Patient-Reported Outcome Measures Following Hyperbaric Oxygen Therapy for Radiation Cystitis: Early Results From the Multicenter Registry for Hyperbaric Oxygen Therapy.

PURPOSE: Our purpose was to determine changes in patient-reported hematuria and urinary symptoms after hyperbaric oxygen (HBO2) treatment for radiation cystitis (RC). MATERIALS AND METHODS: We analyzed prospectively collected data from the Multicenter Registry for Hyperbaric Oxygen Therapy Consortium accumulated within a week of beginning and ending HBO2. Measures included the modified Radiation Therapy Oncology Group (RTOG) Hematuria Scale, Urinary Distress Inventory Short Form, and EuroQol Five Dimension Five Level instrument. RTOG hematuria and Urinary Distress Inventory Short Form scores were compared using the sign test. Logistic regression was used to evaluate characteristics associated with hematuria improvement. RESULTS: A total of 470 registry patients had RC. The median age, number of HBO2 sessions, and years after radiation were 73 (IQR 12) years, 39 (IQR 10) sessions, and 5 (IQR 8) years, respectively. Eighty-four percent of patients (393/470) had prostate cancer‒related radiation. EuroQol Five Dimension Five Level scores improved from 0.83 (IQR 0.14) to 0.85 (IQR 0.22; P < .001. Three hundred seventy patients had complete RTOG hematuria scores that improved from 2 (IQR 2) to 0 (IQR 2; P < .001. Two hundred forty-six patients had complete Urinary Distress Inventory Short Form ratings that decreased from 33.3 (IQR 44) to 22.2 (IQR 33; P < .001). Regression analysis of those with visible hematuria before HBO2 showed lower improvement odds associated with higher HBO2 hematuria scores (odds ratio [OR] 0.44, 95% CI 0.26-0.73; P < .01), a smoking history (OR 0.44, 95% CI 0.21-0.92; P = .03), or a nonprostate cancer history (OR 0.32, 95% CI 0.10-0.99; P = .05). CONCLUSIONS: HBO2 for RC improved reported hematuria, urinary function, and quality of life. Higher baseline hematuria scores, smoking, and nonprostate cancer history were associated with lower odds of hematuria improvement.

TRIB2-mediated modulation of AMPK promotes hepatic insulin resistance.

Insulin resistance and its linked health complications are increasing in prevalence. Recent work has caused the role of Tribbles2 (TRIB2) in metabolism and cellular signaling to be increasingly appreciated, but its role in the progression of insulin resistance has not been elucidated. Here, we explore the functions of TRIB2 in modulating insulin resistance and the mechanism involved in insulin resistance mice and palmitic acid (PA) treated HepG2 cells. We demonstrate that whole-body knockout and hepatic-specific TRIB2 deficiency protect against diet-induced insulin resistance, inflammation and ER stress. Accordingly, upregulation of TRIB2 in the liver aggravates these metabolic disturbances in HFD-induced mice and ob/ob mice. Mechanistically, TRIB2 directly binds to the αγ-SBS domain of PRKAB through its pseudokinase domain, subsequently inhibiting the formation and activity of the AMPK complex. Moreover, the results of intervention against AMPK suggest that the effects of TRIB2 depend on AMPK. Our findings reveal that TRIB2 is a novel target for the treatment of insulin resistance and its associated metabolic complications and clarify the function of TRIB2 as a regulatory component of AMPK activity.

Auditory neural processing in children living with HIV uncovers underlying central nervous system dysfunction.

OBJECTIVE: Central nervous system (CNS) damage from HIV infection or treatment can lead to developmental delays and poor educational outcomes in children living with HIV (CLWH). Early markers of central nervous system dysfunction are needed to target interventions and prevent life-long disability. The frequency following response (FFR) is an auditory electrophysiology test that can reflect the health of the central nervous system. In this study, we explore whether the FFR reveals auditory central nervous system dysfunction in CLWH. STUDY DESIGN: Cross-sectional analysis of an ongoing cohort study. Data were from the child's first visit in the study. SETTING: The infectious disease center in Dar es Salaam, Tanzania. METHODS: We collected the FFR from 151 CLWH and 151 HIV-negative children. To evoke the FFR, three speech syllabi (/da/, /ba/, /ga/) were played monaurally to the child's right ear. Response measures included neural timing (peak latencies), strength of frequency encoding (fundamental frequency and first formant amplitude), encoding consistency (inter-response consistency), and encoding precision (stimulus-to-response correlation). RESULTS: CLWH showed smaller first formant amplitudes ( P  < 0.0001), weaker inter-response consistencies ( P  < 0.0001) and smaller stimulus to response correlations ( P  < 0.0001) than FFRs from HIV-negative children. These findings generalized across the three speech stimuli with moderately strong effect sizes (partial η2 ranged from 0.061 to 0.094). CONCLUSION: The FFR shows auditory central nervous system dysfunction in CLWH. Neural encoding of auditory stimuli was less robust, more variable, and less accurate. As the FFR is a passive and objective test, it may offer an effective way to assess and detect central nervous system function in CLWH.

Regulating Electron Metal-Support Interaction to Suppress N2O Formation in the Selective Catalytic Oxidation of Ammonia.

N2O is a common byproduct in the selective catalytic oxidation of ammonia, and its generation often needs to be inhibited due to its strong greenhouse effect. In this paper, using Ag/ZSO-Y as a model catalyst, the N2O selectivity was reduced by 30% through modulation of the electron metal-support interaction. The results demonstrate that the work function of the support can be regulated by the content of the doping element. As the Zr content increases in SnO2, the work function of the support decreases. Moreover, there is a positive correlation between the charge transfer amount and the work function of the support. A series of in situ DRIFTS and density functional theory calculations revealed that the -NO and -N reactions are the primary pathways for N2O formation. By adjustment of the work function of the support through varying the Zr doping level, the electronic structure of Ag NPs was further tuned, resulting in an increased reaction energy barrier for -NO and -N reactions, effectively suppressing N2O formation.

Differentially expressed genes in orbital adipose/connective tissue of thyroid-associated orbitopathy.

Background: Thyroid-associated orbitopathy (TAO) is a disease associated with autoimmune thyroid disorders and it can lead to proptosis, diplopia, and vision-threatening compressive optic neuropathy. To comprehensively understand the molecular mechanisms underlying orbital adipogenesis in TAO, we characterize the intrinsic molecular properties of orbital adipose/connective tissue from patients with TAO and control individuals. Methods: RNA sequencing analysis (RNA-seq) was performed to measure the gene expression of orbital adipose/connective tissues of TAO patients. Differentially expressed genes (DEGs) were detected and analyzed through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and Gene Set Enrichment Analysis (GSEA). The protein-protein interaction (PPI) network was constructed using the STRING database, and hub genes were identified by the Cytoscape plug-in, cytoHubba. We validated several top DEGs through quantitative real-time polymerase chain reaction (qRT-PCR). Results: We identified 183 DEGs in adipose tissue between TAO patients (n = 3) and control patients (n = 3) through RNA sequencing, including 114 upregulated genes and 69 downregulated genes. The PPI network of these DEGs had 202 nodes and 743 edges. PCR-based validation results of orbital adipose tissue showed multiple top-ranked genes in TAO patients (n = 4) are immune and inflammatory response genes compared with the control individual (n = 4). They include ceruloplasmin isoform x3 (CP), alkaline tissue-nonspecific isozyme isoform x1 (ALPL), and angiotensinogen (AGT), which were overrepresented by 2.27- to 6.40-fold. Meanwhile, protein mab-21-like 1 (MAB21L1), phosphoinositide 3-kinase gamma-subunit (PIK3C2G), and clavesin-2 (CLVS2) decreased by 2.6% to 32.8%. R-spondin 1 (RSPO1), which is related to oogonia differentiation and developmental angiogenesis, was significantly downregulated in the orbital muscle tissues of patients with TAO compared with the control groups (P = 0.024). Conclusions: Our results suggest that there are genetic differences in orbital adipose-connective tissues derived from TAO patients. The upregulation of the inflammatory response in orbital fat of TAO may be consistent with the clinical phenotype like eyelid edema, exophthalmos, and excess tearing. Downregulation of MAB21L1, PIK3C2G, and CLVS2 in TAO tissue demonstrates dysregulation of differentiation, oxidative stress, and developmental pathways.

Lactate and Lactylation: Clinical Applications of Routine Carbon Source and Novel Modification in Human Diseases.

Cell metabolism generates numerous intermediate metabolites that could serve as feedback and feed-forward regulation substances for posttranslational modification. Lactate, a metabolic product of glycolysis, has recently been conceptualized to play a pleiotropic role in shaping cell identities through metabolic rewiring and epigenetic modifications. Lactate-derived carbons, sourced from glucose, mediate the crosstalk among glycolysis, lactate, and lactylation. Furthermore, the multiple metabolic fates of lactate make it an ideal substrate for metabolic imaging in clinical application. Several studies have identified the crucial role of protein lactylation in human diseases associated with cell fate determination, embryonic development, inflammation, neoplasm, and neuropsychiatric disorders. Herein, this review will focus on the metabolic fate of lactate-derived carbon to provide useful information for further research and therapeutic approaches in human diseases. We comprehensively discuss its role in reprogramming and modification during the regulation of glycolysis, the clinical translation prospects of the hyperpolarized lactate signal, lactyl modification in human diseases, and its application with other techniques and omics.

Exendin-4 ameliorates tau hyperphosphorylation and cognitive impairment in type 2 diabetes through acting on Wnt/ß-catenin/NeuroD1 pathway.

BACKGROUND: Type 2 diabetes (T2D) is an independent risk factor for Alzheimer's disease (AD). Exendin-4 (Ex-4), a widely used glucagon-like peptide-1 receptor agonist drug in the treatment of T2D, has been demonstrated the therapeutic effects on diabetic encephalopathy (DE). Especially, the Ex-4 ameliorates the tau hyperphosphorylation and cognitive impairment in DE. And these crucial alterations are also important bridge between T2D and AD. However, its unique mechanism is unclear. METHODS: The db/db mice, high-fat-diet (HFD) / streptozotocin (STZ)-induced diabetic (HF-diabetic) mice, and high-glucose-damaged (HGD) HT-22 hippocampal cells were enrolled to examine the effects of Ex-4 on AD-like changes in T2D. The Novel object recognition test (NORT) and Morris water maze test (MWMT) were conducted to evaluate the cognitive impairment. The Dickkopf-1 (DKK1) was employed to weaken the activation of the Wnt/ß-catenin pathway to explore the mechanism of Ex-4 in protecting the brain functions. The JASPAR was based to predict the interaction between NeuroD1 and the promoter region of Ins2. Moreover, the chromatin immunoprecipitation coupled with quantitative polymerase chain reaction (ChIP-qPCR) and luciferase reporter assays were performed. RESULTS: Ex-4 alleviated the tau hyperphosphorylation, increased the brain-derived insulin, and improved the PI3K/AKT/GSK3-ß signalling in db/db mice, HF-diabetic mice, and HGD HT-22 hippocampal neuronal cells. The NORT and MWMT indicated that Ex-4 alleviated the learning and memory deficits in HF-diabetic mice. The inhibitor Dickkopf-1 (DKK1) of the Wnt/ß-catenin pathway significantly blocked the protective effects of Ex-4. Regarding further molecular mechanisms, NeuroD1 was affected by Ex-4 in vivo and in vitro, and the knockdown or overexpression of NeuroD1 suggested its crucial role in promoting the brain insulin by Ex-4. Meanwhile, the ChIP‒qPCR and luciferase reporter assays confirmed the combination between NeuroD1 and the promoter region of the insulin-encoding gene Ins2. And this interaction could be promoted by Ex-4. CONCLUSIONS: Our study proposes that Ex-4 alleviates tau hyperphosphorylation and cognitive dysfunction by increasing Ins2-derived brain insulin through the Wnt/ß-catenin/NeuroD1 signaling in T2D. And its also show new lights on part of the progress and mechanism on treatment targets for the DE in T2D.

Glutamine Production by Glul Promotes Thermogenic Adipocyte Differentiation Through Prdm9-Mediated H3K4me3 and Transcriptional Reprogramming.

Thermogenic adipocytes have been extensively investigated because of their energy-dissipating property and therapeutic potential for obesity and diabetes. Besides serving as fuel sources, accumulating evidence suggests that intermediate metabolites play critical roles in multiple biological processes. However, their role in adipocyte differentiation and thermogenesis remains unexplored. Here, we report that human and mouse obesity is associated with marked downregulation of glutamine synthetase (Glul) expression and activity in thermogenic adipose tissues. Glul is robustly upregulated during brown adipocyte (BAC) differentiation and in brown adipose tissue (BAT) upon cold exposure and Cl316,243 stimulation. Further genetic, pharmacologic, or metabolic manipulations of Glul and glutamine levels reveal that glutamine cells autonomously stimulate BAC differentiation and function and BAT remodeling and improve systemic energy homeostasis in mice. Mechanistically, glutamine promotes transcriptional induction of adipogenic and thermogenic gene programs through histone modification-mediated chromatin remodeling. Among all the glutamine-regulated writer and eraser genes responsible for histone methylation and acetylation, only Prdm9, a histone lysine methyltransferase, is robustly induced during BAC differentiation. Importantly, Prdm9 inactivation by shRNA knockdown or a selective inhibitor attenuates glutamine-triggered adipogenic and thermogenic induction. Furthermore, Prdm9 gene transcription is regulated by glutamine through the recruitment of C/EBPb to its enhancer region. This work reveals glutamine as a novel activator of thermogenic adipocyte differentiation and uncovers an unexpected role of C/EBPb-Prdm9-mediated H3K4me3 and transcriptional reprogramming in adipocyte differentiation and thermogenesis.

The muscle-enriched myokine Musclin impairs beige fat thermogenesis and systemic energy homeostasis via Tfr1/PKA signaling in male mice.

Skeletal muscle and thermogenic adipose tissue are both critical for the maintenance of body temperature in mammals. However, whether these two tissues are interconnected to modulate thermogenesis and metabolic homeostasis in response to thermal stress remains inconclusive. Here, we report that human and mouse obesity is associated with elevated Musclin levels in both muscle and circulation. Intriguingly, muscle expression of Musclin is markedly increased or decreased when the male mice are housed in thermoneutral or chronic cool conditions, respectively. Beige fat is then identified as the primary site of Musclin action. Muscle-transgenic or AAV-mediated overexpression of Musclin attenuates beige fat thermogenesis, thereby exacerbating diet-induced obesity and metabolic disorders in male mice. Conversely, Musclin inactivation by muscle-specific ablation or neutralizing antibody treatment promotes beige fat thermogenesis and improves metabolic homeostasis in male mice. Mechanistically, Musclin binds to transferrin receptor 1 (Tfr1) and antagonizes Tfr1-mediated cAMP/PKA-dependent thermogenic induction in beige adipocytes. This work defines the temperature-sensitive myokine Musclin as a negative regulator of adipose thermogenesis that exacerbates the deterioration of metabolic health in obese male mice and thus provides a framework for the therapeutic targeting of this endocrine pathway.

Myofiber Baf60c controls muscle regeneration by modulating Dkk3-mediated paracrine signaling.

Obesity and type 2 diabetes (T2D) are the leading causes of the progressive decline in muscle regeneration and fitness in adults. The muscle microenvironment is known to play a key role in controlling muscle stem cell regenerative capacity, yet the underlying mechanism remains elusive. Here, we found that Baf60c expression in skeletal muscle is significantly downregulated in obese and T2D mice and humans. Myofiber-specific ablation of Baf60c in mice impairs muscle regeneration and contraction, accompanied by a robust upregulation of Dkk3, a muscle-enriched secreted protein. Dkk3 inhibits muscle stem cell differentiation and attenuates muscle regeneration in vivo. Conversely, Dkk3 blockade by myofiber-specific Baf60c transgene promotes muscle regeneration and contraction. Baf60c interacts with Six4 to synergistically suppress myocyte Dkk3 expression. While muscle expression and circulation levels of Dkk3 are markedly elevated in obese mice and humans, Dkk3 knockdown improves muscle regeneration in obese mice. This work defines Baf60c in myofiber as a critical regulator of muscle regeneration through Dkk3-mediated paracrine signaling.

Catalytic activity and mechanism of selective catalytic oxidation of ammonia by Ag-CeO2 under different preparation conditions.

Given the problem of the high-temperature window of CeO2 catalyst activity, this study evaluated the catalytic properties of Ag/CeO2 prepared by changing the preparation methods and loadings. Our experiments showed that Ag/CeO2-IM catalysts prepared by the equal volume impregnation method could have better activity at lower temperatures. The Ag/CeO2-IM catalyst achieves 90% NH3 conversion at 200 °C, and the main reason is that the Ag/CeO2-IM catalyst has more vital redox properties, and the NH3 catalytic oxidation temperature is lower. However, its high-temperature N2 selectivity still needs to be improved and may be related to the less acidic sites on the catalyst surface. On both catalyst surfaces, the i-SCR mechanism governs the NH3-SCO reaction.

Impact of the emergency response to COVID-19 on air quality and its policy implications: Evidence from 290 cities in China.

The emergency response to the COVID-19 pandemic had an extreme exogenous impact on society and the economy. This paper aims to explore the impacts of the national emergency response and the subsequent emergency response termination on air quality and its policy implications through regression discontinuity design (RDD) estimation by employing panel data on daily air quality from January 1, 2019, to July 31, 2020, for 290 cities in China. The empirical results showed that the emergency response resulted in a significant decrease in most of the major pollutant concentrations within a short time frame, and the average air quality index (AQI) decreased by approximately 11.0%. The concentrations of PM2.5, PM10, SO2, NO2, and CO decreased by approximately 18.8%, 13.1%, 13.5%, 11.1% and 6.7%, respectively, while the O3 concentration did not change significantly. Further causal analysis found that mandatory traffic restrictions and the shutdown of industries were two important factors that contributed greatly to air quality improvement. Moreover, since the process of returning to normal daily activities and promoting the economy were gradual, the results showed that air pollution did not rebound immediately after the government called for the "resumption of production and work" and announced the "termination of the emergency response". Our findings suggest that to achieve a substantial and sustainable improvement in air quality, it is necessary to continuously implement strict emission control routines and take co-control measures for various VOCs precursors of ozone.

Global determination of reaction rates and lipid turnover kinetics in Mus musculus.

Metabolism is fundamental to life, but measuring metabolic reaction rates remains challenging. Here, we applied C13 fluxomics to monitor the metabolism of dietary glucose carbon in 12 tissues, 9 brain compartments, and over 1,000 metabolite isotopologues over a 4-day period. The rates of 85 reactions surrounding central carbon metabolism are determined with elementary metabolite unit (EMU) modeling. Lactate oxidation, not glycolysis, occurs at a comparable pace with the tricarboxylic acid cycle (TCA), supporting lactate as the primary fuel. We expand the EMU framework to track and quantify metabolite flows across tissues. Specifically, multi-organ EMU simulation of uridine metabolism shows that tissue-blood exchange, not synthesis, controls nucleotide homeostasis. In contrast, isotopologue fingerprinting and kinetic analyses reveal the brown adipose tissue (BAT) having the highest palmitate synthesis activity but no apparent contribution to circulation, suggesting a tissue-autonomous synthesis-to-burn mechanism. Together, this study demonstrates the utility of dietary fluxomics for kinetic mapping in vivo and provides a rich resource for elucidating inter-organ metabolic cross talk.

Distribution of serum uric acid concentration and its association with lipid profiles: a single-center retrospective study in children aged 3 to 12 years with adenoid and tonsillar hypertrophy.

BACKGROUND: Presently, there is no consensus regarding the optimal serum uric acid (SUA) concentration for pediatric patients. Adenoid and tonsillar hypertrophy is considered to be closely associated with pediatric metabolic syndrome and cardiovascular risk and is a common condition in children admitted to the hospital. Therefore, we aimed to evaluate the relationship between SUA and dyslipidemia and propose a reference range for SUA concentration that is associated with a healthy lipid profile in hospitalized children with adenoid and tonsillar hypertrophy. METHODS: Preoperative data from 4922 children admitted for elective adenoidectomy and/or tonsillectomy surgery due to adenoid and tonsillar hypertrophy were collected. SUA concentrations were scaled to standard deviation (SD), and SUA deviations were expressed as SD from the mean SUA of children without dyslipidemia. RESULTS: The mean SUA concentration of the participants was 4.27 ± 1.01 mg/dL, and the prevalence of hyperuricemia was 1.6% when it was defined using an SUA of ≥ 7.0 mg/dL. Participants with dyslipidemia (856, 17.4%) had a higher prevalence of hyperuricemia (3.4% vs. 1.2%, P < 0.001) and higher SUA concentrations (4.51 ± 1.15 vs. 4.22 ± 0.97 mg/dL, P < 0.001) than those with ortholiposis. The circulating lipid status of participants with SUAs < 1 SD below the mean value for the participants with ortholiposis (range 1.80-3.28 mg/dL) was more normal. Each 1-SD increase in SUA was associated with a 27% increase in the risk of dyslipidemia (OR = 1.270, 95% CI, 1.185-1.361). Adjustment for a number of potential confounders reduced the strength of the relationship, but this remained significant (OR = 1.125, 95% CI, 1.042-1.215). The higher risk of dyslipidemia was maintained for participants with SUAs > 1 SD above the mean value of the participants with ortholiposis. CONCLUSIONS: SUA was independently associated with dyslipidemia in children with adenoid and tonsillar hypertrophy, and an SUA < 1 SD below the mean value for patients with ortholiposis was associated with a healthy lipid profile.

Divergent summertime surface O3 pollution formation mechanisms in two typical Chinese cities in the Beijing-Tianjin-Hebei region and Fenwei Plain.

Recently, severe summertime ozone (O3) pollution has swept across most areas of China, especially the Beijing-Tianjin-Hebei (BTH) region and Fenwei Plain. By focusing on Beijing and Yuncheng, which are two typical cities in the BTH region and the Fenwei Plain, we intended to reveal the neglected fact that they had disparate emission features and atmospheric movements but suffered from similar high-O3 pollution levels. Field observations indicated that Yuncheng had lower volatile organic compound (VOC) and NOx concentrations but higher background O3 levels. The model simulation verified that both photochemical reactions and net O3 generation were stronger in Beijing. Ultimately, faster net O3 generation rates (8.4 ppbv/h) plus lower background O3 values in Beijing and lower net O3 generation rates (6.2 ppbv/h) plus higher background O3 values in Yuncheng caused both regions to reach similar O3 peak values in July 2020. However, different O3 control measures were appropriate for the two cities according to the different simulated O3-VOCs-NOx responses. Additionally, as surface O3 levels are greatly affected by the ongoing O3 production/depletion process that occurs in three dimensions, exploring the effects of spatially distributed O3 on surface O3 should be high on the agenda in the future.

The protocol of CUT&Tag for metabolic tissue cells.

Cleavage under target and tagment (CUT&Tag) is a technology that utilizes the fusion protein of Tn5 transposase and protein A/G which can guide Tn5 enzyme to the antibody bound to target protein and cleave the chromatin regions adjacent to target protein. Chromatin libraries are then tagged and sequenced by the high-throughput sequencing to obtain chromatin information at specific sites or protein binding locations. CUT&Tag technology plays an important role in the research of DNA and protein interactions. It can be used to understand the modifications of histone and the bindings of transcription factors. Compared with the traditional chromatin immunoprecipitation-sequencing (ChIP-seq) technology, the CUT&Tag has the strengths of high signal-to-noise ratio, good repeatability, short experimental period, and low cell input. It shows great advantages in early embryonic development, stem cells, cancer, epigenetics and other research fields. In this article, we described the protocol of CUT&Tag for metabolic tissue cells (mouse primary islet cells), to provide an epigenetic method for studying metabolic cells.

Non-obese NAFLD had no better cardio-metabolic risk profile than obese NAFLD in type 2 diabetic patients.

BACKGROUND: Non-obese non-alcoholic fatty liver disease (NAFLD) has been reported to share clinical outcomes with its obese counterpart in the general population. However, conflicting results have been observed regarding the cardio-metabolic risk profile of non-obese NAFLD as compared to obese NAFLD. Moreover, in the context of type 2 diabetes mellitus (T2DM), this issue has been even less addressed. We hence aimed to examine the association of NAFLD with the cardio-metabolic risk profile in patients with T2DM according to their obesity status. METHODS: A total of 2,708 patients with T2DM who were hospitalized between June 2018 and May 2021 were cross-sectionally assessed. RESULTS: The prevalence of NAFLD was 49.3%. NAFLD was found in 34.1% of non-obese patients and 66.0% of obese patients. Non-obese NAFLD patients had more and worse metabolic disorders than obese patients without NAFLD in both men and women. Comparable cardio-metabolic risk profiles were noted between non-obese and obese NAFLD subjects. The associations of worse cardio-metabolic risk profiles with NAFLD were overall stronger in non-obese than in obese subjects among women with T2DM, while more pronounced in obese than in non-obese subjects among men with T2DM. CONCLUSION: In patients with T2DM, non-obese NAFLD had no better cardio-metabolic risk profile than obese NAFLD. The associations of metabolic disorders with NAFLD were stronger in non-obese than in obese patients in women patients with T2DM.

Dietary Antioxidant-Constructed Nanodrugs Can High-Efficiently Kill Cancer Cells while Protecting Noncancer Cells.

Despite great advances, the development of cancer drugs that can efficiently kill cancer cells while protecting noncancer cells has not been achieved. By using only dietary antioxidants vitamin C (VC) and (R)-(+)-lipoic acid (LA), we herein develop a nanodrug VC@cLAV featuring the above function. After entering cells, cLAV dissociates into LA and DHLA (dihydrolipoic acid, reduced form of LA) and releases VC and DHA (dehydroascorbate, oxidized form of VC). In cancer cells, the two redox pairs recycle each other and dramatically promote the intracellular reactive oxygen species production to kill cancer cells at low doses comparable to cytotoxic drugs. Oppositely in noncancer cells, the LA/DHLA and VC/DHA pairs exert anti-oxidant action to actively protect the organism by preventing the normal cells from oxidative stress and repairing cells suffering from oxidative stress. When compared with the first-line cytotoxic drug, VC@cLAV displayed superior therapeutic outcomes yet without side effects in diverse tumor models including patient-derived xenograft (PDX). This drug with efficient cancer cell killing and noncancer cell protection represents a new cancer therapy.

BAF60a Deficiency in Macrophage Promotes Diet-Induced Obesity and Metabolic Inflammation.

Adipose tissue macrophage (ATM) has been shown to play a key role in the pathogenesis of obesity-associated adipose tissue inflammation and metabolic diseases. However, the upstream factors that integrate the environmental signals to control ATM activation and adipose inflammation in obesity remain elusive. Here, we identify BAF60a, a subunit of the switch/sucrose-nonfermentable (SWI/SNF) chromatin remodeling complexes, as the central checkpoint regulator of obesity-induced ATM activation, adipose tissue inflammation, and systemic metabolic impairment. BAF60a expression was robustly downregulated in the adipose tissue stromal vascular fractions in type 2 diabetic mice. Myeloid-specific BAF60a knockout (BaMKO) promotes ATM proinflammatory activation, exacerbating diet-induced obesity, insulin resistance, and metabolic dysfunction. Conversely, myeloid-specific overexpression of BAF60a in mice attenuates macrophage proinflammatory activation. Mechanistically, transcriptome and chromatin landscape analyses demonstrate that BAF60a inactivation triggers the expression of proinflammatory gene program through chromatin remodeling. Moreover, motif analysis of ATAC-Seq and CUT&Tag-Seq data identifies the transcription factor Atf3 that physically interacts with BAF60a to suppress the proinflammatory gene expression, thereby controlling ATM activation and metabolic inflammation in obesity. Consistently, myeloid-specific Atf3 deficiency also promotes the proinflammatory activation of macrophage. This work uncovers BAF60a/Atf3 axis as the key regulator in obesity-associated ATM activation, adipose tissue inflammation, and metabolic diseases.