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Sterol regulatory element-binding protein-1 (SREBP-1) is a transcription factor that regulates the expression of genes related to fatty acid biosynthesis. Its high expression and activation in obesity and associated metabolic diseases make it a potential therapeutic target. However, the role of SREBP-1 in the development and exacerbation of these diseases remains unclear, partly because of the impossibility of inhibiting its function because of the lack of specific inhibitors. Here, we aimed to identify small-molecule compounds that directly bind to SREBP-1 using the recombinant N-terminal region of SREBP-1a, which is required for its transcriptional activity. A high-throughput screening campaign was conducted using a thermal shift assay and surface plasmon resonance assay to evaluate the compound affinity and specificity, which resulted in the identification of two compounds. Future analysis of their structure-activity relationships may lead to the development of specific SREBP-1 inhibitors, thereby potentially validating SREBP-1 as a therapeutic target for obesity and resultant atherosclerotic diseases.
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Background/Objectives: Chronic kidney disease (CKD) and anemia are independent prognostic factors for heart failure. In recent years, hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors have become available for the treatment of renal anemia. This prospective randomized controlled study aimed to investigate the effects of switching from a continuous erythropoietin receptor activator (CERA) to one of four HIF-PH inhibitors in patients with chronic heart failure and renal anemia. Methods: Forty patients were randomized by the envelop method to receive treatment with roxadustat, daprodustat, vadadustat, or molidustat. The primary endpoint was the change in the hemoglobin (Hb) level. Secondary endpoints included changes in erythropoietin, changes in free T3, free T4, and thyroid-stimulating hormone (TSH), adverse effects, and drug dose increases and decreases. This study was preregistered in the University Hospital Medical Information Network Clinical Trials Registry (study ID: UMIN000041651). Results: We found no statistically significant difference between Hb levels with HIF-PH inhibitors and CERA, but at month 6, the Hb level was significantly higher with roxadustat than with vadadustat and daprodustat. Erythropoietin decreased significantly after switching to HIF-PH inhibitors. HIF-PH inhibitors had various significant effects on free T3, free T4, and TSH. No adverse events occurred. The doses of some drugs had to be increased or decreased. Conclusions: In patients with heart failure and renal anemia receiving CERA, Hb, NT-ProBNP, and renal function were similar after switching from CERA to HIF-PH inhibitors. The individual HIF-PH inhibitors appear to have different effects on anemia and thyroid function. However, because this was a single-center study with a limited sample size, the efficacy and potential limitations of HIF-PH inhibitors need to be further clarified.
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BACKGROUND: Transcription factor protein IκBζ (encoded by the Nfkbiz gene) regulates nuclear factor-κB (NF-κB) and is involved in the pathophysiology of various inflammatory diseases. However, the role of IκBζ in secondary damage following spinal cord injury (SCI) remains to be determined. Here, we investigated the effect of IκBζ expressed in hematopoietic cells on the progression of secondary damage and functional recovery after SCI. METHODS: We used conditional IκBζ-knockout mice (Mx1-Cre;Nfkbizfl/f) to examine the role of IκBζ in hematopoietic cells after SCI. Contusion SCI was induced using a force of 60 kdyn. The recovery of locomotor performance was evaluated using the nine-point Basso Mouse Scale (BMS) until 42 days post-injury. Expression patterns of inflammatory cytokines and chemokines were examined by quantitative real-time PCR or proteome array analysis. Bone marrow transplantation (BMT) was performed to eliminate the effect of IκBζ deletion in non-hematopoietic cells. RESULTS: Mx1-Cre;Nfkbizfl/fl mice had significantly improved locomotor function compared with wild-type (WT) mice. The mRNA expression of Nfkbiz in WT mice peaked at 12 h after SCI and then decreased slowly in both the spinal cord and white blood cells. In situ hybridization showed that Nfkbiz mRNA was localized in cell nuclei, including macrophage-like cells, in the injured spinal cord of WT mice at 1 day after SCI. Compared with WT mice, Mx1-Cre;Nfkbizfl/fl mice had significantly increased mRNA expressions of interleukin (Il)-4 and Il-10 in the injured spinal cord. In addition, Mx1-Cre;Nfkbizfl/fl mice had significantly higher protein levels of granulocyte-macrophage colony-stimulating factor and C-C motif chemokine 11 compared with WT mice. BMT from Mx1-Cre;Nfkbizfl/fl mice into WT mice improved functional recovery after SCI compared with control mice (WT cells into WT mice). CONCLUSIONS: IκBζ deletion in hematopoietic cells improved functional recovery after SCI, possibly by shifting the inflammatory balance towards anti-inflammatory and pro-regenerative directions.
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Vaccines against coronavirus disease 2019 (COVID-19) have been distributed in most countries for the prevention of onset and aggravation of COVID-19. Recently, there have been increasing numbers of reports on new-onset autoimmune and autoinflammatory diseases following COVID-19 vaccination, however, only little information is available on the long-term safety of these vaccines. Here, we experienced three cases of new-onset rheumatic diseases following COVID-19 vaccination, one case each of rheumatoid arthritis (RA), anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and systemic lupus erythematosus (SLE). The symptom onset ranged from one day to a few days following vaccination. The patients of AAV and SLE were treated successfully with glucocorticoid therapy, and the patient of RA died due to COVID-19. In the literature review of new-onset rheumatic diseases following COVID-19 vaccination, which including seven cases of RA, 37 cases of AAV and 18 cases of SLE, the mean time from vaccination to onset was approximately 11 to 12 days. Most cases improved with glucocorticoid, immunosuppressive drugs and biologic agents. Although such adverse effects are rare, and vaccines are useful in prevent onset and severity of infections, continued accumulation of similar cases is important in terms of examining the long-term safety and understanding pathogenic mechanism of rheumatic diseases.
Subject(s)
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis , COVID-19 Vaccines , COVID-19 , Lupus Erythematosus, Systemic , SARS-CoV-2 , Humans , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Female , Middle Aged , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/chemically induced , Male , Rheumatic Diseases/drug therapy , Glucocorticoids/therapeutic use , Glucocorticoids/adverse effects , Glucocorticoids/administration & dosage , Arthritis, Rheumatoid/drug therapy , Vaccination/adverse effects , Aged , AdultABSTRACT
We aimed to differentiate the isocitrate dehydrogenase (IDH) status among non-enhanced astrocytic tumors using preoperative MRI and PET. We analyzed 82 patients with non-contrast-enhanced, diffuse, supratentorial astrocytic tumors (IDH mutant [IDH-mut], 55 patients; IDH-wildtype [IDH-wt], 27 patients) who underwent MRI and PET between May 2012 and December 2022. We calculated the fractional anisotropy (FA) and mean diffusivity (MD) values using diffusion tensor imaging. We evaluated the tumor/normal brain uptake (T/N) ratios using 11C-methionine, 11C-choline, and 18F-fluorodeoxyglucose PET; extracted the parameters with significant differences in distinguishing the IDH status; and verified their diagnostic accuracy. Patients with astrocytomas were significantly younger than those with glioblastomas. The following MRI findings were significant predictors of IDH-wt instead of IDH-mut: thalamus invasion, contralateral cerebral hemisphere invasion, location adjacent to the ventricular walls, higher FA value, and lower MD value. The T/N ratio for all tracers was significantly higher for IDH-wt than for IDH-mut. In a composite diagnosis based on nine parameters, including age, 84.4% of cases with 0-4 points were of IDH-mut; conversely, 100% of cases with 6-9 points were of IDH-wt. Composite diagnosis using all parameters, including MRI and PET findings with significant differences, may help guide treatment decisions for early-stage gliomas.
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The use of nivolumab as first-line therapy for unresectable advanced gastric cancer has now become a standard practice, and its efficacy has been established. This is the first report of a patient with advanced gastric cancer who underwent conversion surgery after first-line nivolumab combination chemotherapy. The patient was a 58-year-old woman. Her medical history included hypertension and dyslipidemia. She had advanced gastric cancer with extensive lymph node metastasis in the left supraclavicular fossa and around the abdominal aorta. After confirming the HER2-negative status and the PD-L1 CPS score to be ≥5, nivolumab was administered in combination with chemotherapy. After the treatment, she underwent a total gastrectomy with D2 dissection, combined splenectomy and pancreatic tail resection for adhesions, and para-aortic lymph node sampling as a conversion surgery. There was no obvious cancerous remnant in the resected specimen, and the pathological response was Grade 3. The patient was alive and recurrence-free at 4 months postoperatively.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Gastrectomy , Nivolumab , Stomach Neoplasms , Humans , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Stomach Neoplasms/surgery , Middle Aged , Female , Nivolumab/therapeutic use , Nivolumab/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Treatment OutcomeABSTRACT
Neurosurgery is complex surgery that requires a strategy that maximizes the removal of tumors and minimizes complications; thus, a safe environment during surgery should be guaranteed. In this study, we aimed to verify the safety of brain surgery using intraoperative magnetic resonance imaging (iMRI), based on surgical experience since 2000. Thus, we retrospectively examined 2,018 surgical procedures that utilized iMRI performed in the operating room at Tokyo Women's Medical University Hospital between March 2000 and October 2019. As per our data, glioma constituted the majority of the cases (1,711 cases, 84.8%), followed by cavernous hemangioma (61 cases, 3.0%), metastatic brain tumor (37 cases, 1.8%), and meningioma (31 cases, 1.5%). In total, 1,704 patients who underwent glioma removal were analyzed for mortality within 30 days of surgery and for reoperation rates and the underlying causes within 24 hours and 30 days of surgery. As per our analysis, only one death out of all the glioma cases (0.06%) was reported within the 30-day period. Meanwhile, reoperation within 30 days was performed in 37 patients (2.2%) due to postoperative bleeding in 17 patients (1.0%), infection in 12 patients (0.7%), hydrocephalus in 6 patients (0.4%), cerebrospinal fluid (CSF) leakage in 1 patient, and brain edema in 1 patient (0.06%). Of these, 14 cases (0.8%) of reoperation were performed within 24 hours, that is, 13 cases (0.8%) due to postoperative bleeding and 1 case (0.06%) due to acute hydrocephalus. Mortality rate within 30 days was less than 0.1%. Thus, information-guided surgery with iMRI can improve the safety of surgical resections, including those of gliomas.
Subject(s)
Brain Neoplasms , Glioma , Hydrocephalus , Meningeal Neoplasms , Humans , Female , Retrospective Studies , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/surgery , Glioma/diagnostic imaging , Glioma/surgery , Magnetic Resonance Imaging/methodsABSTRACT
Introduction: Within the realm of chemogenetics, a particular form of agonists targeting designer receptors exclusively activated by designer drugs (DREADDs) has emerged. Deschloroclozapine (DCZ), a recently introduced DREADDs agonist, demonstrates remarkable potency in activating targeted neurons at a lower dosage compared to clozapine-N-oxide (CNO). Methods: We conducted a comparative analysis of the effects of subcutaneously administered CNO (1 mg/kg) and DCZ (0.1 mg/kg) in our transgenic rats expressing hM3Dq and mCherry exclusively in oxytocin (OXT) neurons. Results and Discussion: Notably, DCZ exhibited a swift and robust elevation of serum OXT, surpassing the effects of CNO, with a significant increase in the area under the curve (AUC) up to 3 hours post-administration. Comprehensive assessment of brain neuronal activity, using Fos as an indicator, revealed comparable effects between CNO and DCZ. Additionally, in a neuropathic pain model, both CNO and DCZ increased the mechanical nociceptive and thermal thresholds; however, the DCZ-treated group exhibited a significantly accelerated onset of the effects, aligning harmoniously with the observed alterations in serum OXT concentration following DCZ administration. These findings emphasize the remarkable efficacy of DCZ in rats, suggesting its equivalent or potentially superior performance to CNO at considerably lower dosages, thus positioning it as a promising contender among DREADDs agonists.
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BACKGROUND: In awake surgery, cortical mapping may identify the negative motor area (NMA). However, since speech arrest occurs regardless of whether the NMA or the frontal language area (FLA) is stimulated, the presence of speech arrest alone does not distinguish the NMA from the FLA. Furthermore, the exact location and function of the NMA is not well understood. The purpose of this study was to more accurately locate the NMA in a group of cases in which the NMA and FLA could be identified in different brain gyri, and to describe symptoms in cases in which the NMA was removed. METHODS: There were 18 cases of awake surgery at our institution between 2000 and 2013 in which cortical stimulation allowed identification of FLA and NMA in separate brain gyri. In these cases, the pre- and post-removal mapping results were projected onto a 3D model postoperatively. We investigated the symptoms and social rehabilitation in a case in which the tumour invaded the same brain gyrus as the NMA and the NMA had to be resected in combination with the tumour. RESULTS: In cases where the NMA and FLA could be identified in different brain gyri, NMA was localized inferior to the precentral gyrus in all cases. In four cases where NMA was removed with the tumour, apraxia of speech was observed during the surgery; the same symptoms persisted after it, but it improved within a few months, and the patients were able to return to work. CONCLUSION: In cases where NMA and FLA could be identified separately by awake mapping, the NMA was commonly localized inferior to the precentral gyrus. When NMAs were resected in combination with tumour invasion, they did not lead to serious, long-term complications.
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This research aimed to objectively evaluate the optimal state of desk work (flow state) through physiological measurements and use the data to support workers' mental health and well-being. We suppose that the flow state evaluation in real-time can contribute to a concentrated work environment, improved work efficiency, and stabilize worker's minds. This study reports on the development of the mental task modeled on daily work for the physiological measurement experiment. In the first phase of the research, a field survey was conducted with 55 desk workers to understand the details of their jobs and develop suitable mental tasks. Further, the relationship between daily work content and subjective stress was clarified. In the second phase, based on the results of the field survey, a task inducing the flow state was developed for practical use. Through empirical experiments with 35 participants (22 adults and 13 students), the developed task was evaluated for its usefulness and possible issues by examining the relationships among subjective assessment, task performance, degree of flow state, and individual characteristics. The study results showed that the proposed mental task developed in this study constitutes practical work that can be used for concentrated and goal-directed efforts. The task also demonstrated the property of inducing a flow state. Further, the results suggest that it is necessary to adjust the task difficulty level and implement effective feedback methods to induce the flow state more effectively.
Subject(s)
Mental Health , Workload , Adult , Humans , Research Design , Students , WorkflowABSTRACT
Tumor metastasis is one of the worst prognostic features of cancer. Although metastasis is a major cause of cancer-related deaths, an effective treatment has not yet been established. Here, we explore the antitumor effects of GO-Y030, a curcumin analog, via various mechanisms using a mouse model. GO-Y030 treatment of B16-F10 melanoma cells inhibited TGF-ß expression and glycolysis. The invasion assay results showed almost complete invasion inhibition following GO-Y030 treatment. Mouse experiments demonstrated that GO-Y030 administration inhibited lung tumor metastasis without affecting vascular endothelial cells. Consistent with this result, GO-Y030 treatment led to the downregulation of MMP2 and VEGFα, inhibiting tumor invasion and metastasis. The silencing of eIF4B, a downstream molecule of S6, attenuated MMP2 expression. Our study demonstrates the novel efficacy of GO-Y030 in inhibiting tumor metastasis by regulating metastasis-associated gene expression via inhibiting dual access, glycolytic and TGF-ß pathways.
Subject(s)
Curcumin , Neoplasms , Humans , Curcumin/pharmacology , Matrix Metalloproteinase 2 , Endothelial Cells , Transforming Growth Factor beta , Cell Line, Tumor , Neoplasm MetastasisABSTRACT
Glioma in the left frontal cortex has been reported to cause agrammatic comprehension and induce global functional connectivity alterations within the syntax-related networks. However, it remains unclear to what extent the structural reorganization is affected by preexisting syntax-related networks. We examined 28 patients with a diffuse glioma in the left hemisphere and 23 healthy participants. Syntactic abilities were assessed by a picture-sentence matching task with various sentence types. The lesion responsible for agrammatic comprehension was identified by region-of-interest-based lesion-symptom mapping (RLSM). Cortical structural alterations were examined by surface-based morphometry (SBM), in which the cortical thickness and fractal dimension were measured with three-dimensional magnetic resonance imaging (MRI). Fiber tracking on the human population-averaged diffusion MRI template was performed to examine whether the cortical structural alterations were associated with the syntax-related networks. The RLSM revealed associations between agrammatic comprehension and a glioma in the posterior limb of the left internal capsule. The SBM demonstrated that decreased cortical thickness and/or increased complexity of the right posterior insula were associated not only with agrammatic comprehension of the patients but also with the syntactic abilities of healthy participants. The fiber tracking revealed that the route between these two regions was anatomically integrated into the preexisting syntax-related networks previously identified. These results suggest a potential association between agrammatic comprehension in patients with diffuse glioma and structural variations in specific tracts and cortical regions, which may be closely related to the syntax-related networks.
Subject(s)
Glioma , Language , Humans , Comprehension , Magnetic Resonance Imaging , Glioma/diagnostic imaging , Diffusion Magnetic Resonance Imaging , Brain Mapping/methodsABSTRACT
Fibromyalgia (FM) is a syndrome characterized by chronic pain with depression as a frequent comorbidity. However, efficient management of the pain and depressive symptoms of FM is lacking. Given that endogenous oxytocin (OXT) contributes to the regulation of pain and depressive disorders, herein, we investigated the role of OXT in an experimental reserpine-induced FM model. In FM model, OXT-monomeric red fluorescent protein 1 (OXT-mRFP1) transgenic rats exhibited increased depressive behavior and sensitivity in a mechanical nociceptive test, suggesting reduced pain tolerance. Additionally, the development of the FM-like phenotype in OXT-mRFP1 FM model rats was accompanied by a significant reduction in OXT mRNA expression in the magnocellular neurons of the paraventricular nucleus. OXT-mRFP1 FM model rats also had significantly fewer tryptophan hydroxylase (TPH)- and tyrosine hydroxylase (TH)-immunoreactive (ir) neurons as well as reduced serotonin and norepinephrine levels in the dorsal raphe and locus coeruleus. To investigate the effects of stimulating the endogenous OXT pathway, rats expressing OXT-human muscarinic acetylcholine receptor (hM3Dq)-mCherry designer receptors exclusively activated by designer drugs (DREADDs) were also assessed in the FM model. Treatment of these rats with clozapine-N-oxide (CNO), an hM3Dq-activating drug, significantly improved characteristic FM model-induced pathophysiological pain, but did not alter depressive-like behavior. The chemogenetically induced effects were reversed by pre-treatment with an OXT receptor antagonist, confirming the specificity of action via the OXT pathway. These results indicate that endogenous OXT may have analgesic effects in FM, and could be a potential target for effective pain management strategies for this disorder.
Subject(s)
Fibromyalgia , Oxytocin , Rats , Humans , Animals , Oxytocin/pharmacology , Oxytocin/metabolism , Reserpine/pharmacology , Reserpine/metabolism , Fibromyalgia/chemically induced , Fibromyalgia/metabolism , Luminescent Proteins/genetics , Pain/metabolism , Rats, Transgenic , Neurons/metabolism , Receptors, Oxytocin/metabolismABSTRACT
The mechanisms behind reported decreases in plasma insulin and glucagon during hemodialysis (HD) are not clear. Here, we investigated these mechanisms during HD treatment and the characteristics of insulin and glucagon removal when using two super high-flux membranes. In an experimental study, clearance, adsorption rates, and reduction rates of insulin and glucagon were investigated when using cellulose triacetate (CTA) and polysulfone (PS) membranes in a closed circuit using bovine blood. In a clinical study, 20 diabetes patients with end-stage kidney disease who were stable on HD were randomly selected for two HD sessions with two different membranes. At 1 h after the initiation of HD, insulin and glucagon clearance were measured, and the reduction rates were also investigated. In the experimental study, the PS membrane showed significantly higher clearance, adsorption rates, and reduction rates of insulin and glucagon compared with the CTA membrane. Although glucagon was detected in the ultrafiltration fluids in both membranes, insulin was absent in the PS membrane. In the clinical study, both membranes showed significant reductions in plasma insulin and glucagon at each time point. The PS membrane showed significantly higher insulin clearance and reduction rates compared with the CTA membrane. The two membranes showed no significant difference in glucagon clearance, but the glucagon reduction rate was significantly higher with the PS membrane. Our findings show that HD with the two super high-flux membranes used removes significant amounts of glucoregulatory peptide hormones from plasma in patients with diabetes and end-stage kidney disease, potentially affecting their glucose metabolism.
Subject(s)
Diabetes Mellitus , Kidney Failure, Chronic , Humans , Animals , Cattle , Renal Dialysis , Glucagon , Kinetics , Kidney Failure, Chronic/therapy , Insulin , Insulin, Regular, Human , Membranes, ArtificialABSTRACT
Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the white matter degeneration. Although changes in blood lipids are involved in the pathogenesis of neurological diseases, the pathological role of blood lipids in ALS remains unclear. Methods and results: We performed lipidome analysis on the plasma of ALS model mice, mutant superoxide dismutase 1 (SOD1G93A) mice, and found that the concentration of free fatty acids (FFAs), including oleic acid (OA) and linoleic acid (LA), decreased prior to disease onset. An in vitro study revealed that OA and LA directly inhibited glutamate-induced oligodendrocytes cell death via free fatty acid receptor 1 (FFAR1). A cocktail containing OA/LA suppressed oligodendrocyte cell death in the spinal cord of SOD1G93A mice. Discussion: These results suggested that the reduction of FFAs in the plasma is a pathogenic biomarker for ALS in the early stages, and supplying a deficiency in FFAs is a potential therapeutic approach for ALS by preventing oligodendrocyte cell death.
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Objective: This study aimed to establish a method for differentiating between grades II and III astrocytomas using preoperative imaging. Methods: We retrospectively analyzed astrocytic tumors, including 18 grade II astrocytomas (isocitrate dehydrogenase (IDH)-mutant: IDH-wildtype = 8:10) and 56 grade III anaplastic astrocytomas (37:19). We recorded the maximum methionine (MET) uptake ratios (tumor-to-normal: T/N) on positron emission tomography (PET) and three MRS peak ratios: choline (Cho)/creatine (Cr), N-acetyl aspartate (NAA)/Cr, and Cho/NAA, between June 2015 and June 2020. We then evaluated the cut-off values to differentiate between grades II and III. We compared the grading results between contrast enhancement effects on MR and combinational diagnostic methods (CDM) on a scatter chart using the cutoff values of the T/N ratio and MRS parameters. Results: The IDH-mutant group showed significant differences in the Cho/NAA ratio between grades II and III using univariate analysis; however, multiple regression analysis results negated this. The IDH-wildtype group showed no significant differences between the groups. Contrast enhancement effects also showed no significant differences in IDH status. Accordingly, regardless of the IDH status, no statistically independent factors differentiated between grades II and III. However, CDMs showed higher sensitivity and negative predictive value in distinguishing them than MRI contrast examinations for both IDH statuses. We demonstrated a significantly higher diagnostic rate of grade III than of grade II with CDM, which was more striking in the IDH-mutant group than in the wild-type group. Conclusions: CDM could be valuable in differentiating between grade II and III astrocytic tumors.
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Curcumin has long been recognized for its anti-inflammatory properties. An antitumor effect has been recently reported in curcumin and clinical trials are being conducted. However, a large amount of required intake to obtain the antitumor effect of curcumin has been regarded as a problem. Therefore, curcumin analogs have been created by many researchers to enhance the effects of curcumin. We have synthesized >50 curcumin analogs and revealed greater growth suppression of various tumor cells with mono-carbonyl analogs than curcumin. Mechanistically, mono-carbonyl analogs inhibited transcriptional activity (e.g., nuclear factor kappa B, signal transducer, and activator of transcription 3) or activated caspase-3. Additionally, mono-carbonyl analogs of curcumin control tumor cell metabolism. Herein, we summarize the current knowledge about mono-carbonyl curcumin analogs and discuss their potential clinical applications.
Subject(s)
Curcumin , Neoplasms , Humans , Curcumin/pharmacology , Curcumin/therapeutic use , Neoplasms/drug therapy , Anti-Inflammatory Agents/pharmacology , NF-kappa B/metabolism , Cell Line, TumorABSTRACT
Orexin-A and -B (identical to hypocretin-1 and -2) are neuropeptides synthesized in the lateral hypothalamus and perifornical area, and orexin neurons project their axon terminals broadly throughout the entire central nervous system (CNS). The activity of orexins is mediated by two specific G protein-coupled receptors (GPCRs), termed orexin type1 receptor (OX1R) and orexin type2 receptor (OX2R). The orexin system plays a relevant role in various physiological functions, including arousal, feeding, reward, and thermogenesis, and is key to human health. Orexin neurons receive various signals related to environmental, physiological, and emotional stimuli. Previous studies have reported that several neurotransmitters and neuromodulators influence the activation or inhibition of orexin neuron activity. In this review, we summarize the modulating factors of orexin neurons in the sleep/wake rhythm and feeding behavior, particularly in the context of the modulation of appetite, body fluids, and circadian signaling. We also describe the effects of life activity, behavior, and diet on the orexin system. Some studies have observed phenomena that have been verified in animal experiments, revealing the detailed mechanism and neural pathway, while their applications to humans is expected in future research.
Subject(s)
Orexin Receptors , Orexins , Animals , Humans , Neuropeptides/metabolism , Neurotransmitter Agents/pharmacology , Orexin Receptors/genetics , Orexin Receptors/metabolism , Orexins/metabolism , Receptors, G-Protein-Coupled/metabolism , Sleep/physiologyABSTRACT
Pyrolyzed deketene curcumin GO-Y022 prevents carcinogenesis in a gastric cancer mouse model. However, it is still less clear if GO-Y022 affects tumor-induced immune suppression. In this study, we found that GO-Y022 inhibited Treg generation in the presence of transforming growth factor beta 1 (TGF-ß). However, GO-Y022 showed less impact on Foxp3+ Tregs in the gastric tumor microenvironment. Gastric tumor cells produce a large amount of L-lactate in the presence of GO-Y022 and diminish the inhibitory role of GO-Y022 against Treg generation in response to TGF-ß. Therefore, naïve CD4+ T cells co-cultured with GO-Y022 treated gastric tumor cells increased Treg generation. GO-Y022-induced tumor cell death was further enhanced by 2-deoxy-d-glucose (2DG), a glycolysis inhibitor. Combination treatment of GO-Y022 and 2DG results in reduced L-lactate production and Treg generation in gastric tumor cells. Overall, GO-Y022-treatment with restricted glucose metabolism inhibits gastric tumor cell survival and promotes anti-tumor immunity.
Subject(s)
Curcumin , Stomach Neoplasms , Animals , Mice , T-Lymphocytes, Regulatory , Glucose/metabolism , Deoxyglucose/metabolism , Tumor MicroenvironmentABSTRACT
OBJECTIVE: An autologous formalin-fixed tumor vaccine (AFTV) derived from resected glioblastoma (GBM) tissue can be used against unidentified tumor antigens. Thus, the authors conducted a multicenter double-blind phase IIb trial to investigate the efficacy of an AFTV. METHODS: Eligible patients were adults with supratentorial GBMs, 16-75 years of age, with Karnofsky Performance Scale (KPS) scores ≥ 60%, and no long-term steroid administration. An AFTV comprising fixed paraffin-embedded tumor tissue with immune adjuvants or an identical placebo without fixed tumor tissue was injected intradermally over three courses before and after chemoradiotherapy. The primary and secondary end points were overall survival (OS), progression-free survival (PFS), and 3-year survival rate. RESULTS: Sixty-three patients were enrolled. The average patient age was 61 years. The median KPS score was 80%, and the median resection rate was 95%. The full analysis set of 57 patients indicated no significant difference in OS (p = 0.64) for the AFTV group (median OS 25.6 months, 3-year OS rate 38%) compared with the placebo group (31.5 months and 41%, respectively) and no difference in PFS (median PFS 13.3 months in both groups, p = 0.98). For patients with imaging-based total tumor removal, the 3-year PFS rate was 81% in the AFTV group versus 46% in the placebo group (p = 0.067), whereas the 3-year OS rate was 80% versus 54% (p = 0.16), respectively. Similar results were obtained in the p53-negative subgroups. Severe adverse effects were not observed. CONCLUSIONS: The AFTV may have potential effects in certain patient subgroups. A phase III study for patients with total tumor removal remains warranted to confirm these findings. Clinical trial registration no.: UMIN000010602 (UMIN Clinical Trials Registry).