NK cell transfer overcomes resistance to PD-(L)1 therapy in aged mice.

BACKGROUND: Cancer is the leading cause of death among older adults. Although the integration of immunotherapy has revolutionized the therapeutic landscape of cancer, the complex interactions between age and immunotherapy efficacy remain incompletely defined. Here, we aimed to elucidate the relationship between aging and immunotherapy resistance. METHODS: Flow cytometry was performed to evaluate the infiltration of immune cells in the tumor microenvironment (TME). In vivo T cell proliferation, cytotoxicity and migration assays were performed to evaluate the antitumor capacity of tumor antigen-specific CD8+ T cells in mice. Real-time quantitative PCR (qPCR) was used to investigate the expression of IFN-γ-associated gene and natural killer (NK)-associated chemokine. Adoptive NK cell transfer was adopted to evaluate the effects of NK cells from young mice in overcoming the immunotherapy resistance of aged mice. RESULTS: We found that elderly patients with advanced non-small cell lung cancer (aNSCLC) aged ≥ 75 years exhibited poorer progression-free survival (PFS), overall survival (OS) and a lower clinical response rate after immunotherapy. Mechanistically, we showed that the infiltration of NK cells was significantly reduced in aged mice compared to younger mice. Furthermore, the aged NK cells could also suppress the activation of tumor antigen-specific CD8+ T cells by inhibiting the recruitment and activation of CD103+ dendritic cells (DCs). Adoptive transfer of NK cells from young mice to aged mice promoted TME remodeling, and reversed immunotherapy resistance. CONCLUSION: Our findings revealed the decreased sensitivity of elderly patients to immunotherapy, as well as in aged mice. This may be attributed to the reduction of NK cells in aged mice, which inhibits CD103+ DCs recruitment and its CD86 expression and ultimately leads to immunotherapy resistance.

Identification of hypoxic macrophages in glioblastoma with therapeutic potential for vasculature normalization.

Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients with isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize a Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic niche cues to acquire a hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions by activating adrenomedullin paracrine signaling, thereby stimulating a hyperpermeable neovasculature that hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation or pharmacological blockade of adrenomedullin produced by Hypoxia-TAM restores vascular integrity, improves intratumoral concentration of the anti-tumor agent dabrafenib, and achieves combinatorial therapeutic benefits. Increased proportion of Hypoxia-TAM or adrenomedullin expression is predictive of tumor vessel hyperpermeability and a worse prognosis of glioblastoma. Our findings highlight Mo-TAM diversity and spatial niche-steered Mo-TAM reprogramming in diffuse gliomas and indicate potential therapeutics targeting Hypoxia-TAM to normalize tumor vasculature.

Cardiac magnetic resonance-derived mitral annular plane systolic excursion: a robust indicator for risk stratification after myocardial infarction.

To explore the predictive value of mitral annular plane systolic excursion (MAPSE) derived by cardiac magnetic resonance (CMR) for major adverse cardiovascular events (MACE) in postmyocardial infarction (MI) patients. Patients with MI who underwent 3.0 T CMR (Chinese Clinical Trial Registry, ChiCTR2200055158) were recruited retrospectively. CMR parameters included MAPSE and LVEF. Patients were followed up for MACE for more than 6 months and were separated into a No-MACE group and a MACE group. A total of 165 post-MI patients were included, and 103 patients were finally analyzed (61 patients belonged to the No-MACE group, and 42 patients belonged to the MACE group). The LVEF and MAPSE of the patients belonging to the No-MACE group were considerably higher than those of the patients belonging to the MACE group. Both LVEF and MAPSE were effective indicators of the occurrence of MACE after MI. The risk of MACE decreased as LVEF and MAPSE increased. For the risk prediction of MACE after MI, compared with model I (chi-square value 4.0 vs. 31.4, P < 0.001) and model II (chi-square value 22.7 vs. 31.4, P = 0.003), model III had a significant incremental predictive value. Moreover, the cutoff value of MAPSE was 9.70 mm. CMR-derived MAPSE is an effective predictor of MACE occurrence in patients with MI, and MAPSE provided a significant incremental predictive value. Moreover, MAPSE could complement LVEF for superior risk stratification of MI patients.

NAD+ supplementation prevents STING-induced senescence in CD8+ T cells by improving mitochondrial homeostasis.

Understanding the connection between senescence phenotypes and mitochondrial dysfunction is crucial in aging and premature aging diseases. Loss of mitochondrial function leads to a decline in T cell function, which plays a significant role in this process. However, more research is required to determine if improving mitochondrial homeostasis alleviates senescence phenotypes. Our research has shown an association between NAD+ and senescent T cells through the cGAS-STING pathway, which can lead to an inflammatory phenotype. Further research is needed to fully understand the role of NAD+ in T-cell aging and how it can be utilized to improve mitochondrial homeostasis and alleviate senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence-associated secretory phenotype (SASP) occur in senescent T cells and tumor-bearing mice. Senescence is mediated by a stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD+ levels with nicotinamide mononucleotide (NMN) prevents senescence and SASP by promoting mitophagy. NMN treatment also suppresses senescence and neuroinflammation and improves the survival cycle of mice. Encouraging mitophagy may be a useful strategy to prevent CD8+ T cells from senescence due to mitochondrial dysfunction. Additionally, supplementing with NMN to increase NAD+ levels could enhance survival rates in mice while also reducing senescence and inflammation, and enhancing mitophagy as a potential therapeutic intervention.

Coronary artery fistula with or without aneurysm: A large comparative study.

Background: The knowledge of coronary artery fistula (CAF) with coronary aneurysm mostly comes from case reports and is very limited. However, the management of CAF with and without aneurysm is different, more understanding of its clinical and imaging features is necessary. This is the first research focus on it through a large comparative study. Purpose: To investigate the differences in imaging and clinical features of CAF with and without aneurysms. Methods: We reviewed 96,037 consecutive patients undergoing coronary computed tomography angiogram (CCTA) between 2016 and 2020 and total of 429 CAF adult patients were enrolled. Those patients were divided into the CAF with aneurysm group (321 cases, 74.83%) and CAF without aneurysm group (108 cases, 25.17%) according to whether complicated with coronary aneurysm. Clinical baseline data, electrocardiographic (ECG) characteristics, the presence or absence of coronary atherosclerosis, complication symptoms and fistulous origin, entry site, number and diameter were analyzed. Chi-square test, T-test, Mann-Whitney U tests, and logistic regression analysis were performed. Results: Most of the clinical baseline data did not differ significantly between the two groups (P > 0.05). However, heart murmur, coronary atherosclerosis, infective endocarditis (IE), fistulous diameter and fistulous entry site were significantly different (P＜0.05). Further multivariate logistic regression analysis showed that large fistulous diameter and coronary-cardiac chamber arterial fistulas was dependent risk factors for CAF complicated with aneurysm. Conclusion: CAF patients with aneurysm were more prone to develop heart murmur than those patients without aneurysm. Different from other sites of aneurysms, coronary atherosclerosis is more common in CAF without aneurysm. Larger fistulous diameter and coronary-cardiac chamber arterial fistula are dependent risk factors for CAF with aneurysms.

Metabolic rewiring and epigenetic reprogramming in leptin receptor-deficient db/db diabetic nephropathy mice.

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the United States. Emerging evidence suggests that mitochondrial metabolism and epigenetics play an important role in the development and progression of DN and its complications. For the first time, we investigated the regulation of cellular metabolism, DNA methylation, and transcriptome status by high glucose (HG) in the kidney of leptin receptor-deficient db/db mice using multi-omics approaches. METHODS: The metabolomics was performed by liquid-chromatography-mass spectrometry (LC-MS), while epigenomic CpG methylation coupled with transcriptomic gene expression was analyzed by next-generation sequencing. RESULTS: LC-MS analysis of glomerular and cortex tissue samples of db/db mice showed that HG regulated several cellular metabolites and metabolism-related signaling pathways, including S-adenosylmethionine, S-adenosylhomocysteine, methionine, glutamine, and glutamate. Gene expression study by RNA-seq analysis suggests transforming growth factor beta 1 (TGFß1) and pro-inflammatory pathways play important roles in early DN. Epigenomic CpG methyl-seq showed HG revoked a list of differentially methylated regions in the promoter region of the genes. Integrated analysis of DNA methylation in the promoter regions of genes and gene expression changes across time points identified several genes persistently altered in DNA methylation and gene expression. Cyp2d22, Slc1a4, and Ddah1 are some identified genes that could reflect dysregulated genes involved in renal function and DN. CONCLUSION: Our results suggest that leptin receptor deficiency leading to HG regulates metabolic rewiring, including SAM potentially driving DNA methylation and transcriptomic signaling that could be involved in the progression of DN.

Metabolomic, DNA Methylomic, and Transcriptomic Profiling of Suberoylanilide Hydroxamic Acid Effects on LPS-Exposed Lung Epithelial Cells.

Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase (HDAC) inhibitor with anticancer effects via epigenetic and non-epigenetic mechanisms. The role of SAHA in metabolic rewiring and epigenomic reprogramming to inhibit pro-tumorigenic cascades in lung cancer remains unknown. In this study, we aimed to investigate the regulation of mitochondrial metabolism, DNA methylome reprogramming, and transcriptomic gene expression by SAHA in lipopolysaccharide (LPS)-induced inflammatory model of lung epithelial BEAS-2B cells. LC/MS was used for metabolomic analysis, while next-generation sequencing was done to study epigenetic changes. The metabolomic study reveals that SAHA treatment significantly regulated methionine, glutathione, and nicotinamide metabolism with alteration of the metabolite levels of methionine, S-adenosylmethionine, S-adenosylhomocysteine, glutathione, nicotinamide, 1-methylnicotinamide, and nicotinamide adenine dinucleotide in BEAS-2B cells. Epigenomic CpG methyl-seq shows SAHA revoked a list of differentially methylated regions in the promoter region of the genes, such as HDAC11, miR4509-1, and miR3191. Transcriptomic RNA sequencing (RNA-seq) reveals SAHA abrogated LPS-induced differentially expressed genes encoding proinflammatory cytokines, including interleukin 1α (IL1α), IL1ß, IL2, IL6, IL24, and IL32. Integrative analysis of DNA methylome-RNA transcriptome displays a list of genes, of which CpG methylation correlated with changes in gene expression. qPCR validation of transcriptomic RNA-seq data shows that SAHA treatment significantly reduced the LPS-induced mRNA levels of IL1ß, IL6, DNA methyltransferase 1 (DNMT1), and DNMT3A in BEAS-2B cells. Altogether, SAHA treatment alters the mitochondrial metabolism, epigenetic CpG methylation, and transcriptomic gene expression to inhibit LPS-induced inflammatory responses in lung epithelial cells, which may provide novel molecular targets to inhibit the inflammation component of lung carcinogenesis. PREVENTION RELEVANCE: Inflammation increases the risk of lung cancer and blocking inflammation could reduce the incidence of lung cancer. Herein, we demonstrate that histone deacetylase inhibitor suberoylanilide hydroxamic acid regulates metabolic rewiring and epigenetic reprogramming to attenuate lipopolysaccharide-driven inflammation in lung epithelial cells.

Can left ventricular entropy by cardiac magnetic resonance late gadolinium enhancement be a prognostic predictor in patients with left ventricular non-compaction?

PURPOSE: Left ventricular non-compaction (LVNC) is considered rare; however, the use of cardiac magnetic resonance (CMR) has shown that its incidence is not uncommon, and its clinical presentation remains variable, with an uncertain prognosis. Risk stratification of major adverse cardiac events (MACE) in patients with LVNC remains complex. Therefore, this study aims to determine whether tissue heterogeneity from late gadolinium enhancement-derived entropy is associated with MACE in patients with LVNC. METHODS: This study was registered in the Clinical Trial Registry (CTR2200062045). Consecutive patients who underwent CMR imaging and were diagnosed with LVNC were followed up for MACE, which was defined by heart failure, arrhythmias, systemic embolism, and cardiac death. The patients were divided into MACE and non-MACE groups. The CMR parameters included left ventricular (LV) entropy, LV ejection fraction (LVEF), LV end-diastolic volume, LV end-systolic volume (LVESV), and LV mass (LVM). RESULTS: Eighty-six patients (age: 45.48 ± 16.64 years; female: 62.7%; LVEF: 42.58 ± 17.20%) were followed up for a median of 18 months and experienced 30 MACE events (34.9%). The MACE group showed higher LV entropy, LVESV, and LVM and lower LVEF than the non-MACE group. LV entropy [hazard ratio (HR): 1.710, 95% confidence interval (CI): 1.078-2.714, P = 0.023] and LVEF (HR: 0.961, 95% CI: 0.936-0.988, P = 0.004) were independent predictors of MACE (P <0.050) according to the Cox regression analysis. Receiver operating characteristic curve analysis revealed that the area under the curve of LV entropy was 0.789 (95% CI: 0.687-0.869, P < 0.001), LVEF was 0.804 (95% CI: 0.699-0.878, P < 0.001), and the combined model of LV entropy and LVEF was 0.845 (95% CI: 0.751-0.914, P < 0.050). CONCLUSION: LGE-derived LV entropy and LVEF are independent risk indicators of MACE in patients with LVNC. The combination of the two factors was more conducive to improving the prediction of MACE.

Pharmacokinetics and Pharmacodynamics of Anthocyanins after Administration of Tart Cherry Juice to Individuals with Gout.

SCOPE: Tart cherries (TCs) contain high levels of anthocyanins that exert potent antioxidant and antiinflammatory effects and potentially benefit individuals with gout. METHODS AND RESULTS: This study aims to quantitate the major anthocyanins in TC Juice Concentrate (TCJC) and identify the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of the major anthocyanin cyanidin-3-glucosylrutinoside (C3GR). A PK-PD study enrolling human subjects with a history of gout is performed. Subjects are randomized to receive either 60 or 120 mL of TCJC. Anthocyanins are quantitated using liquid chromatography-mass spectroscopy (LCMS). Antioxidant and antiinflammatory mRNA expression is measured using real-time qPCR before and after the administration of TCJC. A population PK model (popPK) is fit to the experimental data, and an indirect PD model (IDR) is constructed in Monolix. CONCLUSION: Of the bioavailable anthocyanins, C3GR achieves the highest plasma concentration in a dose-dependent manner. A popPK predicts anthocyanin exposure, and an IDR produces reasonable approximations of PD effects.

CD200+ cytotoxic T lymphocytes in the tumor microenvironment are crucial for efficacious anti-PD-1/PD-L1 therapy.

Anti-PD-1/PD-L1 therapy, either by anti-PD-1 antibody or anti-PD-L1 antibody, has efficacy by reinvigorating tumor-infiltrating CD8+ T cells in a subset of patients with cancer, but it has unequal effects on heterogeneous CD8+ T cell populations. Hence, the subset crucial to efficacious PD-1 blockade therapy remains elusive. Here, we found an increase in tumor-infiltrating CD200+ cytotoxic T lymphocytes (CTLs) upon PD-1/PD-L1 blockade, with higher proportions of CD200+ T cells positively related to a favorable clinical outcome to anti-PD-1/PD-L1 therapy in three independent cohorts of patients with cancer. Using multiple mouse tumor models, we demonstrated that CD200+ CTLs are essential for efficacious anti-PD-L1 therapy. Mechanistically, we observed a unique chromatin landscape in CD200+ CTLs and found that these cells are enriched for tumor antigen-specific CTLs and have antitumor effector functions. Coinoculation of CD200+ CTLs with tumor cells led to robust tumor regression in two transplanted mouse models. Clinically, we found that infiltration of CD200+ CTLs into tumors could predict immunotherapy efficacy in six patient cohorts. Together, our findings reveal that CD200+ CTLs in the tumor microenvironment are crucial for efficacious anti-PD-1/PD-L1 therapy and could serve as a predictor of successful immunotherapy in the clinic.

Entropy of left ventricular late gadolinium enhancement and its prognostic value in hypertrophic cardiomyopathy a new CMR assessment method.

PURPOSE: As a novel metric, entropy generated from late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) can be utilized to assess tissue heterogeneity. However, it is unknown if it can be utilized for risk stratification in hypertrophic cardiomyopathy (HCM). In addition, it is unknown if LGE entropy correlates with LGE mass%, which is commonly utilized for fibrosis assessment. This research was done to investigate these issues. MATERIALS AND METHODS: Patients with HCM who underwent 3.0-T CMR between January 2015 and January 2020 were prospectively enrolled and classified into low- and high-risk groups according to the AHA/ACC risk stratification guideline for 2020. The LGE entropy was automatically estimated using a generic Python package algorithm. On CMR imaging, the LGE mass% was determined using the CVI 42 software. Endpoint events included sudden cardiac death (SCD), hospital readmission owing to heart failure, and implantable cardioverter defibrillator (ICD) treatment for ventricular arrhythmias. RESULTS: A total of 109 HCM participants (70 males) were included. During the follow-up (23 ± 7 months), the patients in the high-risk group had higher LGE entropy (p < 0.001) and LGE mass% (p < 0.001) than those in the low-risk group, and patients with endpoint events had higher LGE entropy (p < 0.001) and LGE mass% (p < 0.001) than those without endpoint events. In all participants, there was a link between LGE entropy and LGE mass%, according to the Spearman rank correlation analysis (p < 0.001; r = 0.667). In ROC analysis, the area under the curve (AUC) of LGE entropy was 0.893 (95% CI, 0.794-0.993; P<0.001), AUC of LGE mass% was 0.826 (95% CI, 0.737-0.914; P<0.001), AUC of LVEF was 0.610 (95% CI, 0.473-0.748; P = 0.117) and AUC of 2020 AHA/ACC guideline for risk stratification was 0.716 (95% CI, 0.617-0.815; P = 0.002). According to Kaplan-Meier curves, HCM with a higher LGE entropy (≥cutoff value (<5.873) or ≥ thied tertile (5.540)) were more likely to experience the endpoint events. Following adjustment for the 2020 AHA/ACC guideline for risk categorization, LGE mass%, or decreased LVEF, Cox analysis showed that LGE entropy was independently linked with endpoint events. CONCLUSIONS: The variability and extent of LGE pictures can be reflected by LGE entropy, which is a reliable, usable, and repeatable metric for risk classification in HCM. It is a prognostic indicator of endpoint events that is independent of other risk indicators.

Prognostic Value of Cardiac-MRI Scar Heterogeneity Combined With Left Ventricular Strain in Patients With Myocardial Infarction.

BACKGROUND: Sudden cardiac death (SCD) after myocardial infarction (MI) is mostly caused by ventricular arrhythmias. As an arrhythmogenic substrate, infarct border zone (BZ) results in adverse electrophysiological properties. PURPOSE: To explore myocardial scar entropy (BZ, infarct core [IC], BZ + IC, expressed as IBZ) and to investigate their prognostic value combined with left ventricular (LV) strain parameters (global radial strain [GRS], global circumferential strain [GCS], global longitudinal strain [GLS]) in patients after MI. STUDY TYPE: Prospective. POPULATION: One hundred fifty-seven patients with previous MI, 26 in primary endpoint events group, 30 in secondary endpoint events group, and 43 in total endpoint events (primary + secondary). FIELD STRENGTH/SEQUENCE: 3.0 T/cine, late gadolinium enhancement (LGE). ASSESSMENT: Three-dimensional feature tracking analysis for three directions (radial, circumferential, and longitudinal), entropy and extent of infarct-related areas (BZ, IC, and IBZ), LV functional parameters. STATISTICAL TESTS: Student t-test, Mann-Whitney U, Spearman or Pearson rank correlation analysis, receiver operating characteristic curve, Kaplan-Meier event-free survival curve, and Cox proportional hazards regression were used. Results were considered statistically significant at P < 0.05. RESULTS: LGE extent and entropy of all infarct-related areas (BZ, IC, and IBZ) were significantly higher and GLS were lower in patients with endpoint events than those without. BZ and IBC entropy were further associated with LV strain in after-MI patients. In the univariable and multivariable Cox analysis, BZ entropy manifested independent association with primary endpoint events (hazard ratio: 3.859; 95% confidence interval: 2.136-6.974). Primary and secondary endpoint events prognostic value was improved by the addition of BZ entropy and GLS to the LVEF model (Delong test, Z = 2.729 for primary endpoint events; Z = 3.230 for secondary endpoint events). DATA CONCLUSION: Entropy of myocardial fibrosis was associated with LV strain. Assessment of BZ entropy and GLS improved prognostic value for endpoint events of LVEF. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 5.

Prognostic Value of Entropy Derived from Late Gadolinium Enhancement Images to Adverse Cardiac Events in Post-Myocardial Infarction Patients.

RATIONALE AND OBJECTIVES: To explore the prognostic value of entropy derived from late gadolinium enhancement images on cardiac magnetic resonance (CMR) for major adverse cardiac events (MACE) in post-myocardial infarction (MI) patients. MATERIALS AND METHODS: Participants with MI underwent 3.0T CMR were retrospectively enrolled. CMR parameters, including the entropy of infarct core (IC), peri-infarct border zone (BZ), and infarct core and peri-infarct border zone (IBZ) were analyzed. Patients were divided into the No-MACE group and the MACE group according to the absence or presence of MACE during the follow-up period. RESULTS: Eighty-four patients were included, among whom 51 patients without MACE and 33 patients with MACE. The MACE group showed higher IC mass, IBZ mass, IC entropy, BZ entropy, IBZ entropy, and LV entropy and lower LVEF than those of the NO-MACE group. LVEF, BZ entropy, and IBZ entropy were independent predictors of MACE (p < 0.05). Receiver operating characteristic curve revealed that the predictive values of BZ entropy with AUC of 0.860, IBZ entropy with AUC of 0.930, the combined model of LVEF and BZ entropy with AUC of 0.923, and the combined model of LVEF and IBZ entropy with AUC of 0.954 were higher than that of LVEF with AUC of 0.797. Delong test illustrated there was no significant difference in AUC among the three models with AUC > 0.900 (p > 0.05). CONCLUSION: BZ entropy and IBZ entropy were noninvasive parameters for better risk stratification of post-MI patients. MI Patients with MACE showed higher BZ entropy and IBZ entropy than patients without MACE.

PTEN-knockout regulates metabolic rewiring and epigenetic reprogramming in prostate cancer and chemoprevention by triterpenoid ursolic acid.

PTEN (phosphatase and tensin homolog deleted on chromosome 10) is one of the most frequently mutated/deleted tumor suppressor genes in many human cancers. Ursolic acid (UA) is a natural triterpenoid possessing antioxidant, anti-inflammatory, and anticancer effects. However, how PTEN impacts metabolic rewiring and how UA modifies PTEN-driven metabolic and epigenetic reprogramming in prostate cancer (PCa) remains unknown. In the current study, we found that UA protects against PTEN knockout (KO)-induced tumorigenesis at different stages of PCa. Epigenomic CpG methyl-seq revealed UA attenuated PTEN KO-induced differentially methylated regions (DMRs) profiles. Transcriptomic RNA-seq showed UA abrogated PTEN KO-induced differentially expressed genes (DEGs) of PCa-related oncogenes' Has3, Cfh, and Msx1 overexpression, indicating UA plays a crucial role in PTEN KO-mediated gene regulation and its potential consequences on cancer interception. Association analysis of DEGs and DMRs identified that the mRNA expression of tumor suppressor gene BDH2, and oncogenes Ephas, Isg15, and Nos2 were correlated with the promoter CpG methylation status in the early-stage comparison groups indicating UA could regulate the oncogenes or tumor suppressor genes by modulating their promoter methylation at an early stage of prostate tumorigenesis. The metabolomic study showed UA attenuated PTEN KO-regulated cancer-associated metabolisms like purine metabolism/metabolites correlating with RNAseq findings, glycolysis/gluconeogenesis metabolism, as well as epigenetic-related metabolites pyruvate and lactate indicating UA plays a critical role in PTEN KO-mediated metabolic and epigenetic reprogramming and its consequences on cancer development. In this context, UA impacts metabolic rewiring causing epigenetic and transcriptomic reprogramming potentially contributing to the overall protection against prostate-specific PTEN KO-mediated PCa.

UVB Drives Metabolic Rewiring and Epigenetic Reprograming and Protection by Sulforaphane in Human Skin Keratinocytes.

Sulforaphane (SFN) is a potent anticancer agent which could protect the skin from ultraviolet (UV) radiation-induced insults. Currently, the metabolic rewiring and epigenetic reprograming induced by UVB and the role of SFN in UVB-mediated skin cell transformation remain largely unknown. Herein, we study the metabolome, epigenome, and transcriptome of human keratinocytes (HaCaT cells) exposed to UVB with or without SFN using liquid chromatography-mass spectroscopy, DNA methylation sequencing, and RNA sequencing. UVB increases intracellular reactive oxygen species (ROS) and SFN enhances ROS acutely in post-UVB-exposed HaCaT cells. UVB and SFN alter multiple metabolites and metabolism-related signaling pathways. Pathway analysis shows that UVB impacts numerous signaling pathways including STAT3, inhibition of matrix metalloproteases, and TGF-ß, among others. DNA/CpG methylation analysis shows that SFN could partially reverse some of the alterations of UVB-induced CpG methylome. Integrating RNA-seq and Methyl-seq data, starburst plots show the correlation of mRNA expression and CpG methylation status. The potential linkages between the metabolome, CpG methylome, and transcriptome suggest that metabolites produced during metabolism act as cofactors or substrates for catalytic epigenetic modification and transcriptional regulation. These results indicate that UVB drives metabolic rewiring, epigenetic reprograming, and phenotypic transcriptomic alterations and SFN would block or attenuate many of these aberrations, potentially contributing to the overall protective effect of SFN against UVB-induced skin damage.

Butyrate Drives Metabolic Rewiring and Epigenetic Reprogramming in Human Colon Cancer Cells.

SCOPE: Butyrate (B) is a short-chain fatty acid produced by dietary fiber, known to inhibit histone deacetylases (HDACs) and possess cancer-preventive/anticancer effects. However, the role of B in metabolic rewiring, epigenomic reprogramming, transcriptomic network, NRF2 signaling, and eliciting cancer-preventive effects in colorectal cancer (CRC) HCT116 cell remains unclear. METHODS AND RESULTS: Sodium butyrate (NaB) dose-dependently inhibits the growth of CRC HCT116 cells. NaB inhibits NRF2/NRF2-target genes and blocks NRF2-ARE signaling. NaB increases NRF2 negative regulator KEAP1 expression through inhibiting its promoter methylation. Associative analysis of DEGs (differentially expressed genes) from RNA-seq and DMRs (differentially methylated regions) from CpG methyl-seq identified the tumor suppressor gene ABCA1 and tumor promote gene EGR3 are correlated with their promoters' CpG methylation indicating NaB regulates cancer markers through modulating their promoter methylation. NaB activated the mitochondrial tricarboxylic acid (TCA) cycle while inhibited the methionine metabolism which are both tightly coupled to the epigenetic machinery. NaB regulates the epigenetic enzymes/genes including DNMT1, HAT1, KDM1A, KDM1B, and TET1. Altogether, B's regulation of metabolites coupled to the epigenetic enzymes illustrates the potential underlying biological connectivity between metabolomics and epigenomics. CONCLUSION: B regulates KEAP1/NRF2 signaling, drives metabolic rewiring, CpG methylomic, and transcriptomic reprogramming contributing to the overall cancer-prevention/anticancer effect in the CRC cell model.

Does haze pollution aggravate urban-rural income gap? Evidence from 283 prefecture-level cities in China.

Urban-rural income gap and haze pollution concerns are remained at top priority to achieve sustainable development objectives in China. Based on the panel data of 283 cities in China from 2008 to 2018, the quantile regression model is used to study the impact of haze pollution on the urban-rural income gap. In addition, we adopt ventilation coefficients as the instrumental variable of haze pollution to control for potential endogeneity. Findings obtained from the quantile regression estimator suggest that haze pollution can significantly increase the urban-rural income gap. The effect of haze pollution on urban-rural income gap is more significant in the low quantile than the high quantile state. After alleviating endogenous bias through instrumental variables, the promotion effect is more obvious. Furthermore, haze pollution affects the urban-rural income gap through healthy human capital. Our results shed new light on the relationship between haze pollution and urban-rural income gap and provide support for policymakers in tackling the dual tasks of urban-rural income gap and haze pollution. A less haze pollution, our findings suggest, may exert positive effects in relation to the mitigation of urban-rural income gap in China.

Nfe2l2 Regulates Metabolic Rewiring and Epigenetic Reprogramming in Mediating Cancer Protective Effect by Fucoxanthin.

Fucoxanthin (FX) is a carotenoid with many pharmaceutical properties due to its antioxidant/anti-inflammatory and epigenetic effects. NFE2L2 is involved in the defense against oxidative stress/inflammation-mediated diseases, like anticancer effects elicited by phytochemicals including FX. However, the role of FX and NFE2L2 in metabolic rewiring, epigenomic reprogramming, and transcriptomic network in blocking pro-tumorigenic signaling and eliciting cancer-protective effects remains unknown. Herein, we utilized multi-omics approaches to evaluate the role of NFE2L2 and the impact of FX on tumor promoter TPA-induced skin cell transformation. FX blocked TPA-induced ROS and oxidized GSSG/reduced GSH in Nfe2l2wild-type(WT) but not Nfe2l2-knockdown (KD) cells. Both Nfe2l2 KD and TPA altered cellular metabolisms and metabolites which are tightly coupled to epigenetic machinery. The suppressive effects of FX on TPA-enhancedSAM/SAH was abrogated by Nfe2l2 KD indicating Nfe2l2 plays a critical role in FX-mediated metabolic rewiring and its potential consequences on epigenetic reprogramming. Epigenomic CpG methyl-seq revealed that FX attenuated TPA-induced differentially methylated regions (DMRs) of Uhrf1 and Dnmt1 genes. Transcriptomic RNA-seq showed that FX abrogated TPA-induced differentially expressed genes (DEGs) of Nfe2l2-related genes Nqo1, Ho1, and Keap1. Associative analysis of DEGs and DMRs identified that the mRNA expressions of Uhrf1 and Dnmt1 were correlated with the promoter CpG methylation status. Chromatin immunoprecipitation assay showed that FX restored Uhrf1 expression by regulating H3K27Me3 enrichment in the promoter region. In this context, FX/Nfe2l2's redox signaling drives metabolic rewiring causing epigenetic and transcriptomic reprogramming potentially contributing to the protection of TPA-induced JB6 cellular transformation skin cancer model. Graphical abstract.

Triterpenoid ursolic acid drives metabolic rewiring and epigenetic reprogramming in treatment/prevention of human prostate cancer.

Ursolic acid (UA) is a triterpenoid phytochemical with a strong anticancer effect. The metabolic rewiring, epigenetic reprogramming, and chemopreventive effect of UA in prostate cancer (PCa) remain unknown. Herein, we investigated the efficacy of UA in PCa xenograft, and its biological effects on cellular metabolism, DNA methylation, and transcriptomic using multi-omics approaches. The metabolomics was quantified by liquid-chromatography-mass spectrometry (LC-MS) while epigenomic CpG methylation in parallel with transcriptomic gene expression was studied by next-generation sequencing technologies. UA administration attenuated the growth of transplanted human VCaP-Luc cells in immunodeficient mice. UA regulated several cellular metabolites and metabolism-related signaling pathways including S-adenosylmethionine (SAM), methionine, glucose 6-phosphate, CDP-choline, phosphatidylcholine biosynthesis, glycolysis, and nucleotide sugars metabolism. RNA-seq analyses revealed UA regulated several signaling pathways, including CXCR4 signaling, cancer metastasis signaling, and NRF2-mediated oxidative stress response. Epigenetic reprogramming study with DNA Methyl-seq uncovered a list of differentially methylated regions (DMRs) associated with UA treatment. Transcriptome-DNA methylome correlative analysis uncovered a list of genes, of which changes in gene expression correlated with the promoter CpG methylation status. Altogether, our results suggest that UA regulates metabolic rewiring of metabolism including SAM potentially driving epigenetic CpG methylation reprogramming, and transcriptomic signaling resulting in the overall anticancer chemopreventive effect.

Utilization of physiologically-based pharmacokinetic model to assess disease-mediated therapeutic protein-disease-drug interaction in immune-mediated inflammatory diseases.

It is known that interleukin-6 (IL-6) can significantly modulate some key drug-metabolizing enzymes, such as phase I cytochrome P450s (CYPs). In this study, a physiologically-based pharmacokinetic (PBPK) model was developed to assess CYPs mediated therapeutic protein drug interactions (TP-DIs) in patients with immune-mediated inflammatory diseases (IMIDs) with elevated systemic IL-6 levels when treated by anti-IL-6 therapies. Literature data of IL-6 levels in various diseases were incorporated in SimCYP to construct respective virtual patient populations. The modulation effects of systemic IL-6 level and local IL-6 level in the gastrointestinal tract (GI) on CYPs activities were assessed. Upon blockade of the IL-6 signaling pathway by an anti-IL-6 treatment, the area under plasma concentration versus time curves (AUCs) of S-warfarin, omeprazole, and midazolam were predicted to decrease by up to 40%, 42%, and 46%, respectively. In patients with Crohn's disease and ulcerative colitis treated with an anti-IL-6 therapy, the lowering of the elevated IL-6 levels in the local GI tissue were predicted to result in further decreases in AUCs of those CYP substrates. The propensity of TP-DIs under comorbidity conditions, such as in patients with cancer with IMID, were also explored. With further validation with relevant clinical data, this PBPK model may provide an in silico way to quantify the magnitude of potential TP-DI in patients with elevated IL-6 levels when an anti-IL-6 therapeutic is used with concomitant small-molecule drugs. This model may be further adapted to evaluate the CYP modulation effect by other therapeutic modalities, which would significantly alter levels of proinflammatory cytokines during the treatment period.