Liver Lipidomics Analysis Revealed the Novel Ameliorative Mechanisms of L-Carnitine on High-Fat Diet-Induced NAFLD Mice.

The beneficial effects of L-carnitine on non-alcoholic fatty liver disease (NAFLD) were revealed in previous reports. However, the underlying mechanisms remain unclear. In this study, we established a high fat diet (HFD)-induced NAFLD mice model and systematically explored the effects and mechanisms of dietary L-carnitine supplementation (0.2% to 4%) on NAFLD. A lipidomics approach was conducted to identify specific lipid species involved in the ameliorative roles of L-carnitine in NAFLD. Compared with a normal control group, the body weight, liver weight, concentrations of TG in the liver and serum AST and ALT levels were dramatically increased by HFD feeding (p < 0.05), accompanied with obvious liver damage and the activation of the hepatic TLR4/NF-κB/NLRP3 inflammatory pathway. L-carnitine treatment significantly improved these phenomena and exhibited a clear dose-response relationship. The results of a liver lipidomics analysis showed that a total of 12 classes and 145 lipid species were identified in the livers. Serious disorders in lipid profiles were noticed in the livers of the HFD-fed mice, such as an increased relative abundance of TG and a decreased relative abundance of PC, PE, PI, LPC, LPE, Cer and SM (p < 0.05). The relative contents of PC and PI were significantly increased and that of DG were decreased after the 4% L-carnitine intervention (p < 0.05). Moreover, we identified 47 important differential lipid species that notably separated the experimental groups based on VIP ≥ 1 and p < 0.05. The results of a pathway analysis showed that L-carnitine inhibited the glycerolipid metabolism pathway and activated the pathways of alpha-linolenic acid metabolism, glycerophospholipid metabolism, sphingolipid metabolism and Glycosylphosphatidylinositol (GPI)-anchor biosynthesis. This study provides novel insights into the mechanisms of L-carnitine in attenuating NAFLD.

Dietary supplementation of L-carnitine ameliorates metabolic syndrome independent of trimethylamine N-oxide produced by gut microbes in high-fat diet-induced obese mice.

Metabolic syndrome (MS) is a collection of risk factors of serious metabolic diseases. L-Carnitine is an essential nutrient for human health, and the precursor of trimethylamine N-oxide (TMAO). Previous studies have shown that the effect of L-carnitine on MS is controversial, and no studies have considered the role of gut microbiota in the regulation of MS by L-carnitine. In the present study, we established a high-fat diet (HFD)-induced obese mice model and systematically explored the effect of a broad range of dietary L-carnitine concentrations (0.2% to 4%) on the major components of MS. The results show that L-carnitine (0.5%-4%) reduced HFD-caused body-weight gain, visceral adipose tissue, glucose intolerance, hyperglycemia, HOMA-IR index, hyperlipemia, hypertension, and hyperuricemia. The elevation in the concentrations of IL-6, IL-1ß, and TNF-α and decline in IL-10 in both serum and adipose tissue were also attenuated by L-carnitine. Furthermore, dietary L-carnitine increased the serum levels of TMAO produced by gut microbes. High-dose L-carnitine (2% and 4%), but not low-dose L-carnitine (0.2%-1%), notably modulated the composition of gut microbiota and partially attenuated HFD-induced gut microbiota dysbiosis. These results suggest that the ameliorative effect of L-carnitine on MS was independent of TMAO production and only partially related to the regulation of gut microbiota. This study provides crucial evidence for the utilization of L-carnitine as a safe and effective supplement for MS.

A Photosensitizer Discretely Loaded Nanoaggregate with Robust Photodynamic Effect for Local Treatment Triggers Systemic Antitumor Responses.

Photodynamic therapy (PDT), is a rising star for suppression of in situ and metastatic tumors, yet it is impeded by low ROS production and off-target phototoxicity. Herein, an aggregation degree editing strategy, inspired by gene editing, was accomplished by the coordination of an aggregation degree editor, p(MEO2MA160-co-OEGMA40)-b-pSS30 [POEGS; MEO2MA = 2-(2-methoxyethoxy)ethyl methacrylate, OEGMA = oligo(ethylene glycol) methacrylate; pSS = poly(styrene sulfonate)] and indocyanine green (ICG) to nontoxic Mg2+, forming an ICG discretely loaded nanoaggregate (ICG-DNA). Optimization of the ICG aggregation degree [POEGS/ICG (P/I) = 6.55] was achieved by tuning the P/I ratio, alleviating aggregation-caused-quenching (ACQ) and photobleaching concurrently. The process boosts the PDT efficacy, spurring robust immunogenic cell death (ICD) and systemic antitumor immunity against primary and metastatic immunogenic "cold" 4T1 tumors via intratumoral administration. Moreover, the temperature-sensitive phase-transition property facilitates intratumoral long-term retention of ICG-DNA, reducing undesired phototoxicity to normal tissues; meanwhile, the photothermal-induced tumor oxygenation further leads to an augmented PDT outcome. Thus, this simple strategy improves PDT efficacy, boosting the singlet oxygen quantum yield (ΦΔ)-dependent ICD effect and systemic antitumor responses via local treatment.

Polysaccharide-based recoverable double-network hydrogel with high strength and self-healing properties.

Polysaccharide-based hydrogels (PSBHs) have received significant attention for numerous bio-applications due to their biocompatibility and non-immunogenic performance. However, the construction of PSBH with superior mechanical properties by a simple method is rarely adequately researched. This study focuses on the construction of a novel PSBH with superior mechanical and recoverable properties by integrating the synergistic and complementary interactions of covalent bond-associated oxidized sodium alginate (SA-CHO) gel and hydrogen bond-associated agarose (Aga) gel. With the synergy and complementarity of the SA-CHO and Aga networks, the hydrogel exhibited 17 and 15 times (20 and 9 times) greater compressive stress and modulus, respectively, compared with the SA-CHO gel (Aga gel). The hydrogel also displayed excellent fatigue resistance, recurrent shapeability, acid resistance and recovery ability, as well as self-healing ability. This study provides a unique perspective for enhancing the mechanical properties of PSBH through the synergy and complementarity of different kinds of polysaccharides without sacrificing the functionality of the PSBH.