Ferulic acid supplementation alleviates hyperuricemia in high-fructose/fat diet-fed rats via promoting uric acid excretion and mediating the gut microbiota.

The prevalence of hyperuricemia (HUA) has been rising, and it is typically accompanied by renal injury and intestinal flora disorder, leading to a non-negligible health crisis. Ferulic acid (FA), as a familiar polyphenol, has been proven to exert anti-hyperuricemic properties via inhibiting uric acid (UA) synthesis; however, the detailed underlying mechanisms remain unclear. The aim of this study was to explore the regulatory effect of FA on UA excretion as a potential strategy for reducing UA levels, and the comorbidities of HUA. FA treatment downregulated the expression of urate absorption transporter genes and repressed the toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway in UA-stimulated HK-2 cells. To examine these effects in vivo, FA or allopurinol (positive control) was given to rats with HUA induced by a high-fructose/fat diet (HFFD) for 20 weeks. FA markedly decreased the serum UA, blood urea nitrogen, and creatinine levels. The expression of urate absorption transporters was downregulated, whereas the expression of secretion transporters was upregulated in the kidneys and intestines of FA-treated HUA rats. Additionally, FA mitigated renal oxidative stress, and suppressed the activation of the TLR4/NF-κB pathway and the downstream inflammatory response-related markers in the kidneys. Moreover, FA remodeled the composition of the gut microbiota, characterized by an increase in beneficial bacteria (e.g., Lactobacillus and Ruminococcus) and a decrease in pathogenic bacteria (e.g., Bacteroides). In conclusion, our study validated FA as an effective nutrient to ameliorate HFFD-induced HUA, suggesting its potential to mitigate the HUA-associated renal impairment and intestinal microbiota disturbance.

New Insights Into Cancer Chronotherapies.

Circadian clocks participate in the coordination of various metabolic and biological activities to maintain homeostasis. Disturbances in the circadian rhythm and cancers are closely related. Circadian clock genes are differentially expressed in many tumors, and accelerate the development and progression of tumors. In addition, tumor tissues exert varying biological activities compared to normal tissues due to resetting of altered rhythms. Thus, chronotherapeutics used for cancer treatment should exploit the timing of circadian rhythms to achieve higher efficacy and mild toxicity. Due to interpatient differences in circadian functions, our findings advocate an individualized precision approach to chronotherapy. Herein, we review the specific association between circadian clocks and cancers. In addition, we focus on chronotherapies in cancers and personalized biomarkers for the development of precision chronotherapy. The understanding of circadian clocks in cancer will provide a rationale for more effective clinical treatment of tumors.

Synergistic therapeutic efficacy of ebselen and silver ions against multidrug-resistant Acinetobacter baumannii-induced urinary tract infections.

Ebselen (EbSe), an organo-selenium compound with well-characterized toxicology and pharmacology, exhibited potent antibacterial activity against glutathione (GSH)-positive bacteria when combined with silver ions (Ag+). In this paper, the strong bactericidal activity of EbSe-Ag+ against multidrug-resistant (MDR) Acinetobacter baumannii has been confirmed, and its efficacy was mainly based on the inhibition of thioredoxin reductase (TrxR) activity and the depletion of the total GSH amount. Moreover, the therapeutic effect of EbSe-Ag+ on urinary tract infection was assessed in a mouse model induced with A. baumannii 0361# strain. The treatment with EbSe-Ag+ significantly reduced the bacterial load and expression levels of the pro-inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in bladder lesions; meanwhile, the pathological experiment showed that A. baumannii-induced changes in EbSe-Ag+ treated mice were much attenuated than that in the control group. Thus, all the results obtained here may lay the foundation for further analysis and development of EbSe-Ag+ as potential antibacterial agents for MDR A. baumannii-induced urinary tract infection treatment.

Topical Therapeutic Efficacy of Ebselen Against Multidrug-Resistant Staphylococcus aureus LT-1 Targeting Thioredoxin Reductase.

As a thiol-dependent enzyme, thioredoxin reductase (TrxR) is a promising antibacterial drug target. Ebselen, an organo-selenium with well-characterized toxicology and pharmacology, was recently reported to have potent antibacterial activity against Staphylococcus aureus. In this paper, we demonstrated that ebselen has strong bactericidal activity against multidrug-resistant (MDR) S. aureus based on taking TrxR as a major target and disruption of the redox microenvironment. Further, the topical therapeutic efficacy of ebselen for staphylococcal skin infections was assessed in a rat model. Treatment with ebselen significantly reduced the bacterial load and the expression of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1 beta (IL-1ß) in S. aureus skin lesions; further, wound healing and pathological changes were obvious improved in ebselen-treated rats compare to controls. Finally, ebselen was found to sensitize S. aureus to curcumin, which may be due to their synergistic effects in inhibiting bacterial TrxR. Altogether, ebselen is an effective topical antibacterial agent in animal model of MDR S. aureus LT-1 skin infection. This may lay the foundation for further analysis and development of ebselen as an antibacterial agent for topical treatment of MDR staphylococcal infections.

Prevalence of Pain and Effects of a Brief Mindfulness-Based Intervention on Chinese Community-Dwelling Older Adults with Chronic Pain.

This study aimed to screen the prevalence of pain in Chinese community-dwelling older adults and to evaluate the effects of a brief mindfulness-based intervention on chronic pain. The prevalence of pain among Chinese older adults was 40.5%. The brief mindfulness intervention had significant effects on reducing pain intensity (P = 0.004), and increasing the mindfulness measures: observing, acting with awareness, non-judging and non-reactivity inner experience (all P values < 0.05). Pain prevalence among Chinese older adults was relatively high. This study showed that a brief mindfulness-based intervention reduced ratings of pain intensity and enhanced ratings of the perception of mindfulness.

Selenoprotein N Was Required for the Regulation of Selenium on the Uterine Smooth Muscle Contraction in Mice.

Selenium (Se) is an essential micronutrient affecting various aspects of health. The balance of the Se concentration has an important protective and promoter effect on physiological function in inducing muscular disorders in smooth muscle. Selenoprotein N (SelN) is closely related to Ca2+ release. The present study aimed to determine the effects and mechanism of action of dietary Se on uterine smooth muscle contraction via SelN using a mouse model. Quantitative polymerase chain reaction (qPCR) analysis was performed to detect mRNA levels. Western blotting was performed to detect protein levels. The results of the immunohistochemical analysis showed that Se had an effect on the uterine smooth muscle. The Se-supplement increased the release of Ca2+, Ca2+-calmodulin (CaM) expression, myosin light chain kinase (MLCK) expression, and myosin light chain (MLC) phosphorylation but did not affect ROCK and RhoA in uterine smooth muscle. Furthermore, the lack of Se showed an opposite impact. The effects of Se regulation were closely related to SelN. The interference of mouse SelN was performed on the uterine smooth muscle cell. Additionally, the results displayed the regulation of Se on the release of Ca2+, CaM expression, MLCK expression, and MLC phosphorylation were significant inhibited, and there was no effect on ROCK and RhoA. In conclusion, Se played an important role in regulating the process of contraction in uterine smooth muscle with SelN.

Se Enhances MLCK Activation by Regulating Selenoprotein T (SelT) in the Gastric Smooth Muscle of Rats.

Selenium (Se), a nutritionally essential trace element, is associated with health and disease. Selenoprotein T (SelT) was identified as a redoxin protein with a selenocystein, localizing in the endoplasmic reticulum. The myosin light chain kinase (MLCK) and myosin light chain (MLC) play key roles in the contraction process of smooth muscle. The present study was to detect the effect and mechanism of SelT on the contraction process of gastric smooth muscle. The WT rats were fed with different Se concentration diets, and Se and Ca(2+) concentrations were detected in the gastric smooth muscle. Western blot and qPCR were performed to determine SelT, CaM, MLCK, and MLC expressions. MLCK activity was measured by identifying the rates of [γ-32P]ATP incorporated into the MLC. The results showed Se and Ca(2+) concentrations were enhanced with Se intake in gastric smooth muscle tissues. With increasing Se, SelT, CaM, MLCK and MLC expressions increased, and MLCK and MLC activation improved in gastric smooth muscle tissue. The SelT RNA interference experiments showed that Ca(2+) release, MLCK activation, and MLC phosphorylation were regulated by SelT. Se affected the gastric smooth muscle constriction by regulating Ca(2+) release, MLCK activation, and MLC phosphorylation through SelT. Se plays a major role in regulating the contraction processes of gastric smooth muscle with the SelT.