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Immune cells are vital constituents of the adipose microenvironment that influence both local and systemic lipid metabolism. Mice lacking IL10 have enhanced thermogenesis, but the roles of specific cell types in the metabolic response to IL10 remain to be defined. We demonstrate here that selective loss of IL10 receptor α in adipocytes recapitulates the beneficial effects of global IL10 deletion, and that local crosstalk between IL10-producing immune cells and adipocytes is a determinant of thermogenesis and systemic energy balance. S ingle N uclei A di p ocyte RNA -seq uencing (SNAP-seq) of subcutaneous adipose tissue defined a metabolically-active mature adipocyte subtype characterized by robust expression of genes involved in thermogenesis whose transcriptome was selectively responsive to IL10Rα deletion. Furthermore, single-cell transcriptomic analysis of adipose stromal populations identified lymphocytes as a key source of IL10 production in response to thermogenic stimuli. These findings implicate adaptive immune cell-adipocyte communication in the maintenance of adipose subtype identity and function.

Aster proteins mediate the nonvesicular transport of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER). However, the importance of nonvesicular sterol movement for physiology and pathophysiology in various tissues is incompletely understood. Here we show that loss of Aster-B leads to diet-induced obesity in female but not in male mice, and that this sex difference is abolished by ovariectomy. We further demonstrate that Aster-B deficiency impairs nonvesicular cholesterol transport from the PM to the ER in ovaries in vivo, leading to hypogonadism and reduced estradiol synthesis. Female Aster-B-deficient mice exhibit reduced locomotor activity and energy expenditure, consistent with established effects of estrogens on systemic metabolism. Administration of exogenous estradiol ameliorates the diet-induced obesity phenotype of Aster-B-deficient female mice. These findings highlight the key role of Aster-B-dependent nonvesicular cholesterol transport in regulating estradiol production and protecting females from obesity.

Breast cancer is a significant public health problem globally and prevention strategies have become of great interest as its incidence rises. Exploring the connection between dietary patterns and the reduction of breast cancer risk is considered a promising approach. High levels of fiber, phytochemicals, a good antioxidant profile, and a composition of advantageous fatty acids are characteristics of healthy dietary programs such as the Mediterranean diet. This review summarized and discussed the active compounds that are considered important in preventing breast cancer, including dietary components from recent related reports. These include polyunsaturated fatty acids, fiber, phytochemicals, and alcohol. Although the exact mechanism for preventing breast cancer using these dietary factors is not well understood, the combination of all the elements in a healthy diet plays a role in reducing breast cancer risk. Considering the elevated probability of breast cancer relapse and mortality, it is crucial to investigate the correlation between a nutritious dietary pattern and breast cancer, while identifying bioactive components that have the potential to mitigate the risk of breast cancer incidence.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a group of functionally versatile proteins that play critical roles in the biogenesis, cellular localization and transport of RNA. Here, we outline a role for hnRNPs in gene regulatory circuits controlling sterol homeostasis. Specifically, we find that tissue-selective loss of the conserved hnRNP RALY enriches for metabolic pathways. Liver-specific deletion of RALY alters hepatic lipid content and serum cholesterol level. In vivo interrogation of chromatin architecture and genome-wide RALY-binding pattern reveal insights into its cooperative interactions and mode of action in regulating cholesterogenesis. Interestingly, we find that RALY binds the promoter region of the master metabolic regulator Srebp2 and show that it directly interacts with coactivator Nuclear Transcription Factor Y (NFY) to influence cholesterogenic gene expression. Our work offers insights into mechanisms orchestrating selective promoter activation in metabolic control and a model by which hnRNPs can impact health and disease states. Heterogeneous nuclear ribonucleoproteins (hnRNPs) play critical roles in the biogenesis, localization and transport of RNA. Here authors investigate a role for hnRNPs in sterol metabolism in mice and provide insights into their role in selective promoter activation.

Sleeve gastrectomy is one of the most common bariatric procedures because of its simplicity and effectiveness. Gastro-esophageal reflux disease (GERD) symptoms and weight regain after SG are common issues. Roux-en-Y gastric bypass (RYGB) is currently the most promising approach to achieve satisfying weight loss and GERD remission; however, remnant gastric cancer is still a major concern for patients. We present a video case that individualized procedure of Nissen fundoplication, and SASI bypass (N-SASI) was designed and applied to the patient with class III obesity and severe GERD. This is a 37-year-old man with obesity (BMI: 41.8 kg/m2, categorized as class III obesity) and associated disease of stage 1 hypertension, hyperlipidemia, obstructive sleep apnea syndrome, and non-alcoholic steatohepatitis as well as severe symptoms of GERD. Esophageal-gastro-duodenal scope revealed GERD grade C, hiatal hernia, and duodenal ulcer. He refused RYGB recommended initially due to serious concern about remnant gastric cancer. We therefore performed Nissen fundoplication for his GERD symptoms and adapted SASI bypass instead of RYGB as the individualized bariatric surgery to achieve the optimal surgical outcome. The postoperative course was smooth, and the patient was discharged on postoperative day 8.

Microporous annealed particle (MAP) scaffolds are flowable, in situ crosslinked, microporous scaffolds composed of microgel building blocks and were previously shown to accelerate wound healing. To promote more extensive tissue ingrowth before scaffold degradation, we aimed to slow MAP degradation by switching the chirality of the crosslinking peptides from l - to d -amino acids. Unexpectedly, despite showing the predicted slower enzymatic degradation in vitro, d -peptide crosslinked MAP hydrogel ( d -MAP) hastened material degradation in vivo and imparted significant tissue regeneration to healed cutaneous wounds, including increased tensile strength and hair neogenesis. MAP scaffolds recruit IL-33 type 2 myeloid cells, which is amplified in the presence of d -peptides. Remarkably, d -MAP elicited significant antigen-specific immunity against the d -chiral peptides, and an intact adaptive immune system was required for the hydrogel-induced skin regeneration. These findings demonstrate that the generation of an adaptive immune response from a biomaterial is sufficient to induce cutaneous regenerative healing despite faster scaffold degradation. Microporous annealed-particle degradable scaffolds have been developed and shown to induce type 2 innate and adaptive immune response that facilitated skin wound healing.

Plasma membranes of animal cells are enriched for cholesterol. Cholesterol-dependent cytolysins (CDCs) are pore-forming toxins secreted by bacteria that target membrane cholesterol for their effector function. Phagocytes are essential for clearance of CDC-producing bacteria; however, the mechanisms by which these cells evade the deleterious effects of CDCs are largely unknown. Here, we report that interferon (IFN) signals convey resistance to CDC-induced pores on macrophages and neutrophils. We traced IFN-mediated resistance to CDCs to the rapid modulation of a specific pool of cholesterol in the plasma membrane of macrophages without changes to total cholesterol levels. Resistance to CDC-induced pore formation requires the production of the oxysterol 25-hydroxycholesterol (25HC), inhibition of cholesterol synthesis and redistribution of cholesterol to an esterified cholesterol pool. Accordingly, blocking the ability of IFN to reprogram cholesterol metabolism abrogates cellular protection and renders mice more susceptible to CDC-induced tissue damage. These studies illuminate targeted regulation of membrane cholesterol content as a host defense strategy. Bensinger and colleagues show that interferons promote host cell resistance to bacterial cytolysins by decreasing cholesterol synthesis and promoting the esterification of cholesterol, which alters the availability of this pool of ‘free’ cholesterol needed for pore formation.

Background Prior studies have shown an association between generalized periodontitis and anemia in older or undernourished adults. The aim of the study was to examine the associations of erythrocyte indices with localized periodontitis in robust young adults, which has never been reported before. Methods The study included 1286 military participants, aged 19–40 years, with regular exercise training in Hualien, Taiwan. Localized periodontitis was grouped to healthy/stage I and stage II/III (n = 803 and 325) in men and (n = 130 and 28) in women according to the 2017 criteria of the world workshop. Systemic inflammation was evaluated by leukocyte counts. Multiple logistic regression analysis with adjustment for age, tobacco smoking status, betel nut chewing status, body mass index and leucocyte counts were used to determine the associations. Results Greater mean corpuscular volume in young men [odds ratio (OR) and 95% confidence intervals 1.03 (1.01–1.06)], and greater hematocrit and hemoglobin levels in young women were associated with a higher risk of localized stage II/III periodontitis [OR: 1.17 (1.02–1.34) and 1.60 (1.06–2.41), respectively]. However, there were no associations for erythrocyte counts. Conclusions The localized stage II/III periodontitis risk increased with greater erythrocyte indices in robust young adults. This finding could be explained in part by that localized periodontitis may promote physical stress, possibly resulting in an increase of erythrocyte indices. On the other side, greater physical fitness associated with a lower risk of periodontitis may consume iron storage in the body, leading to exercise-induced anemia or smaller erythrocyte volume.

Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). HCV core protein is considered as a positive regulator of telomerase activity. In this study, we focused on the deregulated microRNA-138 (miR-138) in HCV-associated HCC. Differential expression of miR-138 was determined by TaqMan quantitative real-time PCR. The target gene of miR-138 was verified by luciferase reporter assay, quantitative real-time PCR, and Western blotting. Moreover, three assays based on telomerase activity, cell proliferation, and senescence-associated β-galactosidase activity were performed. The correlation analysis revealed a significantly negative correlation between miR-138 and telomerase reverse transcriptase (TERT) mRNA expression in HCC. Further, we showed that mature HCV core protein of 173 amino acids, but not full-length form of 191 amino acids, suppressed miR-138 expression. TERT was verified as a direct target of miR-138 in HCC cells. Furthermore, TERT-targeting miR-138 supplementation can prevent HCV core protein from repressing HCC cell replicative senescence. Collectively, HCV core protein can enhance TERT protein expression through downregulating TERT-targeting miR-138 expression, which in turn inhibits HCC cell replicative senescence. This study may further help our understanding on the pathogenic mechanisms of HCV core protein in HCV-associated HCC development. Key message miR-138 is downregulated in HCV-associated HCC. Mature HCV core protein plays a pathogenic role in suppressing miR-138 expression. Telomerase reverse transcriptase represents a direct target of miR-138 in HCC cells. miR-138 promotes HCC cell senescence, suggesting potential for HCC treatment.

Introduction Esophagogastric varices bleeding is a common complication due to portal hypertension in patients with liver cirrhosis. With the advancement of nonoperative management including vasoactive agents, endoscopic hemostasis or transjugular intrahepatic portosystemic shunt, surgical management has played a lesser role in recent decades. The present report describes a patient with hepatitis B (HBV)-related liver cirrhosis and portal vein thrombosis with recurrent esophagogastric varices bleeding despite the use of medical and endoscopic therapy. The modified Sugiura procedure was performed as an alternative bridge surgery for liver transplantation in order not to change the anatomic structure of the great vessels and to avoid hepatic encephalopathy related to shunting procedures like the transjugular intrahepatic portosystemic shunt. Case presentation A 56-year-old Chinese man with a history of portal hypertension due to HBV-related liver cirrhosis and known former recurrent esophageal varices bleeding status post Sengstaken-Blakemore tube tamponade was referred to our hospital for liver transplantation evaluation because of persistent esophagogastric varices bleeding with hypovolemic shock, even after medical and endoscopic therapies in a local hospital. As a result, liver cirrhosis with Child-Pugh class B function was diagnosed. Despite the use of vasoactive agents, and endoscopic hemostasis management, esophagogastric varices bleeding still occurred episodically with hypovolemic shock, which could not be reversed by blood transfusion or Sengstaken-Blakemore tube tamponade. The modified Sugiura procedure, as an alternative bridge therapy for patients who are candidates for liver transplantation, was performed, despite the fact that his liver transplantation was not yet completed. He then received a living donor liver transplantation with the right lobe of liver from his daughter. The postoperative course was uneventful, and he was discharged two weeks later. He had no evidence of recurrent esophagogastric varices bleeding during the six-month follow-up. Conclusions The treatment experience of this case gave us not only the idea but also the practical way of applying the modified Sugiura operation as a bridge and rescue therapy without alteration of the vascular anatomy and hemodynamic stability for patients who have experienced refractory esophagogastric varices bleeding, despite the use of medication and endoscopic treatment, and are candidates for receiving a liver transplantation.