and February 2023 in Fujian, China, with 120 participants (intervention = 60, comparison = 60) from two separate nursing homes. The intervention group participants received a 6-week RBIRT, involving Reminiscence Interview, Emotional Venting, Reconstruction Strategies, Planning for the Future and Strengthening Support. The control group participants received routine institutional care. Participants were assessed using the Nursing Home Adjustment Scale, Resourcefulness Scale, General Self-efficacy Scale, Perceived Social Support Scale and the 12-item Short-Form Health Survey. Outcomes were evaluated at baseline (T0), immediately post intervention (T1) and at 1-month (T2) and 3-months (T3) post-intervention. RESULTS: Participants in the intervention group showed significant improvement in 'psychological adjustment,' 'learned resourcefulness,' 'self-efficacy,' 'social support' and 'QoL-mental health dimension' compared to the control group (P < 0.001). These effects were sustained at the 1- and 3-month follow-ups. CONCLUSIONS: Innovative RBIRT improved psychological adjustment, learned resourcefulness, self-efficacy, social support and mental health-related QoL among nursing home residents.
Subject(s)
Emotional Adjustment , Quality of Life , Humans , Aged , Emotions , Learning , Nursing HomesABSTRACT
Microneedles (MNs) are increasingly used in transdermal drug delivery due to high bioavailability, simple operation, and improved patient compliance. However, further clinical applications are hindered by unsatisfactory mechanical strength and uncontrolled drug release. Herein, an enzyme-mediated approach is reported for the fabrication of nanocomposite hydrogel-based MNs with tunable mechanical strength and controllable transdermal efficiency. As a proof-of-concept, tetrakis(1-methyl-4-pyridinio)porphyrin (TMPyP) was chosen as a model drug for photodynamic therapy of melanoma. TMPyP-loaded PLGA nanoparticles (NP/TMPyP) served as an inner phase of MNs for controlled release of photosensitizers, and enzyme-mediated hyaluronic acid-tyramine (HAT) hydrogels served as an external phase for optimizing the mechanical strength of MNs. By changing the concentration of HRP and H2O2, three types of MNs were fabricated for transdermal delivery of TMPyP, which demonstrated different cross-linking densities and various mechanical strength. Among the three MNs, the HAT-Medium@NP/TMPyP-MN with a medium mechanical strength exhibited the highest values of transdermal efficiency in vitro and the longest retention time in vivo. As compared to pure TMPyP and TMPyP-loaded nanoparticles, the HAT-Medium@NP/TMPyP-MN demonstrated higher anticancer efficacy in both melanoma A375 cells and a xenografted tumor mouse model. Therefore, the enzyme-mediated nanocomposite hydrogel MNs show great promise in the transdermal delivery of therapeutic drugs with enhanced performance. STATEMENT OF SIGNIFICANCE: This study reports an enzyme-mediated approach for the fabrication of photodynamically-active microneedles (HAT@NP/TMPyP-MNs) with tunable mechanical strength and controllable transdermal efficiency. On one hand, HAT hydrogels that bear different cross-linking densities, facilitate tunable mechanical strength and optimized transdermal performances of MNs; on the other hand, NP/TMPyP and HAT network contribute to sustained release of photosensitizers. Comparing to other formulation (i.e., NP/TMPyP or TMPyP), the HAT-Medium@NP/TMPyP-MN exhibited excelling anticancer efficacy in photodynamic therapy in vitro and in vivo. We believe that the combination of enzyme-mediated polymeric cross-linking and slow-releasing nano-vehicles in a single nanocomposite platform provides a versatile approach for the fabrication of MNs with enhanced therapeutic efficacy, which holds great promise in the transdermal delivery of various therapeutic drugs in future.
Subject(s)
Melanoma , Photosensitizing Agents , Humans , Mice , Animals , Nanogels , Melanoma/drug therapy , Hydrogen Peroxide , Administration, Cutaneous , Hyaluronic Acid , Hydrogels/pharmacology , Drug Delivery Systems , NeedlesABSTRACT
Visceral adiposity is a strong predictor of cardiometabolic risk. Thiazolidinediones (TZDs) are associated with a shift in fat redistribution from visceral adipose tissue (VAT) to subcutaneous adipose tissue (SAT). We aimed to compare the effects of TZD and other interventions on fat remodeling in adults in randomized controlled trials. Among the 1331 retrieved studies, 39 trials with 1765 participants were included in the meta-analysis. The standardized mean difference in VAT change was not significantly different between TZD and comparators across the overall studies. Intriguingly, TZD treatment resulted in significant decreases in VAT compared with placebo and sulfonylureas (p < 0.05), although recombinant human growth hormone was superior to TZD regarding VAT reduction (p < 0.05). Data from 216 participants showed TZD leading to a greater reduction in liver fat percentage than comparators (p < 0.05). Compared with the controls, TZD significantly increased SAT, total body fat, weight, waist circumference, and body mass index (p < 0.05). However, TZD pronouncedly improved glucose control, insulin resistance, adiponectin, and lipid profile (p < 0.05). TZD provides a favorable effect on fat redistribution and benefits insulin sensitivity, suggesting a potentially valuable approach in cardiometabolic risk management.
Subject(s)
Cardiovascular Diseases , Insulin Resistance , Thiazolidinediones , Adult , Humans , Thiazolidinediones/pharmacology , Thiazolidinediones/therapeutic use , Randomized Controlled Trials as Topic , Adipose Tissue , Subcutaneous Fat , Intra-Abdominal FatABSTRACT
Tumors in which the microenvironment is characterized by lack of immune cell infiltration are referred as "cold tumors" and typically exhibit low responsiveness to immune therapy. Targeting the factors contributing to "cold tumors" formation and converting them into "hot tumors" is a novel strategy for improving the efficacy of immunotherapy. Adenosine, a hydrolysis product of ATP, accumulates with a significantly higher concentration in the tumor microenvironments compared with normal tissue and exerts inhibitory effects on tumor-specific adaptive immunity. Tumor cells, dendritic cells, macrophages, and T cells express abundant adenosine receptors on their surfaces. The binding of adenosine to these receptors initiates downstream signaling pathways that suppress tumor antigen presentation and immune cell activation, consequently dampening adaptive immune responses against tumors. Adenosine down-regulates the expression of major histocompatibility complex â ¡ and co-stimulatory factors on dendritic cells and macrophages, thereby inhibiting antigen presentation to T cells. Adenosine also inhibits ligand-receptor binding and transmembrane signaling on T cells, concomitantly suppressing the secretion of anti-tumor cytokines and impairing T cell activation. Furthermore, adenosine hinders effector T cell trafficking to tumor sites and infiltration by inhibiting chemokine secretion and KCa3.1 channels. Additionally, adenosine promotes the secretion of immunosuppressive cytokines, increases immune checkpoint protein expression, and enhances the activity of immunosuppressive cells, collectively curbing cytotoxic T cell-mediated tumor cell killing. Given the immunosuppressive role of adenosine in adaptive antitumor immunity, several inhibitors targeting adenosine generation or adenosine receptor blockade are currently in preclinical or clinical development with the aim of enhancing the effectiveness of immunotherapies. This review provides an overview of the inhibitory effects of adenosine on adaptive antitumor immunity, elucidate the molecular mechanisms involved, and summarizes the latest advances in application of adenosine inhibition strategies for antitumor immunotherapy.
Subject(s)
Adenosine , Neoplasms , Humans , Adenosine/metabolism , Adenosine/pharmacology , T-Lymphocytes , Adaptive Immunity , Cytokines , Neoplasms/therapy , Tumor MicroenvironmentABSTRACT
To simultaneously achieve the objectives of waste resource utilization and clean production, a novel approach involving the utilization of corn straw-sludge hybrid biochar was proposed for the adsorption of VOCs emitted from biomass power plants. This study analyzed the effect of straw-sludge biochar on the adsorption characteristics of VOCs (toluene, isopentane, and ethylene) under different preparation conditions (raw material ratio, activation temperature, and activation time). The findings revealed that the adsorption efficiency of the mixed biochar was significantly superior to that of individual corn straw biochar and sludge biochar. The adsorption of methylbenzene, isopentane, and ethylene was 78.32, 40.81, and 41.18% higher, respectively, compared to the control groups consisting of pure sludge biochar and pure corn straw biochar. Moreover, the adsorption performance of the activated biochar followed the sequence of ethylene < isopentane < methylbenzene in terms of both saturation time and adsorption capacity. The adsorption capacity of VOCs on straw biochar-sludge biochar demonstrated a consistent correlation with the boiling point and molecular weight of the adsorbate, with higher adsorption capacities observed for adsorbates with larger boiling points and molecular weights, specifically methylbenzene > isopentane > ethylene.
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[This corrects the article DOI: 10.1016/j.apsb.2023.04.002.].
ABSTRACT
Recent studies have pointed to the role of Krüpple-like factor 12 (KLF12) in cancer-associated processes, including cancer proliferation, apoptosis, and metastasis. However, the role of KLF12 in tumor immunity remains obscure. Here, we found that KLF12 expression was significantly higher in non-small cell lung cancer (NSCLC) cells with higher programmed death-ligand 1 (PD-L1) expression. Additionally, a positive correlation between KLF12 and PD-L1 was observed in clinical patient tumor tissues. By chromatin immunoprecipitation (ChIP) analysis, KLF12 was identified to bind to the CACCC motif of the PD-L1 promoter. Overexpression of KLF12 promoted PD-L1 transcription, whereas silencing of KLF12 inhibited PD-L1 transcription. Furthermore, signal transducer and activator of transcription 1 (STAT1)- and STAT3-triggered PD-L1 transcription was abolished in the absence of KLF12, and KLF12 knockdown weakened the binding of STAT1 and STAT3 to the PD-L1 promoter. Mechanistically, KLF12 physically interacted with P300, a histone acetyltransferase. In addition, KLF12 silencing reduced P300 binding to the PD-L1 promoter, which subsequently caused decreased acetylation of histone H3. PD-L1 transcription driven by KLF12 overexpression was eliminated by EP300 silencing. In immunocompetent mice, KLF12 knockout inhibited tumor growth and promoted infiltration of CD8+ T cells. However, this phenomenon was not observed in immunodeficient mice. Overall, this study reveals KLF12-mediated transcriptional regulation of PD-L1 in NSCLC; targeting KLF12 may be a potential therapeutic strategy for NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Animals , Mice , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Factor XII/metabolism , CD8-Positive T-Lymphocytes/metabolism , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Signal Transduction , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolismABSTRACT
Mevalonate metabolism plays an important role in regulating tumor growth and progression; however, its role in immune evasion and immune checkpoint modulation remains unclear. Here, we found that non-small cell lung cancer (NSCLC) patients with higher plasma mevalonate response better to anti-PD-(L)1 therapy, as indicated by prolonged progression-free survival and overall survival. Plasma mevalonate levels were positively correlated with programmed death ligand-1 (PD-L1) expression in tumor tissues. In NSCLC cell lines and patient-derived cells, supplementation of mevalonate significantly up-regulated the expression of PD-L1, whereas deprivation of mevalonate reduced PD-L1 expression. Mevalonate increased CD274 mRNA level but did not affect CD274 transcription. Further, we confirmed that mevalonate improved CD274 mRNA stability. Mevalonate promoted the affinity of the AU-rich element-binding protein HuR to the 3'-UTR regions of CD274 mRNA and thereby stabilized CD274 mRNA. By in vivo study, we further confirmed that mevalonate addition enhanced the anti-tumor effect of anti-PD-L1, increased the infiltration of CD8+ T cells, and improved cytotoxic function of T cells. Collectively, our findings discovered plasma mevalonate levels positively correlated with the therapeutic efficacy of anti-PD-(L)1 antibody, and provided the evidence that mevalonate supplementation could be an immunosensitizer in NSCLC.
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Atrial fibrillation (AF) is a frequent arrhythmia associated with cardiovascular morbidity and mortality. Neutrophil extracellular traps (NETs) are DNA fragments with cytoplasm proteins released from neutrophils, which are involved in various cardiovascular diseases. To elucidate the role of NETs in AF, we investigated the effect of NETs on AF progression and the secretion of NETs in AF. Results showed that: NETs induced the autophagic apoptosis of cardiomyocytes, and NETs also led to mitochondrial injury by promoting mitochondrial depolarization and ROS production. Ongoing tachy-pacing led to the structural loss of cardiomyocytes and provided potent stimuli to induce NETs secretion from neutrophils. In the meanwhile, increased Ang II in AF facilitated NETs formation through the upregulation of AKT phosphorylation, while it could not directly initiate NETosis as the autophagy was not induced. In vivo, DNase I was administrated to abrogate NETs formation, and AF-related fibrosis was ameliorated as expected. Correspondingly, the duration of the induced AF was reduced. Our study addresses the formation mechanism of NETs in AF and demonstrates the lethal effects of NETs on cardiomyocytes through the induction of mitochondrial injury and autophagic cell death, which comprehensively describes the positive feedback comprised of NETs and stimuli secreted by cardiomyocytes that sustains the progression of AF and AF related fibrosis.
Subject(s)
Atrial Fibrillation , Extracellular Traps , Humans , Extracellular Traps/genetics , Atrial Fibrillation/genetics , Myocytes, Cardiac/metabolism , Neutrophils/metabolism , DNAABSTRACT
Recent studies have expanded the known functions of cGAS-STING in inflammation to a role in cancer due to its participation in activating immune surveillance. In cancer cells, the cGAS-STING pathway can be activated by cytosolic dsDNA derived from genomic, mitochondrial and exogenous origins. The resulting immune-stimulatory factors from this cascade can either attenuate tumor growth or recruit immune cells for tumor clearance. Furthermore, STING-IRF3-induced type I interferon signaling can enforce tumor antigen presentation on dendritic cells and macrophages and thus cross-prime CD8+ T cells for antitumor immunity. Given the functions of the STING pathway in antitumor immunity, multiple strategies are being developed and tested with the rationale of activating STING in tumor cells or tumor-infiltrating immune cells to elicit immunostimulatory effects, either alone or in combination with a range of established chemotherapeutic and immunotherapeutic regimens. Based on the canonical molecular mechanism of STING activation, numerous strategies for inducing mitochondrial and nuclear dsDNA release have been used to activate the cGAS-STING signaling pathway. Other noncanonical strategies that activate cGAS-STING signaling, including the use of direct STING agonists and STING trafficking facilitation, also show promise in type I interferon release and antitumor immunity priming. Here, we review the key roles of the STING pathway in different steps of the cancer-immunity cycle and characterize the canonical and noncanonical mechanisms of cGAS-STING pathway activation to understand the potential of cGAS-STING agonists for cancer immunotherapy.
Subject(s)
Interferon Type I , Neoplasms , Humans , CD8-Positive T-Lymphocytes , Immunity, Innate , Immunotherapy , Neoplasms/drug therapy , Nucleotidyltransferases/geneticsABSTRACT
BACKGROUND: Lung adenocarcinoma (LUAD) is one of the most common pathological types of lung cancer. The gene Chloride Intracellular Channel 5 (CLIC5) has an important role in neurophysiology, cardiovascular biology, and tumour biology. Here, we explored the prognostic value and immune infiltration of CLIC5 expression in LUAD patients. METHODS: We extracted transcriptional LUAD data from The Cancer Genome Atlas (TCGA) and the University of Alabama Cancer Database to explore CLIC5 expression profiles and their relation to CLIC5 and clinicopathological parameters. The relationship between CLIC5 and survival time was explored using Kaplan-Meier Plotter. Then, we integrated the data from TCGA and the Gene Expression Omnibus (GEO) database to perform univariate and multivariate Cox regression. We performed CLIC5 immunohistochemical staining on 167 lung adenocarcinoma samples for further verification. In addition, we analysed the Gene Ontology (GO) database, Kyoto Encyclopaedia of Genes and Genomes pathways and network analysis of protein-protein interactions in lung tissue, to explore the potential mechanism of CLIC5. To analyse the correlation between immune infiltration and CLIC5 expression, we first compared the expression of immune cells in tumour tissues and normal tissues based on the TCGA and GEO databases. We found 51 immunomodulators related to CLIC5 and structured their enrichment pathways as well as those of 50 correlated genes. We used a Cox regression model to identify multiple-gene risk prediction signatures. Finally, we assessed the prognostic accuracy of the risk scores via receiver operating characteristic curves. RESULTS: CLIC5 expression levels were significantly lower in LUAD tissue than in normal tissue. Lower CLIC5 expression was negatively correlated to the overall survival of LUAD patients based on survival analysis. We identified CLIC5 as an independent prognosis predictor. Functional network analysis suggested that CLIC5 is related to multiple pathways. CLIC5 expression is closely related to infiltration levels of many immune cells and immune marker sets in LUAD patients. Furthermore, the risk score based on immunomodulators related to CLIC5 was an independent prognosis predictor in the TCGA lung cohorts. CONCLUSION: Our findings suggest that CLIC5 is a promising molecular marker for the prognosis and immune infiltration of LUAD patients.
Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Humans , Prognosis , Adjuvants, Immunologic , Immunologic Factors , Adenocarcinoma of Lung/diagnosis , Adenocarcinoma of Lung/genetics , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Microfilament Proteins , Chloride Channels/geneticsABSTRACT
Understanding the regulatory mechanisms of PD-L1 expression in tumors provides key clues for improving immune checkpoint blockade efficacy or developing novel oncoimmunotherapy. Here, we showed that the FDA-approved sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin dramatically suppressed PD-L1 expression and enhanced T cell-mediated cytotoxicity. Mechanistic study revealed that SGLT2 colocalized with PD-L1 at the plasma membrane and recycling endosomes and thereby prevented PD-L1 from proteasome-mediated degradation. Canagliflozin disturbed the physical interaction between SGLT2 and PD-L1 and subsequently allowed the recognition of PD-L1 by Cullin3SPOP E3 ligase, which triggered the ubiquitination and proteasome-mediated degradation of PD-L1. In mouse models and humanized immune-transformation models, either canagliflozin treatment or SGLT2 silencing significantly reduced PD-L1 expression and limited tumor progression - to a level equal to the PD-1 mAb - which was correlated with an increase in the activity of antitumor cytotoxic T cells. Notably, prolonged progression-free survival and overall survival curves were observed in the group of PD-1 mAb-treated patients with non-small cell lung cancer with high expression of SGLT2. Therefore, our study identifies a regulator of cell surface PD-L1, provides a ready-to-use small-molecule drug for PD-L1 degradation, and highlights a potential therapeutic target to overcome immune evasion by tumor cells.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Mice , Animals , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Canagliflozin/pharmacology , Sodium-Glucose Transporter 2 , Lung Neoplasms/pathology , Proteasome Endopeptidase Complex/metabolism , B7-H1 Antigen , Programmed Cell Death 1 Receptor , Cell Line, TumorABSTRACT
Nanobubble water (NBW) could improve methane production from anaerobic digestion (AD) of corn straw without secondary contamination. In this study, the effect of carbon dioxide nanobubble water (CO2-NBW) volumes (0%, 25%, 50%, 75%, 100%) on methane production from corn straw was investigated. The results showed that addition of CO2-NBW could improve methane production and promote substrate degradation in AD process. The highest cumulative methane production of 132.16 mL g-1VSadded was obtained in the 100% CO2-NBW added reactor, which was 17% higher than that in the control group. Additionally, the addition of CO2-NBW could mitigate the sharp decrease in pH by acting as a buffer. CO2-NBW could also enhance microorganism activity throughout the AD process. The electron transport system (ETS) activity was increased by 23%, while the ß-glucosidase, dehydrogenase (DHA), and coenzyme F420 activities were increased by 15%, 23%, and 11%, respectively, at optimum addition of CO2-NBW. Meanwhile, addition of CO2-NBW accelerated the production and consumption of reducing sugar and volatile fatty acids (VFAs), promoting the reduction rates of TS (Total solid) and VS (Volatile solid).
Subject(s)
Bioreactors , Zea mays , Anaerobiosis , Carbon Dioxide , Water , Methane , Dietary Supplements , BiofuelsABSTRACT
The use of lonidamine (LND) in photodynamic therapy (PDT) provides a viable approach to develop low-dose PDT modules with high efficacy, for LND potentiates cytotoxicity of photosensitizers through dysregulation of mitochondrial function. Yet, the efficacy of LND is restricted by its low accumulation in cancer cells, especially in the mitochondrial compartments. To address the problem, we design an LND-derived self-assembling peptide molecule (LND-K) that dually targets integrin receptors and mitochondria of cancer cells. The targeted cellular delivery of LND-K gives higher efficacy in ablation of mitochondrial function in melanoma cells A375, as compared to free LND or the control molecule that lacks mitochondria-targeting moieties. To integrate LND-K in a typical PDT module, we develop a nanofibrillar hydrogel system through co-assembly of LND-K and TPPS4, an anionic photosensitizer that forms tight electrostatic interactions with cationic residues of LND-K. Notably, hydrogel formulation of LND-K/TPPS4 facilitates slow release of TPPS4 over 14 days in vitro, and displays a longer retention time than aqueous solution of TPPS4in vivo. By integrating a mitochondria-targeted molecule (LND-K) in a typical PDT module, we achieve synergistic killing of A375 cells with dual drugs, where LND-K not only serves as a chemotherapeutic drug, but also potentiates the cytotoxicities of TPPS4 toward A375 cells in vitro and in vivo. The peptide-based drug self-delivery system promises the development of efficacious combination treatments against cancer, that integrate cell sensitization with existing anticancer modules (e.g., chemotherapy and PDT) for enhanced therapeutic efficacy. STATEMENT OF SIGNIFICANCE: This study reports the design and synthesis of a lonidamine (LND)-derived self-assembling peptide (LND-K) that dually targets integrin receptors and mitochondria of cancer cells. Under the precision guidance of a mitochondria-targeting sequence, LND-K-containing nanofibers target mitochondria and ablate mitochondrial functions. On one hand, the targeted delivery of LND-K reduces cell viabilities through a chemotherapy route; on the other hand, LND-K sensitizes cancer cells for subsequent PDT treatment with enhanced efficacy, which is mediated by induction of ROS, loss of mitochondrial membrane potential, and decrease of cellular ATP level. We believe that the design of mitochondria-targeted drug delivery systems with a self-assembling molecule provides a new approach to potentiate cytotoxicity of photosensitizers in a low-dose PDT module.