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Objectives: This study is intended to reveal whether the boost in immune function in immunocompromised mice from niacin supplementation is connected to the upkeep of intestinal homeostasis and the modulation of the hydroxycarboxylic acid receptor 2 (HCAR2)/NOD-like receptor protein 3 (NLRP3) and prostaglandin endoperoxide synthase 2 (PTGS2)/prostaglandin E2 (PGE2) signaling pathways. Methods: Balb/c mice were employed in this study as a model for immunosuppression caused by cyclophosphamide (CTX) injection. Results: The study showed that niacin supplementation restored spleen and liver indices, enhanced cytokine secretion, and increased Th1/Th2 cytokine levels. Niacin effectively enhanced the phagocytic index, natural killer cell (NK cell) activity, splenic lymphocyte activity and delayed-type hypersensitivity (DTH) reaction in immunocompromised mice. Histopathological examination showed that niacin intervention alleviated injury in mice ilea. Intestinal barrier tight junction proteins were expressed at much higher levels, while the serum concentrations of diamine oxidase (DAO) and fatty acid-binding protein 2 (FABP2) were markedly lowered. Furthermore, the expression of the intestinal HCAR2/NLRP3 signaling pathway and subsequent inflammatory mediators was significantly elevated after niacin administration compared with the CTX group. Niacin supplementation improved the composition of the gut microbiota, increasing the Firmicutes/Bacteroidetes (F/B) ratio. Spearman correlation analysis showed significant correlations between cytokine-related indices and several gut microbiotas. Within a network pharmacology framework including target screening, network construction and molecular docking, PTGS2 emerged as a candidate target of niacin, suggesting its role in counteracting immunosuppression. Further experimental findings showed that niacin markedly decreased the protein expression of PTGS2 and the levels of its downstream mediators PGE2, E-prostanoid receptor type 2 (EP2) and (E-prostanoid receptor type 4 (EP4) in the ileal tissue of mice treated with CTX. Conclusions: In conclusion, niacin supplementation alleviated CTX-induced immunosuppression by maintaining intestinal homeostasis and regulating the intestinal HCAR2/NLRP3 and PTGS2/PGE2/EP2-EP4 pathways.

Objectives: The purpose of this study is to observe the preventive effect of folic acid (FA) combined with melatonin (MLT) on high-fat diet (HFD)-induced hepatic steatosis and to explore its potential mechanism. Methods: Fifty male C57BL/6J mice were randomized into five groups: control group (CN), high-fat diet group (HD), FA supplementation group (HF), MLT supplementation group (HM), and FA combined with MLT supplementation group (HFM). The experiment lasted for 10 weeks. Results: FA combined with MLT effectively inhibited HFD-induced increases in liver index, hepatic TG levels, and serum TG levels. Histological examination revealed that FA combined with MLT significantly reduced the area of hepatic steatosis and the accumulation of lipid droplets (LD). Western blot analysis showed FA combined with MLT activated AMPK, inhibiting the expression of ERS-related proteins, thereby reducing the expression of LD lipolysis-associated proteins. Conclusions: FA combined with MLT might prevent HFD-induced hepatic steatosis by attenuating ERS and subsequently promoting LD lipolysis.

Objective: To explore the preventive effect and mechanism of melatonin on high-fructose-induced renal injury in mice. Methods: A total of forty male C57BL/6J mice aged six weeks were randomly assigned to four groups: control group (CON), melatonin group (MLT), fructose group (FRU), and fructose + melatonin group (FRU + MLT). The concentration of the fructose solution was 30%, and the dose of melatonin was 10 mg/kg/day by intragastric administration. The experiment lasts for 10 weeks. Results: Liquid intake and energy intake were comparable between the FRU and FRU + MLT, both of which were significantly higher than that in the CON and MLT. MLT inhibited fructose-induced increased levels in serum creatinine (Cre), serum urea nitrogen (BUN), serum uric acid (UA), serum triglyceride (TG), renal kidney injury molecule-1 (KIM-1), and renal TG. Hematoxylin and Eosin (H&E) staining and Oil Red O (ORO) staining showed that MLT alleviated renal tubular dilatation, loss of brush border, epithelial cell detachment and lipid accumulation. Transmission electron microscope (TEM) observations showed that MLT increased autophagic vacuoles among mitochondria. Western blot analysis showed that, compared with the FRU, the FRU + MLT had elevated expression of AMP-activated protein kinase (AMPK) phosphorylation, along with a significant increase in the expression of its downstream mitophagy-related proteins (including PINK1, Parkin, LC3 II, and Beclin1), whereas the expression of p62 was markedly decreased. Furthermore, the expression levels of FAO-related proteins (including PPARα and CPT1A) in the FRU + MLT were significantly upregulated. Conclusions: MLT alleviates renal injury caused by high-fructose exposure in male mice and its mechanism might be associated with the regulation of mitophagy and fatty acid oxidation.

Objectives: This study aims to observe the preventive effect of nicotinamide riboside (NR) on fructose-induced lipid metabolism disorders and explore its mechanism. Methods: Male C57BL/6J mice were fed a 20% fructose solution and given 400 mg/kg NR daily by gavage for 10 weeks. Results: The results indicated that NR supplementation significantly reduced the body weight, liver weight, white adipose tissue (WAT) weight, serum, and hepatic lipid levels. NR upregulated the protein expression levels of sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), PR domain containing 16 (PRDM16), uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor-gamma coactiva-tor-1-alpha (PGC-1α), nuclear respiratory factor 1-encoding gene (NRF1), mitochondrial transcription factor A (TFAM), cluster of differentiation 137 (CD137), transmembrane protein 26 (TMEM26), and T-box 1 (TBX1). Moreover, NR enhanced the Actinobacteria and Enterorhabdus abundance. Spearman’s correlation analysis revealed that significant correlations exist between Firmicutes, Bacteroidetes, and Erysipelotrichaceae with browning-related indicators. Conclusions: In conclusion, NR could alleviate lipid metabolic abnormalities induced by fructose through activating SIRT1/AMPK-mediated browning of WAT. The mechanism by which NR improves fructose-induced lipid metabolism disorders may also be associated with the modulation of intestinal flora.

Background: Proactively preventing postpartum weight retention (PPWR) is one of the effective intervention strategies to reduce the occurrence of obesity in women. Population studies have shown that serum folate levels are closely related to body weight. The regulation of folic acid on lipid metabolism has been fully confirmed in both in vivo and in vitro studies. For many years, folic acid supplementation has been widely used in periconceptional women due to its role in preventing fetal neural tube defects. However, whether folic acid supplementation prior to and throughout pregnancy exerts preventive effects on PPWR remains uncertain. This study aims to investigate the preventive effect of folic acid on PPWR in rats and further explore the underlying mechanisms. Methods: In this study, pregnant rats were administered one of the dietary schedules: control diet (CON), high-fat diet (HF), control diet combined with folic acid (FA) and high-fat diet combined with folic acid (HF + FA). Results: We discovered that folic acid supplementation inhibited high-fat diet-induced elevations in body weight, visceral fat weight, liver weight, hepatic lipid levels and serum lipid levels at 1 week post-weaning (PW). Western blot analysis showed that folic acid supplementation inhibited the expression of endoplasmic reticulum (ER) stress-specific proteins including GRP78, PERK, eIF2α, IRE1α, XBP1 and ATF6, subsequently decreasing the expression of proteins related to lipid synthesis including SREBP-1c, ACC1 and FAS. Conclusions: In conclusion, folic acid supplementation prior to and throughout pregnancy exerts preventive effects on high-fat diet-induced PPWR in rats, and the mechanism is associated with the inhibition of ER stress-mediated lipogenesis signaling pathways in the liver. Folic acid supplementation may serve as a potential strategy for preventing PPWR. In the future, the effectiveness of folic acid in PPWR prevention can be further verified by population studies.

Cytosolic DNA activates cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling, which triggers interferon and inflammatory responses that help defend against microbial infection and cancer. However, aberrant cytosolic self-DNA in Aicardi–Goutière’s syndrome and constituently active gain-of-function mutations in STING in STING-associated vasculopathy with onset in infancy (SAVI) patients lead to excessive type I interferons and proinflammatory cytokines, which cause difficult-to-treat and sometimes fatal autoimmune disease. Here, in silico docking identified a potent STING antagonist SN-011 that binds with higher affinity to the cyclic dinucleotide (CDN)-binding pocket of STING than endogenous 2′3′-cGAMP. SN-011 locks STING in an open inactive conformation, which inhibits interferon and inflammatory cytokine induction activated by 2′3′-cGAMP, herpes simplex virus type 1 infection, Trex1 deficiency, overexpression of cGAS-STING, or SAVI STING mutants. In Trex1 −/− mice, SN-011 was well tolerated, strongly inhibited hallmarks of inflammation and autoimmunity disease, and prevented death. Thus, a specific STING inhibitor that binds to the STING CDN-binding pocket is a promising lead compound for STING-driven disease.

The geometric distances of active galactic nuclei (AGNs) are challenging to measure because of their exceptionally compact structure, yet vast cosmic distances. A combination of spectroastrometry and reverberation mapping (SARM) of broad-line regions (BLRs) constitutes a novel means to probe the geometric distance of AGNs, which has recently become practically feasible owing to successful interferometric observations with the Very Large Telescope Interferometer/GRAVITY. Here, we perform SARM analysis of four nearby quasars: Mrk 509, PDS 456, 3C 273, and NGC 3783. Results for the former two are reported for the first time, and the latter two are revisited using our improved BLR dynamical modeling that includes the radial-dependent responsivity of BLRs. This allows us to self-consistently account for the emissivity weighting of the BLR in spectroastrometry and responsivity weighting in reverberation mapping. We obtain angular-diameter distances of the four quasars, from which we derive a Hubble constant of H0=69−10+12kms−1Mpc−1 . Although this constitutes a large uncertainty for a measurement of H0, it is anticipated that the precision will improve to a competitive level once a greater number of AGNs are accessible following the upgrade of GRAVITY in the near future. From SARM analysis, the black hole masses of the four quasars are also measured with the statistical uncertainty ranging from 0.06 to 0.23 dex, consistent with the correlations between black hole masses and properties of the host bulges.

Hydrogel, as one of potential soft materials for articular cartilage, has encountered pressing obstacles, such as insufficient mechanical properties, poor lubrication, and easy to wear. To tackle these, we propose a strong yet slippery polyvinyl alcohol/chitosan (PVA/CS) hydrogel with dual-physically crosslinked networks by harnessing freeze-thawing, salting-out, annealing, and rehydration. High mechanical properties of PVA/CS hydrogel can be readily regulated by adjusting proportion of PVA/CS and annealing temperature. The optimized hydrogel exhibits high mechanical properties with tensile strength of ∼ 19 MPa at strain of 550%, compression strength of ∼ 11 MPa at small strain of 39%, and outstanding toughness and antifatigue owing to the robust physical interactions, including hydrogen bonds, crystallization, and ionic coordination. Moreover, the equilibrium hydrogel shows low friction coefficient of ∼ 0.05 against Al 2 O 3 ball under the condition of 30 N, 1 Hz, with water as the tribological medium, which is close to the lubrication performance of native cartilage. And meanwhile, the proposed cartilage-like slippery hydrogel displays stable long-term lubrication performance for 1 × 10 5 reciprocating cycles without destructive wear and structure damage. It is therefore believed that the biocompatible cartilage-like slippery hydrogel opens innovative scenarios for developing cartilage-mimicking water-lubricated coating and biomedical implants with satisfactory load-bearing and lubrication performance.

This paper has studied the adaptive fuzzy fault-tolerant control (FTC) for active suspension systems via the sensor failure compensation method. In the control design, fuzzy logic systems (FLSs) are used to identify the unknown nonlinear dynamics, and the projection technique is utilized to deal with the multiple sensor failures. Combining with the backstepping technique, a novel FTC method has been developed. The proposed control method can guarantee that all the signals in the closed-loop system are all bounded, and the tracking error can converge to the neighbourhood of the origin. Finally, a simulation for the quarter active suspension system is given to verify the effectiveness of the developed control scheme.

Data on risk of developing chronic kidney disease (CKD) between non-obese and obese non-alcoholic fatty liver disease (NAFLD) patients are limited. We aimed to reveal the risk difference of incident CKD between non-obese and obese NAFLD patients. We searched PubMed, Embase, and Web of Science databases for studies which reported the incidence of CKD in non-obese and obese NAFLD from inception to 10 March 2024. The primary and secondary outcomes were pooled. Subgroup analysis was used to examine the heterogeneity. A total of 15 studies were incorporated. The incidence of CKD in non-obese and obese NAFLD were 1,450/38,720 (3.74%) and 3,067/84,154 (3.64%), respectively. Non-obese NAFLD patients had a comparable risk of CKD as obese NAFLD (odds ratio [OR] 0.92, 95% confidence interval [95% CI] [0.72-1.19], I = 88%). No differences in estimated glomerular filtration rate and serum creatinine between non-obese and obese NAFLD were found. The mean differences (MD) and 95% CI were 0.01 [-0.02 to 0.04] and 0.50 [-0.90 to 1.90], respectively. In subgroup analyses, non-obese NAFLD had higher eGFR when diagnosed with ultrasound (MD 1.45, 95% CI [0.11-2.79], I = 21%). Non-obese NAFLD had higher creatinine in non-Asian (MD 0.06, 95% CI [0.01-0.11], I = 55%) and when taking BMI > 30 as the criterion for obesity (MD 0.06, 95% CI [0.00-0.12], I = 76%). The occurrence of CKD did not differ when non-obese NAFLD were categorized into overweight and normal-weight types. Non-obese NAFLD patients experienced the same risk of CKD compared to obese NAFLD.