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Regulatory T cells (Tregs) in the tumor microenvironment regulate tumor immunity. Programmed cell death protein 1 (PD‐1) is known to be expressed on Tregs and plays crucial roles in suppressing tumor immunity. However, the immune checkpoint inhibitor, anti‐PD‐1 antibody, is known to promote the proliferation of the Treg population in tumor‐infiltrating lymphocytes, thereby restricting the efficacy of cancer immunotherapy. In this study, we focused on the curcumin analog GO‐Y030, an antitumor chemical. GO‐Y030 inhibited the immune‐suppressive ability of Tregs via metabolic changes in vitro, even in the presence of immune checkpoint inhibitors. Mechanistically, GO‐Y030 inhibited the mTOR‐S6 axis in Tregs, which plays a pivotal role in their immune‐suppressive ability. GO‐Y030 also controlled the metabolism in cultured CD4+ T cells in the presence of TGF‐β + IL‐6; however, it did not prevent Th17 differentiation. Notably, GO‐Y030 significantly inhibited IL‐10 production from Th17 cells. In the tumor microenvironment, L‐lactate produced by tumors is known to support the suppressive ability of Tregs, and GO‐Y030 treatment inhibited L‐lactate production via metabolic changes. In addition, experiments in the B16‐F10 melanoma mouse model revealed that GO‐Y030 helped inhibit the anti‐PD‐1 immune checkpoint and reduce the Treg population in tumor‐infiltrating lymphocytes. Thus, GO‐Y030 controls the metabolism of both Tregs and tumors and could serve as a booster for anti‐immune checkpoint inhibitors. Curcumin analog GO‐Y030 boosts cancer immunotherapy via metabolic changes.

Altered function of mitochondrial respiratory chain in brain cells is related to many neurodegenerative diseases. NADH Dehydrogenase (Ubiquinone) Fe-S protein 4 (Ndufs4) is one of the subunits of mitochondrial complex I and its mutation in human is associated with Leigh syndrome. However, the molecular biological role of Ndufs4 in neuronal function is poorly understood. In this study, upon Ndufs4 expression confirmation in NeuN-positive neurons, and GFAP-positive astrocytes in WT mouse hippocampus, we found significant decrease of mitochondrial respiration in Ndufs4-KO mouse hippocampus. Although there was no change in the number of NeuN positive neurons in Ndufs4-KO hippocampus, the expression of synaptophysin, a presynaptic protein, was significantly decreased. To investigate the detailed mechanism, we silenced Ndufs4 in Neuro-2a cells and we observed shorter neurite lengths with decreased expression of synaptophysin. Furthermore, western blot analysis for phosphorylated extracellular regulated kinase (pERK) revealed that Ndufs4 silencing decreases the activity of ERK signalling. These results suggest that Ndufs4-modulated mitochondrial activity may be involved in neuroplasticity via regulating synaptophysin expression.

Engaging in social activities, interacting with peers, and participating in community events may promote health and well-being. Recently, interventions leveraging information and communications technology have emerged as potent tools for promoting social connections and well-being. Particularly, messenger apps have become an integral part of our daily lives, facilitating communication, information dissemination, and social interaction. However, there remains a gap in the literature regarding the utilization of widely adopted messenger apps for this purpose. This study aimed to evaluate the impact of messenger app-based information provision aimed at promoting social participation on the enhancement of subjective well-being among Japanese community-dwelling adults. A 2-arm, parallel-group randomized controlled trial was conducted from October 2022 to January 2023 in the Kashiwa-no-ha campus area, Japan-an urban community with active local events. A total of 358 community-dwelling adults who use messenger apps daily were recruited for the study. Of these, 235 (65.6%) participants completed the follow-up survey. Participants were randomly assigned to either the intervention group, receiving the health benefits of social participation and information about local events or spots via a messenger app, or the control group, receiving general health information. The primary outcome was subjective happiness after the intervention, measured on an 11-point scale ranging from 0 (Unhappy) to 10 (Happy). Secondary outcomes included life satisfaction, meaning of life, purpose in life, and participation in local events. The outcomes were analyzed with t tests (2-tailed) and multivariable regression based on the intention-to-treat method. After the intervention, the intervention group reported a mean happiness score of 7.7 (SD 1.7), while the control group reported a score of 7.5 (SD 2.0), with no statistically significant difference (P=.40). Multivariable linear regression analysis adjusted for baseline outcome values and covariates showed that the coefficient of the intervention for life satisfaction was 0.30 (95% CI -0.07 to 0.68; P=.12), while that for meaning of life was 0.33 (95% CI -0.03 to 0.70; P=.07). There was no significant difference in event participation rates between the 2 groups during the study period (P=.22). However, 82.2% (102/124) of the intervention group acknowledged the utility of the event information provided. Messenger app-based information provision did not yield a significant increase in subjective happiness, while there was a positive but not significant trend in life satisfaction. The findings underscore the need for more intensive intervention in future studies to harness the potential of digital interventions. UMIN Clinical Trials Registry UMIN000049047; https://tinyurl.com/2zzrrae8.

Background Tenapanor is a novel selective inhibitor of intestinal sodium/hydrogen exchanger 3 transporter. This is the first trial to assess the efficacy and safety of tenapanor in Japanese patients with hyperphosphatemia who are undergoing peritoneal dialysis. Methods This phase 3, open-label, multicenter, single-arm clinical trial targeted patients whose serum phosphorus was within 3.5–7.0 mg/dL with phosphate binders at screening. After phosphate binder washout, tenapanor was orally administered twice-daily, stepwise from 5 to 30 mg/dose for 16 weeks. The primary endpoint, mean change in serum phosphorus level, was evaluated at week 8. The 16-week treatment period was completed with tenapanor alone, and only one phosphate binder type was allowed for combined use after the primary endpoint. Results Of the 54 patients enrolled, 34 completed the study. At week 8, the primary endpoint, mean change in serum phosphorus level (last observation carried forward), was − 1.18 mg/dL (95% confidence interval: − 1.54, − 0.81 mg/dL) with tenapanor. From a baseline value of 7.65 mg/dL, serum phosphorus decreased to 6.14 and 5.44 mg/dL at weeks 8 and 16, respectively, and 46.3% and 76.5% of patients achieved serum phosphorus within 3.5–6.0 mg/dL at week 8 and week 16, respectively. The most common adverse event, diarrhea, occurred in 74.1% of patients; the severity of diarrhea was mild or moderate. Thus, the discontinuation percentage due to diarrhea was low at 5.6%. Conclusions Administration of tenapanor resulted in a sufficient reduction in serum phosphorus level at week 8 and was considered safe and tolerable. Trial registration NCT04766385.

PurposeFatty acid-binding protein 7 (FABP7) involved in intracellular lipid dynamics, is highly expressed in melanomas and associated with decreased patient survival. Several studies put FABP7 at the center of melanoma cell proliferation. However, the underlying mechanisms are not well deciphered. This study examines the effects of FABP7 on Wnt/β-catenin signaling that enhances proliferation in melanoma cells.MethodsSkmel23 cells with FABP7 silencing and Mel2 cells overexpressed with wild-type FABP7 (FABP7wt) and mutated FABP7 (FABP7mut) were used. Cell proliferation and migration were analyzed by proliferation and wound-healing assay, respectively. Transcriptional activation of the Wnt/β-catenin signaling was measured by luciferase reporter assay. The effects of a specific FABP7 inhibitor, MF6, on proliferation, migration, and modulation of the Wnt/β-catenin signaling were examined.ResultsFABP7 siRNA knockdown in Skmel23 decreased proliferation and migration, cyclin D1 expression, as well as Wnt/β-catenin activity. Similarly, FABP7wt overexpression in Mel2 cells increased these effects, but FABP7mut abrogated these effects. Pharmacological inhibition of FABP7 function with MF6 suppressed FABP7-regulated proliferation of melanoma cells.ConclusionThese results suggest the importance of the interaction between FABP7 and its ligands in melanoma proliferation modulation, and the beneficial implications of therapeutic targeting of FABP7 for melanoma treatment.

INTRODUCTION: Obstructive fibrinous tracheal pseudomembrane, an extremely rare but potentially fatal complication of tracheal intubation, occurs several days after intubation and is characterized by central airway obstruction due to the formation of a fibrinous pseudomembrane. Early diagnosis is crucial. Treatment typically involves bronchoscopic removal of the pseudomembrane. Herein, we describe a patient whose pseudomembrane was successfully cored out using fiberoptic intubation after achieving preoxygenation with high-flow nasal cannula oxygen therapy.CASE PRESENTATION: An 83-year-old woman (height 146 cm, weight 38 kg) underwent left lower lobe lobectomy with left atrial resection for squamous cell carcinoma (cT4N1M0, Stage IIIA). The surgery was completed successfully with no immediate complications. On POD 3, she developed prolonged expiration and inspiratory wheezing that was unresponsive to steroid inhalation. Her condition progressively worsened with stridor, labored breathing, and inability to lie supine. Bronchoscopy revealed 90% circumferential subglottic stenosis. High-flow nasal cannula oxygen therapy significantly improved her respiratory distress, enabling her to lie supine. Fiberoptic intubation was then performed under conscious sedation with spontaneous breathing, and the circumferential membranous structure was cored out by the intubation tube. Pathological examination confirmed fibrinous exudate with atypical cells, establishing a diagnosis of obstructive fibrinous tracheal pseudomembrane.CONCLUSIONS: Obstructive fibrinous tracheal pseudomembrane, a rare condition, causes upper airway obstruction within days after extubation. Preoxygenation with high-flow nasal cannula oxygen therapy, followed by coring the pseudomembrane out with an intubation tube, may be an effective, rapid, and minimally invasive means of treatment in selected patients with a subglottic, obstructive, fibrinous tracheal pseudomembrane.

Dietary obesity is regarded as a problem worldwide, and it has been revealed the strong linkage between obesity and allergic inflammation. Fatty acid-binding protein 5 (FABP5) is expressed in lung cells, such as alveolar epithelial cells (ECs) and alveolar macrophages, and plays an important role in infectious lung inflammation. However, we do not know precise mechanisms on how lipid metabolic change in the lung affects allergic lung inflammation. In this study, we showed that Fabp5 −/− mice exhibited a severe symptom of allergic lung inflammation. We sought to examine the role of FABP5 in the allergic lung inflammation and demonstrated that the expression of FABP5 acts as a novel positive regulator of ST2 expression in alveolar ECs to generate retinoic acid (RA) and supports the synthesis of RA from type II alveolar ECs to suppress excessive activation of innate lymphoid cell (ILC) 2 during allergic lung inflammation. Furthermore, high-fat diet (HFD)-fed mice exhibit the downregulation of FABP5 and ST2 expression in the lung tissue compared with normal diet (ND)-fed mice. These phenomena might be the reason why obese people are more susceptible to allergic lung inflammation. Thus, FABP5 is potentially a therapeutic target for treating ILC2-mediated allergic lung inflammation.

PurposeAblation index (AI) is a useful tool of the CARTO® system to make effective lesions during pulmonary vein isolation (PVI) for atrial fibrillation (AF). However, the optimal distance between neighboring ablation points (interlesion distance (ILD)) is still unclear. Here, we evaluated the optimal ILDs in the AI-guided PVI.MethodsForty-nine AF patients who underwent AI-guided PVI in our institute from July 2018 to March 2019 were retrospectively enrolled in this study. Target AI was set at 500 and 400 for anterior and posterior walls, respectively, and we compared the ILDs with and without electrical gaps after a first encircling PVI.ResultsIn both PV, the ILDs with electrical gaps were longer than those without electrical gaps. The best cutoff values of ILD to detect the electrical gaps using the ROC curve were 5.4 mm for the RPV anterior wall (AUC, 0.67; sensitivity, 0.42; specificity, 0.84, P < 0.01) and 4.4 mm for the RPV posterior wall (AUC, 0.68; sensitivity, 0.91; specificity, 0.39, P < 0.01). Similarly, the best cutoff values of ILD were 5.5 mm for the LPV anterior wall (AUC, 0.74; sensitivity, 0.65; specificity, 0.82, P < 0.01) and 5.1 mm for the LPV posterior wall (AUC, 0.67; sensitivity, 0.79; specificity, 0.53, P =0.03).ConclusionThe optimal interlesion distances for PVI were different in each PV segment. To achieve the first-pass isolation, less than 5.4/4.4 mm for the RPV anterior/posterior and 5.5/5.1 mm for the LPV anterior/posterior walls of interlesion distances were the best cutoff values in the patients with AF.

Novel proanthocyanidin fractions from grape stem extracts were purified using Amberlite XAD-1180N, Sephadex-LH-20, Toyopearl HW40F and reverse phase high-performance liquid chromatography. Two key compounds were estimated as epigallocatechin-(epicatechin) 7 gallate using electron-spray ionization time-of-flight mass spectrometry. Epigallocatechin-(epicatechin) 7 gallate (compound 1 ) showed significant anti-cancer activity in PC-3 prostate cancer cells. In particular, compound 1 suppressed the gene expression of fatty acid-binding protein 5 ( FABP5 ), which is involved in promoting cell proliferation and metastasis in prostate cancer cells.

Hepatic macrophages respond to various microenvironmental signals and play a central role in maintaining hepatic homeostasis, dysregulation of which leads to various liver diseases. Fatty acid‐binding protein 7 (FABP7), an intracellular lipid chaperone for polyunsaturated fatty acids (PUFAs), is highly expressed in liver macrophages. However, the mechanisms by which FABP7 regulates hepatic macrophage activation remain unclear. Therefore, we aimed to elucidate the mechanisms underlying the effects of FABP7 on the functions of hepatic macrophages in metabolic dysfunction‐associated steatohepatitis (MASH) and liver fibrosis models. In this study, we found that FABP7‐deficient macrophages exhibited impaired M2 polarization, which reduced the fibrotic response of myofibroblasts and CD4 + T‐cell infiltration into the liver tissues in a carbon tetrachloride (CCl 4 )‐induced hepatic fibrosis model. In vitro, FABP7‐deficient macrophages exhibited decreased levels of peroxisome proliferator‐activated receptor (PPAR)‐ γ and its target genes, including C–C motif chemokine ligand (CCL)‐17 and transforming growth factor‐ β (TGF‐ β ), compared to the wild‐type (WT) macrophages post‐interleukin (IL)‐4 stimulation. However, these effects were inhibited by a PPAR γ inhibitor. IL‐4‐stimulated WT macrophages also promoted CD4 + T‐cell migration and hepatic fibroblast (TWNT‐1 hepatic stellate cell [HSC]) activation, indicated by increased mRNA levels of actin alpha 2, smooth muscle ( ACTA2 ), and collagen type I alpha 1 ( COL1A1 ); however, these effects were inhibited in FABP7‐deficient macrophages. Overall, FABP7 in hepatic macrophages modulated the crosstalk between hepatic fibroblasts and T cells by regulating M2 polarization. Therefore, regulation of hepatic macrophage function by FABP7 is a potential therapeutic target for liver fibrosis.