Metabolic rewiring of macrophages by epidermal-derived lactate promotes sterile inflammation in the murine skin.

Dysregulated macrophage responses and changes in tissue metabolism are hallmarks of chronic inflammation in the skin. However, the metabolic cues that direct and support macrophage functions in the skin are poorly understood. Here, we show that during sterile skin inflammation, the epidermis and macrophages uniquely depend on glycolysis and the TCA cycle, respectively. This compartmentalisation is initiated by ROS-induced HIF-1α stabilization leading to enhanced glycolysis in the epidermis. The end-product of glycolysis, lactate, is then exported by epithelial cells and utilized by the dermal macrophages to induce their M2-like fates through NF-κB pathway activation. In addition, we show that psoriatic skin disorder is also driven by such lactate metabolite-mediated crosstalk between the epidermis and macrophages. Notably, small-molecule inhibitors of lactate transport in this setting attenuate sterile inflammation and psoriasis disease burden, and suppress M2-like fate acquisition in dermal macrophages. Our study identifies an essential role for the metabolite lactate in regulating macrophage responses to inflammation, which may be effectively targeted to treat inflammatory skin disorders such as psoriasis.

Prospective study on the clinical and economic burden of venous leg ulcers in the tropics.

OBJECTIVE: Venous leg ulcers (VLUs) are both chronic and recurrent. The treatment of such ulcers often require multiple outpatient visits and dressing changes. Several reports on the costs of treating such VLUs have been reported in the west. We prospectively evaluated the clinical and economic burden of VLUs in a population of Asian patients in the tropics. METHODS: Patients from a prospective two-center study conducted at two tertiary hospitals in Singapore, as a part of the Wound Care Innovation in the Tropics program, between August 2018 and September 2021 were recruited. The patients were followed up for 12 weeks (visit 1 to visit 12), until index ulcer healing, death, or lost to follow-up (whichever came first). These patients were then followed up 12 weeks later to determine the longer term outcome of the wound (healed, recurrence, remained unhealed). The itemized costs derived from the medical service were retrieved from the relevant departments of the study sites. The patients' health-related quality of life was assessed at baseline and the last visit of the 12-week follow-up period (or until index ulcer healing), using the official Singapore version of the EuroQol five-dimension-5L questionnaire, which also includes a visual analog scale (EQ-VAS). RESULTS: A total of 116 patients were enrolled; 63% were men, and the mean patient age was 64.7 years. Of the 116 patients, 85 (73%) had a healed ulcer at 24 weeks (mean duration to ulcer healing, 49 days), and 11 (12.9%) had experienced ulcer recurrence within the study period. Within the 6-month follow-up period, the mean direct healthcare cost per patient was USD$1998. The patients with healed ulcers had significantly lower costs per patient compared with those with unhealed ulcers (USD$1713 vs USD$2780). Regarding health-related quality of life, 71% of the patients had a lower quality of life at baseline, which had improved at 12 weeks of follow-up, with only 58% of the patients reported to have a lower quality of life. Also, the patients with healed ulcers scored higher for both utilities (societal preference weights) and EQ-VAS at follow-up (P < .001). In contrast, patients with unhealed ulcers only scored higher EQ-VAS at follow-up (P = .003). CONCLUSIONS: The findings from this exploratory study provide information on the clinical, quality of life, and economic burden of VLUs in an Asian population and suggest the importance of healing VLUs to reduce the effects on patients. The present study provides data as a basis for economic evaluation as a consideration for the treatment of VLUs.

Fructose intolerance is not associated with malabsorption in patients with functional gastrointestinal disorders.

BACKGROUND: Symptoms following fructose ingestion, or fructose intolerance, are common in patients with functional gastrointestinal disorders (FGID) and are generally attributed to intestinal malabsorption. The relationships between absorption, symptoms, and intestinal gas production following fructose ingestion were studied in patients with FGID. METHODS: Thirty FGID patients ingested a single dose of fructose 35 g or water in a randomized, double-blind, crossover study. Blood and breath gas samples were collected, and gastrointestinal symptoms rated. Plasma fructose metabolites and short-chain fatty acids were quantified by targeted liquid chromatography-tandem mass spectrometry. Patients were classified as fructose intolerant or tolerant based on symptoms following fructose ingestion. KEY RESULTS: The median (IQR) areas under the curve of fructose plasma concentrations within the first 2 h (AUC0-2 h ) after fructose ingestion were similar for patients with and without fructose intolerance (578 (70) µM·h vs. 564 (240) µM·h, respectively, p = 0.39), as well as for the main fructose metabolites. There were no statistically significant correlations between the AUC0-2 h of fructose or its metabolites concentrations and the AUCs of symptoms, breath hydrogen, and breath methane. However, the AUCs of symptoms correlated significantly and positively with the AUC0-2 h of hydrogen and methane breath concentrations (r = 0.73, r = 0.62, respectively), and the AUCs of hydrogen and methane concentrations were greater in the fructose-intolerant than in the fructose-tolerant patients after fructose ingestion (p ≤ 0.02). CONCLUSIONS & INFERENCES: Fructose intolerance in FGID is not related to post-ingestion plasma concentrations of fructose and its metabolites. Factors other than malabsorption, such as altered gut microbiota or sensory function, may be important mechanisms.

Tryptophan-kynurenine ratio as a biomarker of bladder cancer.

OBJECTIVES: To investigate plasma and urinary kynurenine (KYN)-tryptophan (TRP) ratios in bladder cancer, expression of indoleamine 2,3-dioxygenase 1 (IDO1) in relation to tryptophan 2,3-dioxygenase (TDO2) in bladder tumour, and the correlation of KYN-TRP ratio with bladder tumour burden. METHODS: Metabotyping of the TRP-KYN metabolic axis was performed via a clinical case-control study. Expression of IDO1 and TDO2 was measured in human biopsied tissues. Correlational experiments between KYN-TRP ratio and bladder tumour were performed using a murine orthotopic prostate-specific antigen (PSA)-secreting MB49 bladder cancer model. RESULTS: We established for the first time that plasma TRP level was significantly decreased, while both plasma and urinary KYN-TRP ratios were significantly higher in bladder cancer patients, and expression level of IDO1 but not TDO2 was increased in human bladder tumour. We reported the positive correlation between IDO1 expression, KYN-TRP ratio, normalized PSA to creatinine, and bladder tumour burden in the murine model. CONCLUSION: Kynurenine-tryptophan ratio is a promising surveillance biomarker for bladder cancer, but would require further validation before clinical translation.

Polyphenol-rich curry made with mixed spices and vegetables benefits glucose homeostasis in Chinese males (Polyspice Study): a dose-response randomized controlled crossover trial.

PURPOSE: To investigate acute effects of two doses of a polyphenol-rich curry made with seven different spices and four base vegetables, eaten with white rice, on 24 h glucose response, postprandial insulinemia, triglyceridemia and 24 h urinary total polyphenol excretion (TPE). METHODS: Randomized, controlled, dose-response crossover trial in healthy, Chinese men [n = 20, mean ± standard deviation (SD) age 23.7 ± 2.30 years, BMI 23.0 ± 2.31 kg/m2] who consumed test meals matched for calories, macronutrients and total vegetables content, consisting either Dose 0 Control (D0C) or Dose 1 Curry (D1C) or Dose 2 Curry (D2C) meal. 24 h glucose concentration was measured using continuous glucose monitoring (CGM), together with postprandial plasma insulin and triglyceride for up to 7 h. Total polyphenol content (TPC) of test meals and urinary TPE were measured using the Folin-Ciocalteu assay. RESULTS: TPC for D0C, D1C and D2C were 130 ± 18, 556 ± 19.7 and 1113 ± 211.6 mg gallic acid equivalent (GAE) per portion served, respectively (p < 0.0001). Compared with D0C meal, we found significant linear dose-response reductions in the 3-h postprandial incremental AUC (iAUC) for CGM glucose of 19% and 32% during D1C and D2C meals respectively (p < 0.05) and non-significant linear dose response reductions in iAUC of insulin (p = 0.089). Notably, we found significant dose-dependent increases in postprandial triglyceride with increasing curry doses (p < 0.01). Significant increases in TPE with increasing curry doses were also observed (p < 0.01). CONCLUSION: Polyphenol-rich curry intake can improve postprandial glucose homeostasis. The longer term effects remain to be established.

Dose-Dependent Increase in Unconjugated Cinnamic Acid Concentration in Plasma Following Acute Consumption of Polyphenol Rich Curry in the Polyspice Study.

Spices that are rich in polyphenols are metabolized to a convergent group of phenolic/aromatic acids. We conducted a dose-exposure nutrikinetic study to investigate associations between mixed spices intake and plasma concentrations of selected, unconjugated phenolic/aromatic acids. In a randomized crossover study, 17 Chinese males consumed a curry meal containing 0 g, 6 g, and 12 g of mixed spices. Postprandial blood was drawn up to 7 h at regular intervals and plasma phenolic/aromatic acids were quantified via liquid chromatography tandem mass spectrometry (LC-MS/MS). Cinnamic acid (CNA, p < 0.0001) and phenylacetic acid (PAA, p < 0.0005) concentrations were significantly increased with mixed spices consumption, although none of the other measured phenolic/aromatic acids differ significantly between treatments. CNA displayed a high dose-exposure association (R² > 0.8, p < 0.0001). The adjusted mean area under the plasma concentration-time curve until 7 h (AUC0⁻7 h) for CNA during the 3 increasing doses were 8.4 ± 3.4, 376.1 ± 104.7 and 875.7 ± 291.9 nM.h respectively. Plasma CNA concentration may be used as a biomarker of spice intake.

The liver-gut microbiota axis modulates hepatotoxicity of tacrine in the rat.

The gut microbiota possesses diverse metabolic activities, but its contribution toward heterogeneous toxicological responses is poorly understood. In this study, we investigated the role of the liver-gut microbiota axis in underpinning the hepatotoxicity of tacrine. We employed an integrated strategy combining pharmacokinetics, toxicology, metabonomics, genomics, and metagenomics to elucidate and validate the mechanism of tacrine-induced hepatotoxicity in Lister hooded rats. Pharmacokinetic studies in rats demonstrated 3.3-fold higher systemic exposure to tacrine in strong responders that experienced transaminitis, revealing enhanced enterohepatic recycling of deglucuronidated tacrine in this subgroup, not attributable to variation in hepatic disposition gene expression. Metabonomic studies implicated variations in gut microbial activities that mapped onto tacrine-induced transaminitis. Metagenomics delineated greater deglucuronidation capabilities in strong responders, based on differential gut microbial composition (e.g., Lactobacillus, Bacteroides, and Enterobacteriaceae) and approximately 9% higher ß-glucuronidase gene abundance compared with nonresponders. In the validation study, coadministration with oral ß-glucuronidase derived from Escherichia coli and pretreatment with vancomycin and imipenem significantly modulated the susceptibility to tacrine-induced transaminitis in vivo. CONCLUSION: This study establishes pertinent gut microbial influences in modifying the hepatotoxicity of tacrine, providing insights for personalized medicine initiatives. (Hepatology 2018;67:282-295).

Progress in Exosome Isolation Techniques.

Exosomes are one type of membrane vesicles secreted into extracellular space by most types of cells. In addition to performing many biological functions particularly in cell-cell communication, cumulative evidence has suggested that several biological entities in exosomes like proteins and microRNAs are closely associated with the pathogenesis of most human malignancies and they may serve as invaluable biomarkers for disease diagnosis, prognosis, and therapy. This provides a commanding impetus and growing demands for simple, efficient, and affordable techniques to isolate exosomes. Capitalizing on the physicochemical and biochemical properties of exosomes, a number of techniques have been developed for the isolation of exosomes. This article summarizes the advances in exosome isolation techniques with an emphasis on their isolation mechanism, performance, challenges, and prospects. We hope that this article will provide an overview of exosome isolation techniques, opening up new perspectives towards the development more innovative strategies and devices for more time saving, cost effective, and efficient isolations of exosomes from a wide range of biological matrices.