Gold nanomakura: nanoarchitectonics and their photothermal response in association with carrageenan hydrogels.

Photothermal conversion of light into heat energy is an intrinsic optical property of metal nanoparticles when irradiated using near-infrared radiation. However, the impact of size and shape on the photothermal behaviour of gold nanomakura particles possessing optical absorption within 600-700 nm as well as on incorporation in hydrogels is not well reported. In this study, nanomakura-shaped anisotropic gold nanoparticles (AuNMs) were synthesized via a surfactant-assisted seed-mediated protocol. Quaternary cationic surfactants having variable carbon tail length (n = 16, 14, 12) were used as capping for tuning the plasmon peak of gold nanomakura within a 600-700 nm wavelength. The aspect ratio as well as anisotropy of synthesized gold nanomakura can influence photothermal response upon near-infrared irradiation. The role of carbon tail length was evident via absorption peaks obtained from longitudinal surface plasmon resonance analysis at 670, 650, and 630 nm in CTAB-AuNM, MTAB-AuNM, and DTAB-AuNM, respectively. Furthermore, the impact of morphology and surrounding milieu of the synthesized nanomakuras on photothermal conversion is investigated owing to their retention of plasmonic stability. Interestingly, we found that photothermal conversion was exclusively assigned to morphological features (i.e., nanoparticles of higher aspect ratio showed higher temperature change and vice versa irrespective of the surfactant used). To enable biofunctionality and stability, we used kappa-carrageenan- (k-CG) based hydrogels for incorporating the nanomakuras and further assessed their photothermal response. Nanomakura particles in association with k-CG were also able to show photothermal conversion, depicting their ability to interact with light without hindrance. The CTAB-AuNM, MTAB-AuNM, and DTAB-AuNM after incorporation into hydrogel beads attained up to ≈17.2, ≈17.2, and ≈15.7 °C, respectively. On the other hand, gold nanorods after incorporation into k-CG did not yield much photothermal response as compared to that of AuNMs. The results showed a promising platform to utilize nanomakura particles along with kappa-carrageenan hydrogels for enabling usage on nanophotonic, photothermal, and bio-imaging applications.

Epigenetically active chromatin in neonatal iWAT reveals GABPα as a potential regulator of beige adipogenesis.

Background: Thermogenic beige adipocytes, which dissipate energy as heat, are found in neonates and adults. Recent studies show that neonatal beige adipocytes are highly plastic and contribute to >50% of beige adipocytes in adults. Neonatal beige adipocytes are distinct from recruited beige adipocytes in that they develop independently of temperature and sympathetic innervation through poorly defined mechanisms. Methods: We characterized the neonatal beige adipocytes in the inguinal white adipose tissue (iWAT) of C57BL6 postnatal day 3 and 20 mice (P3 and P20) by imaging, genome-wide RNA-seq analysis, ChIP-seq analysis, qRT-PCR validation, and biochemical assays. Results: We found an increase in acetylated histone 3 lysine 27 (H3K27ac) on the promoter and enhancer regions of beige-specific gene UCP1 in iWAT of P20 mice. Furthermore, H3K27ac ChIP-seq analysis in the iWAT of P3 and P20 mice revealed strong H3K27ac signals at beige adipocyte-associated genes in the iWAT of P20 mice. The integration of H3K27ac ChIP-seq and RNA-seq analysis in the iWAT of P20 mice reveal epigenetically active signatures of beige adipocytes, including oxidative phosphorylation and mitochondrial metabolism. We identify the enrichment of GA-binding protein alpha (GABPα) binding regions in the epigenetically active chromatin regions of the P20 iWAT, particularly on beige genes, and demonstrate that GABPα is required for beige adipocyte differentiation. Moreover, transcriptomic analysis and glucose oxidation assays revealed increased glycolytic activity in the neonatal iWAT from P20. Conclusions: Our findings demonstrate that epigenetic mechanisms regulate the development of peri-weaning beige adipocytes via GABPα. Further studies to better understand the upstream mechanisms that regulate epigenetic activation of GABPα and characterization of the metabolic identity of neonatal beige adipocytes will help us harness their therapeutic potential in metabolic diseases.

Prevalence of test anxiety and its determinants among nursing students in Selangor, Malaysia.

The current education system significantly emphasizes tests and evaluations as crucial factors in determining a student's future career path. It has been shown that nursing students have moderate to high levels of Test Anxiety (TA), which results in decreased academic performance, low self-esteem, and an inability to complete the program and pursue a career in nursing successfully. This study aimed to determine nursing students' level of TA and its relationship with demographic characteristics. Four hundred twenty-one nursing students at seven private universities and colleges in Selangor participated in this cross-sectional study. The level of TA was measured using the TA Inventory (TAI). A total of 62.5% of the respondents had mild TA, 25.4% had moderate TA and 2.1% had severe TA. There were significant relationships between TA level and household income (χ2 = 6.70, p = 0.035) and ethnic groups (F (3,417) = 5.20, p = 0.002) where Chinese and Indians are protective from TA compared to the Malays and other ethnic groups and high anxiety was significant in the Ringgit Malaysia (RM 3000) and below group. The study's findings indicate that a significant percentage of nursing students involved in the research had mild to moderate levels of test anxiety (TA) and there is a significant association between TA and demographic characteristics. The results indicate the importance of early identification of TA and the need for interventions to overcome TA to ensure they are emotionally, physically, and academically successful.

Hepatic ketogenesis regulates lipid homeostasis via ACSL1-mediated fatty acid partitioning.

Liver-derived ketone bodies play a crucial role in fasting energy homeostasis by fueling the brain and peripheral tissues. Ketogenesis also acts as a conduit to remove excess acetyl-CoA generated from fatty acid oxidation and protects against diet-induced hepatic steatosis. Surprisingly, no study has examined the role of ketogenesis in fasting-associated hepatocellular lipid metabolism. Ketogenesis is driven by the rate-limiting mitochondrial enzyme 3-hydroxymethylglutaryl CoA synthase (HMGCS2) abundantly expressed in the liver. Here, we show that ketogenic insufficiency via disruption of hepatic HMGCS2 exacerbates liver steatosis in fasted chow and high-fat-fed mice. We found that the hepatic steatosis is driven by increased fatty acid partitioning to the endoplasmic reticulum (ER) for re-esterification via acyl-CoA synthetase long-chain family member 1 (ACSL1). Mechanistically, acetyl-CoA accumulation from impaired hepatic ketogenesis is responsible for the elevated translocation of ACSL1 to the ER. Moreover, we show increased ER-localized ACSL1 and re-esterification of lipids in human NASH displaying impaired hepatic ketogenesis. Finally, we show that L-carnitine, which buffers excess acetyl-CoA, decreases the ER-associated ACSL1 and alleviates hepatic steatosis. Thus, ketogenesis via controlling hepatocellular acetyl-CoA homeostasis regulates lipid partitioning and protects against hepatic steatosis.

Short-acting ß2-agonist prescription patterns and clinical outcomes in Malaysia: A nationwide cohort of the SABINA III study.

Introduction: SABINA III assessed short-acting ß2-agonist (SABA) prescription patterns and their association with asthma-related outcomes globally. Herein, we examined SABA prescription and clinical outcomes in the Malaysian cohort of SABINA III. Method: In this observational, cross-sectional study, patients (≥12 years) were recruited between July and December 2019 from 15 primary and specialty care centres in Malaysia. Prescribed asthma treatments and severe exacerbation history within 12 months prior and asthma symptom control during the study visit were evaluated. Associations of SABA prescription with asthma control and severe exacerbation were analysed using multivariable regression models. Results: Seven hundred thirty-one patients (primary care, n=265 [36.3%]; specialty care, n=466 [63.7%]) were evaluated. The prevalence of SABA over-prescription (≥3 SABA prescriptions/year) was 47.4% (primary care, 47.1%; specialty care, 47.6%), 51.8% and 44.5% among all patients and patients with mild and moderate-to-severe asthma, respectively. Altogether 9.0% (n=66) purchased SABA without a prescription; among them, 43.9% (n=29) purchased ≥3 inhalers. The mean (standard deviation) number of severe asthma exacerbations was 1.38 (2.76), and 19.7% (n=144) and 25.7% (n=188) had uncontrolled and partly controlled symptoms, respectively. Prescriptions of ≥3 SABA inhalers (vs 1-2) were associated with lower odds of at least partly controlled asthma (odds ratio=0.42; 95% confidence interval [CI]=0.27-0.67) and higher odds of having severe exacerbation(s) (odds ratio=2.04; 95% CI=1.44-2.89). Conclusion: The prevalence of SABA over-prescription in Malaysia is high, regardless of the prescriber type, emphasising the need for healthcare providers and policymakers to adopt latest evidence-based recommendations to address this public health concern.

Interventional Strategies to Reduce Test Anxiety among Nursing Students: A Systematic Review.

Nursing students are reported to have moderate to high test anxiety, leading to reduced academic performance, poor self-esteem, and failure to complete the program and practice nursing. This review aims to examine the interventions for test anxiety reduction in nursing students. Following the PRISMA guidelines, peer-reviewed experimental studies published in English between 2016 and 2021 from four databases, EBSCOhost, PubMed, Science Direct, and Scopus, were systematically searched. The findings were presented in tabular and narrative form. Among the 722 studies retrieved, 14 selected studies were critically appraised, guided by the Joanna Briggs checklist for Randomized Controlled Trials and the checklist for Quasi-Experimental Studies, resulting in 11 studies for inclusion in the systematic review. Test anxiety was assessed by different scales. Aromatherapy hand massage, aromatherapy using a diffuser in combination with music therapy, confidence training for test relaxation, coping program, music therapy, emotional freedom technique, animal-assisted intervention, and guided imagery were all found to be effective in reducing test anxiety. In conclusion, while numerous interventions to reduce test anxiety in nursing students were found to be effective, the quality of the studies investigating these interventions was varied with generally small sample sizes and limited follow-up. Future research should be conducted, and the same interventions should be carried out using a larger sample size to strengthen the body of evidence.

Emerging Role of Hepatic Ketogenesis in Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver diseases, arise from non-alcoholic fatty liver (NAFL) characterized by excessive fat accumulation as triglycerides. Although NAFL is benign, it could progress to non-alcoholic steatohepatitis (NASH) manifested with inflammation, hepatocyte damage and fibrosis. A subset of NASH patients develops end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is highly complex and strongly associated with perturbations in lipid and glucose metabolism. Lipid disposal pathways, in particular, impairment in condensation of acetyl-CoA derived from ß-oxidation into ketogenic pathway strongly influence the hepatic lipid loads and glucose metabolism. Current evidence suggests that ketogenesis dispose up to two-thirds of the lipids entering the liver, and its dysregulation significantly contribute to the NAFLD pathogenesis. Moreover, ketone body administration in mice and humans shows a significant improvement in NAFLD. This review focuses on hepatic ketogenesis and its role in NAFLD pathogenesis. We review the possible mechanisms through which impaired hepatic ketogenesis may promote NAFLD progression. Finally, the review sheds light on the therapeutic implications of a ketogenic diet in NAFLD.

Oxidative Stress and Redox Signaling in the Pathophysiology of Liver Diseases.

The increased production of derivatives of molecular oxygen and nitrogen in the form of reactive oxygen species (ROS) and reactive nitrogen species (RNS) lead to molecular damage called oxidative stress. Under normal physiological conditions, the ROS generation is tightly regulated in different cells and cellular compartments. Any disturbance in the balance between the cellular generation of ROS and antioxidant balance leads to oxidative stress. In this article, we discuss the sources of ROS (endogenous and exogenous) and antioxidant mechanisms. We also focus on the pathophysiological significance of oxidative stress in various cell types of the liver. Oxidative stress is implicated in the development and progression of various liver diseases. We narrate the master regulators of ROS-mediated signaling and their contribution to liver diseases. Nonalcoholic fatty liver diseases (NAFLD) are influenced by a "multiple parallel-hit model" in which oxidative stress plays a central role. We highlight the recent findings on the role of oxidative stress in the spectrum of NAFLD, including fibrosis and liver cancer. Finally, we provide a brief overview of oxidative stress biomarkers and their therapeutic applications in various liver-related disorders. Overall, the article sheds light on the significance of oxidative stress in the pathophysiology of the liver. © 2022 American Physiological Society. Compr Physiol 12:3167-3192, 2022.

Enhanced photo-fenton and photoelectrochemical activities in nitrogen doped brownmillerite KBiFe2O5.

Visible-light-driven photo-fenton-like catalytic activity and photoelectrochemical (PEC) performance of nitrogen-doped brownmillerite KBiFe2O5 (KBFO) are investigated. The effective optical bandgap of KBFO reduces from 1.67 to 1.60 eV post N-doping, enabling both enhancement of visible light absorption and photoactivity. The photo-fenton activity of KBFO and N-doped KBFO samples were analysed by degrading effluents like Methylene Blue (MB), Bisphenol-A (BPA) and antibiotics such as Norfloxacin (NOX) and Doxycycline (DOX). 20 mmol of Nitrogen-doped KBFO (20N-KBFO) exhibits enhanced catalytic activity while degrading MB. 20N-KBFO sample is further tested for degradation of Bisphenol-A and antibiotics in the presence of H2O2 and chelating agent L-cysteine. Under optimum conditions, MB, BPA, and NOX, and DOX are degraded by 99.5% (0.042 min-1), 83% (0.016 min-1), 72% (0.011 min-1) and 95% (0.026 min-1) of its initial concentration respectively. Photocurrent density of 20N-KBFO improves to 8.83 mA/cm2 from 4.31 mA/cm2 for pure KBFO. Photocatalytic and photoelectrochemical (PEC) properties of N-doped KBFO make it a promising candidate for energy and environmental applications.

Consumption of vitamin A-deficient diet elevates endoplasmic reticulum stress marker and suppresses high fructose-induced orexigenic gene expression in the brain of male Wistar rats.

OBJECTIVE: Here, we assessed the impact of vitamin A deficiency (both alone and in combination with fructose) on the retinol status, phospholipids fatty acid composition and pathways associated with the endoplasmic reticulum (ER) stress and energy homeostasis of the brain. For this purpose, weanling male Wistar rats were divided into four groups consisting of 8 rats each, except 16 for the second group and they received one of the following diets; control, vitamin A-deficient (VAD), high fructose (HFr) and HFr with VAD for 16 weeks, except half of the VAD diet-fed rats, were shifted to HFr diet, after 8 weeks period. RESULTS: The retinol content of the whole brain remained comparable across the groups, despite a significant reduction in the plasma at the end of VAD diet feeding. However, it suppressed the HFr-induced neuropeptide Y and agouti-related peptide, while rescuing the leptin receptor mRNA. Among ER stress markers, CCAAT/Enhancer-binding protein homologues protein levels were elevated significantly in the VAD diet-fed group. Further, the long-chain polyunsaturated fatty acid levels showed an increase in the brain phospholipids across the experimental groups, compared to that of the control. CONCLUSION: Vitamin A deficiency causes ER stress in the brain, and retinol seems to play a regulatory role in the fructose-mediated transcriptional regulation of the genes involved in energy homeostasis.

Intestinal HIF-2α Regulates GLP-1 Secretion via Lipid Sensing in L-Cells.

BACKGROUND & AIMS: Compelling evidence shows that glucagon-like peptide-1 (GLP-1) has a profound effect in restoring normoglycemia in type 2 diabetic patients by increasing pancreatic insulin secretion. Although L-cells are the primary source of circulating GLP-1, the current therapies do not target L-cells to increase GLP-1 levels. Our study aimed to determine the molecular underpinnings of GLP-1 secretion as an impetus to identify new interventions to target endogenous L-cells. METHODS: We used genetic mouse models of intestine-specific overexpression of hypoxia-inducible factor (HIF)-1α and HIF-2α (VhlΔIE), conditional overexpression of intestinal HIF-2α (Hif-2αLSL;Vilin-Cre/ERT2), and intestine-specific HIF-2α knockout mice (Hif-2αΔIE) to show that HIF signaling, especially HIF-2α, regulates GLP-1 secretion. RESULTS: Our data show that intestinal HIF signaling improved glucose homeostasis in a GLP-1-dependent manner. Intestinal HIF potentiated GLP-1 secretion via the lipid sensor G-protein-coupled receptor (GPR)40 enriched in L-cells. We show that HIF-2α regulates GPR40 in L-cells and potentiates fatty acid-induced GLP-1 secretion via extracellular regulated kinase (ERK). Using a genetic model of intestine-specific overexpression of HIF-2α, we show that HIF-2α is sufficient to increase GLP-1 levels and attenuate diet-induced metabolic perturbations such as visceral adiposity, glucose intolerance, and hepatic steatosis. Lastly, we show that intestinal HIF-2α signaling acts as a priming mechanism crucial for postprandial lipid-mediated GLP-1 secretion. Thus, disruption of intestinal HIF-2α decreases GLP-1 secretion. CONCLUSIONS: In summary, we show that intestinal HIF signaling, particularly HIF-2α, regulates the lipid sensor GPR40, which is crucial for the lipid-mediated GLP-1 secretion, and suggest that HIF-2α is a potential target to induce endogenous GLP-1 secretion.

Fixed dose combination of capecitabine and cyclophosphamide in metastatic breast cancer: Results from THE ENCLOSE phase 2/3 randomized multicenter study.

AIM: To evaluate pharmacokinetics, efficacy and safety of fixed-dose combination (FDC) of oral capecitabine + cyclophosphamide in metastatic breast cancer (MBC) patients progressing after anthracycline and/or taxane chemotherapy. METHODS: In this prospective, adaptive, phase-2/3, open-label study (CTRI/2014/12/005234), patients were randomized (1:1:1) to three FDC doses (doses/day: D1, capecitabine + cyclophosphamide 1400 mg + 60 mg; D2, 1800 mg + 80 mg; D3, 2200 mg + 100 mg) for 14 days, in 21-day cycles. In Part-I, multiple-dose pharmacokinetics and optimal dose(s) were evaluated with futility analysis. Group(s) with <3 responders based on best overall response rate (BOR, complete response [CR]+partial response [PR]), were discontinued. Efficacy (BOR, disease control rates [DCR; CR + PR + stable disease]) and safety of optimal dose(s) were evaluated in Part-II. RESULTS: Of 66 patients (n = 22/group) in Part-I, pharmacokinetics (D1 = 7/22, D2 = 9/22, D3 = 8/22) showed dose-proportionality for cyclophosphamide and greater than dose-proportionality for capecitabine. Modified intent-to-treat (mITT) analysis showed BOR of 7.14% (1/14) in D1 (discontinued), and 22.22% (4/18) each in D2 and D3, respectively. In Part-II, 50 additional patients were randomized in D2 and D3 (n = 144; total 72 [22 + 50] patients/group). mITT analysis in D2 (n = 54) and D3 (n = 58) showed BOR of 29.63% (16/54, 95%CI: 17.45-41.81%) and 22.41% (13/58, 95%CI: 11.68-33.15%), respectively. DCR in D2 and D3 were 87.04% (47/54, 95%CI: 78.08-96.00%) and 82.76% (48/58; 95%CI: 73.04-92.48%) after 3 and 57.41% (31/54; 95%CI: 52.41-79.50%) and 50.00% (29/58; 95%CI: 40.40-67.00%), after 6-cycles, respectively. Hand-foot syndrome (16.67%), vomiting (9.72%) in D2, and hand-foot syndrome (18.06%), asthenia (15.28%) in D3 were most-common adverse events. CONCLUSION: FDC of capecitabine + cyclophosphamide (1800 + 80 mg/day) showed high disease control rates and good safety profile in MBC patients.

g-C3N4/Ca2Fe2O5 heterostructures for enhanced photocatalytic degradation of organic effluents under sunlight.

g-C3N4/Ca2Fe2O5 heterostructures were successfully prepared by incorporating g-C3N4 into Ca2Fe2O5 (CFO). As prepared g-C3N4/CFO heterostructures were initially utilized to photodegrade organic effluent Methylene blue (MB) for optimization of photodegradation performance. 50% g-C3N4 content in CFO composition showed an enhanced photodegradation efficiency (~ 96%) over g-C3N4 (48.15%) and CFO (81.9%) due to mitigation of recombination of photogenerated charge carriers by Type-II heterojunction. The optimized composition of heterostructure was further tested for degradation of Bisphenol-A (BPA) under direct sunlight, exhibiting enhanced photodegradation efficiency of about 63.1% over g-C3N4 (17%) and CFO (45.1%). The photoelectrochemical studies at various potentials with and without light illumination showed significant improvement in photocurrent response for g-C3N4/Ca2Fe2O5 heterostructures (~ 1.9 mA) over CFO (~ 67.4 µA). These studies revealed efficient solar energy harvesting ability of g-C3N4/Ca2Fe2O5 heterostructures to be utilized for organic effluent treatment.

Expression of Autophagy and Mitophagy Markers in Breast Cancer Tissues.

Mitochondria play important roles in regulating cell bioenergetics status and reactive oxygen species (ROS) generation. ROS-induced mitochondrial damage is among the main intracellular signal inducers of autophagy. Autophagy is a cellular catabolic process that regulates protein and organelle turnover, while a selective form of autophagy, mitophagy, specifically targets dysfunctional mitochondrial degradation. This study aims to measure the levels of autophagy, mitophagy, oxidative stress, and apoptosis in invasive breast carcinoma tissues using immunohistochemistry (IHC). Tissue microarrays of 76 patients with breast cancer were stained with six IHC markers (MnSOD, Beclin-1, LC3, BNIP3, Parkin, and cleaved caspase 3). The expression intensity was determined for each tumor tissue and the adjacent tumor-matched control tissues. Intermediate and strong staining scores of MnSOD, Beclin-1, LC-3, BNIP-3, and Parkin were significantly higher in tumor tissues compared to the adjacent matched control. The scoring intensity was further classified into tissues with negative staining and positive staining, which showed that positive scores of Beclin-1 and Parkin were significantly high in tumor tissues compared to other markers. Positive association was also noted between BNIP-3 and Beclin-1 as well as LC-3 and cleaved caspase-3 immunostaining. To our knowledge, this is one of the first studies that measure both mitophagy and autophagy in the same breast cancer tissues and the adjacent matched control. The findings from this study will be of great potential in identifying new cancer biomarkers and inspire significant interest in applying anti-autophagy therapies as a possible treatment for breast cancer.

The role of deep eutectic solvents and carrageenan in synthesizing biocompatible anisotropic metal nanoparticles.

Plasmonic metal nanoparticles are widely used for many applications due to their unique optical and chemical properties. Over the past decade, anisotropic metal nanoparticles have been explored for imaging, sensing, and diagnostic applications. The variations and flexibility of tuning the size and shape of the metal nanoparticles at the nanoscale made them promising candidates for biomedical applications such as therapeutics, diagnostics, and drug delivery. However, safety and risk assessment of the nanomaterials for clinical purposes are yet to be made owing to their cytotoxicity. The toxicity concern is primarily due to the conventional synthesis route that involves surfactants as a structure-directing agent and as a capping agent for nanoparticles. Wet chemical methods employ toxic auxiliary chemicals. However, the approach yields monodispersed nanoparticles, an essential criterion for their intended application and a limitation of the green synthesis of nanoparticles using plant extracts. Several biocompatible counterparts such as polymers, lipids, and chitosan-based nanoparticles have been successfully used in the synthesis of safe nanomaterials, but there were issues regarding reproducibility and yield. Enzymatic degradation was one of the factors responsible for limiting the efficacy. Hence, it is necessary to develop a safer and nontoxic route towards synthesizing biocompatible nanomaterials while retaining morphology, high yield, and monodispersity. In this regard, deep eutectic solvents (DESs) and carrageenan as capping agent for nanoparticles can ensure the safety. Carrageenan has the potential to act as antibacterial and antiviral agent, and adds enhanced stability to the nanoparticles. This leads to a multidimensional approach for utilizing safe nanomaterials for advanced biomedical and clinical applications.

Carrot Juice Consumption Reduces High Fructose-Induced Adiposity in Rats and Body Weight and BMI in Type 2 Diabetic Subjects.

Nutritional intervention is a key strategy in the control and management of non-communicable diseases. Here, initially, we evaluated the effects of carrot juice (CJ) on some of the physical and biochemical parameters in rats fed with high-fructose diet, then in type 2 diabetic subjects. For the animal study, weanling male Wistar rats were given control (n = 6) or high fructose (HFr; n = 24) diet for 8 weeks. Then, the HFr group rats were subdivided into 4 groups (n = 6 in each) and continued either on HFr diet or shifted to control diet, with or without CJ (0.3 mg ß-carotene) ingestion orally for 8 weeks. At the end, the ingestion of CJ reversed the HFr-induced adiposity (23 ± 1.6 vs 18 ± 1.1, P = .038), hypertriglyceridemia (182 ± 18.2 vs 90 ± 10.5 mg/dL, P<0.001), and hyperinsulinemia (81 ± 14.7 vs 40 ± 7.5 µU/mL, P = .014), while increased the retinol levels in liver (240 ± 38.4 vs 492 ± 61.2 µg/g, P = .002) and adipose tissue (1.8 ± 0.09 vs 2.5 ± 0.18 µg/g, P = .026). On the other hand, in the diabetic subjects (7 males and females each, n = 14) compared to their baseline, the daily consumption of 50 mL CJ (~2400 µg ß-carotene) for 6 weeks significantly reduced the body weight (69.4 ± 4.13 vs 69.0 ± 4.09 kg, P = .014), BMI (27.4 ± 1.07 vs 27.2 ± 1.06 kg/m2, P = .007), and fat% (33.4 ± 1.87 vs 31.9 ± 2.13, P = .029) with an increase in plasma ß-carotene levels (0.21 ± 0.045 vs 0.45 ± 0.089 µmol/L, P = .044). Although CJ increased the glucose (145 ± 10.4 vs 165 ± 11.4 mg/dL, P = .039), insulin, and glycated hemoglobin levels remained unaltered. In conclusion, the consumption of carrot juice reversed the HFr-induced metabolic abnormalities in a rat model and decreased body weight and BMI of diabetic subjects.

Hypoxia via ERK Signaling Inhibits Hepatic PPARα to Promote Fatty Liver.

BACKGROUND & AIMS: Fatty liver or nonalcoholic fatty liver disease (NAFLD) is the most common liver disease associated with comorbidities such as insulin resistance and cardiovascular and metabolic diseases. Chronic activation of hypoxic signaling, in particular, hypoxia-inducible factor (HIF)2α, promotes NAFLD progression by repressing genes involved in fatty acid ß-oxidation through unclear mechanisms. Therefore, we assessed the precise mechanism by which HIF2α promotes fatty liver and its physiological relevance in metabolic homeostasis. METHODS: Primary hepatocytes from VHL (VhlΔHep) and PPARα (Ppara-null) knockout mice that were loaded with fatty acids, murine dietary protocols to induce hepatic steatosis, and fasting-refeeding dietary regimen approaches were used to test our hypothesis. RESULTS: Inhibiting autophagy using chloroquine did not decrease lipid contents in VhlΔHep primary hepatocytes. Inhibition of ERK using MEK inhibitor decreased lipid contents in primary hepatocytes from a genetic model of constitutive HIF activation and primary hepatocytes loaded with free fatty acids. Moreover, MEK-ERK inhibition potentiated ligand-dependent activation of PPARα. We also show that MEK-ERK inhibition improved diet-induced hepatic steatosis, which is associated with the induction of PPARα target genes. During fasting, fatty acid ß-oxidation is induced by PPARα, and refeeding inhibits ß-oxidation. Our data show that ERK is involved in the post-prandial repression of hepatic PPARα signaling. CONCLUSIONS: Overall, our results demonstrate that ERK activated by hypoxia signaling plays a crucial role in fatty acid ß-oxidation genes by repressing hepatocyte PPARα signaling.

Tregs facilitate obesity and insulin resistance via a Blimp-1/IL-10 axis.

Interleukin-10 (IL-10) is a critical cytokine used by immune cells to suppress inflammation. Paradoxically, immune cell-derived IL-10 can drive insulin resistance in obesity by suppressing adipocyte energy expenditure and thermogenesis. However, the source of IL-10 necessary for the suppression of adipocyte thermogenesis is unknown. We show here that CD4+Foxp3+ regulatory T cells (Tregs) are a substantial source of IL-10 and that Treg-derived IL-10 can suppress adipocyte beiging. Unexpectedly, Treg-specific loss of IL-10 resulted in increased insulin sensitivity and reduced obesity in high-fat diet-fed male mice. Mechanistically, we determined that Treg-specific loss of the transcription factor Blimp-1, a driver of IL-10 expression by Tregs, phenocopied the Treg-specific IL-10-deficient mice. Loss of Blimp-1 expression in Tregs resulted in reduced ST2+KLRG1+, IL-10-secreting Tregs, particularly in the white adipose tissue. Blimp-1-deficient mice were protected from glucose intolerance, insulin resistance, and diet-induced obesity, through increased white adipose tissue browning. Taken together, our data show that Blimp-1-regulated IL-10 secretion by Tregs represses white adipose tissue beiging to maintain adipose tissue homeostasis.