Vitamin K (VK) is a ligand of the pregnane X receptor (PXR), which plays a critical role in the detoxification of xenobiotics and metabolism of bile acids. VK1 may reduce the risk of death in ...patients with chronic liver failure. VK deficiency is associated with intrahepatic cholestasis, and is already being used as a drug for cholestasis-induced liver fibrosis in China. In Japan, to treat osteoporosis in patients with primary biliary cholangitis, VK2 formulations are prescribed, along with vitamin D3. Animal studies have revealed that after bile duct ligation-induced cholestasis, PXR knockout mice manifested more hepatic damage than wild-type mice. Ligand-mediated activation of PXR improves biochemical parameters. Rifampicin is a well-known human PXR ligand that has been used to treat intractable pruritus in severe cholestasis. In addition to its anti-cholestatic properties, PXR has anti-fibrotic and anti-inflammatory effects. However, because of the scarcity of animal studies, the mechanism of the effect of VK on cholestasis-related liver disease has not yet been revealed. Moreover, the application of VK in cholestasis-related diseases is controversial. Considering this background, the present review focuses on the effect of VK in cholestasis-related diseases, emphasizing its function as a modulator of PXR.
Nearly six million people worldwide have died from the coronavirus disease (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although COVID-19 ...vaccines are largely successful in reducing the severity of the disease and deaths, the decline in vaccine-induced immunity over time and the continuing emergence of new viral variants or mutations underscore the need for an alternative strategy for developing broad-spectrum host-mediated therapeutics against SARS-CoV-2. A key feature of severe COVID-19 is dysregulated innate immune signaling, culminating in a high expression of numerous pro-inflammatory cytokines and chemokines and a lack of antiviral interferons (IFNs), particularly type I (alpha and beta) and type III (lambda). As a natural host defense, the myeloid differentiation primary response protein, MyD88, plays pivotal roles in innate and acquired immune responses via the signal transduction pathways of Toll-like receptors (TLRs), a type of pathogen recognition receptors (PRRs). However, recent studies have highlighted that infection with viruses upregulates MyD88 expression and impairs the host antiviral response by negatively regulating type I IFN. Galectin-3 (Gal3), another key player in viral infections, has been shown to modulate the host immune response by regulating viral entry and activating TLRs, the NLRP3 inflammasome, and NF-κB, resulting in the release of pro-inflammatory cytokines and contributing to the overall inflammatory response, the so-called “cytokine storm”. These studies suggest that the specific inhibition of MyD88 and Gal3 could be a promising therapy for COVID-19. This review presents future directions for MyD88- and Gal3-targeted antiviral drug discovery, highlighting the potential to restore host immunity in SARS-CoV-2 infections.
Persistent inflammatory reactions in microglial cells are strongly associated with neurodegenerative pathogenesis. Additionally, geranylgeraniol (GGOH), a plant-derived isoprenoid, has been found to ...improve inflammatory conditions in several animal models. It has also been observed that its chemical structure is similar to that of the side chain of menaquinone-4, which is a vitamin K2 sub-type that suppresses inflammation in mouse-derived microglial cells. In this study, we investigated whether GGOH has a similar anti-inflammatory effect in activated microglial cells. Particularly, mouse-derived MG6 cells pre-treated with GGOH were exposed to lipopolysaccharide (LPS). Thereafter, the mRNA levels of pro-inflammatory cytokines were determined via qRT-PCR, while protein expression levels, especially the expression of NF-κB signaling cascade-related proteins, were determined via Western blot analysis. The distribution of NF-κB p65 protein was also analyzed via fluorescence microscopy. Thus, it was observed that GGOH dose-dependently suppressed the LPS-induced increase in the mRNA levels of Il-1β, Tnf-α, Il-6, and Cox-2. Furthermore, GGOH inhibited the phosphorylation of TAK1, IKKα/β, and NF-κB p65 proteins as well as NF-κB nuclear translocation induced by LPS while maintaining IκBα expression. We showed that GGOH, similar to menaquinone-4, could alleviate LPS-induced microglial inflammation by targeting the NF-kB signaling pathway.
Hypogonadism, associated with low levels of testosterone synthesis, has been implicated in several diseases. Recently, the quest for natural alternatives to prevent and treat hypogonadism has gained ...increasing research interest. To this end, the present study explored the effect of
-allyl cysteine (SAC), a characteristic organosulfur compound in aged-garlic extract, on testosterone production. SAC was administered at 50 mg/kg body weight intraperitoneally into 7-week-old BALB/c male mice in a single-dose experiment. Plasma levels of testosterone and luteinizing hormone (LH) and testis levels of proteins involved in steroidogenesis were measured by enzymatic immunoassay and Western blot, respectively. In addition, mouse testis-derived I-10 cells were also used to investigate the effect of SAC on steroidogenesis. In the animal experiment, SAC significantly elevated testosterone levels in both the plasma and the testis without changing the LH level in plasma and increased phosphorylated protein kinase A (p-PKA) levels. Similar results were also observed in I-10 cells. The findings demonstrating the increasing effect of SAC on p-PKA and mRNA levels of
suggest that SAC increases the testosterone level by activating the PKA pathway and could be a potential target for hypogonadism therapeutics.
Fermentation is thought to alter the composition and bioavailability of bioactive compounds in rice bran. However, how this process affects the anti-inflammatory effects of rice bran and the ...bioactive compounds that might participate in this function is yet to be elucidated. This study aimed to isolate bioactive compounds in fermented rice bran that play a key role in its anti-inflammatory function. The fermented rice bran was fractionated using a succession of solvent and solid-phase extractions. The fermented rice bran fractions were then applied to lipopolysaccharide (LPS)-activated murine macrophages to evaluate their anti-inflammatory activity. The hot water fractions (FRBA), 50% ethanol fractions (FRBB), and n-hexane fractions (FRBC) were all shown to be able to suppress the pro-inflammatory cytokine expression from LPS-stimulated RAW 264.7 cells. Subsequent fractions from the hot water fraction (FRBF and FRBE) were also able to reduce the inflammatory response of these cells to LPS. Further investigation revealed that tryptamine, a bacterial metabolite of tryptophan, was abundantly present in these extracts. These results indicate that tryptamine may play an important role in the anti-inflammatory effects of fermented rice bran. Furthermore, the anti-inflammatory effects of FRBE and tryptamine may depend on the activity of the aryl hydrocarbon receptor.
Pregnane X receptor (PXR) is a nuclear receptor activated by various compounds, including prescribed drugs and dietary ingredients. Ligand-specific activation of PXR alters drug metabolism and ...affects many other physiological conditions. Species-specific ligand preference is a considerable challenge for studies of PXR function. To increase translational value of the results of mouse studies, humanized mouse model expressing human PXR (hPXR) has been developed. Menaquinone-4 (MK-4), one of vitamin K₂ analogs prescribed in osteoporosis, is a PXR ligand. We hypothesized that MK-4 could modulate the physiological conditions endogenously influenced by PXR, including those that have not been yet properly elucidated. In the present study, we investigated the effects of a single oral treatment with MK-4 on hepatic gene expression in wild-type and hPXR mice by using quantitative RT-PCR and DNA microarray. MK-4 administration altered mRNA levels of genes involved in drug metabolism (
,
,
), bile acid synthesis (
,
), and energy homeostasis (
,
). Similar mRNA changes of
and
were observed in human hepatocarcinoma HepG2 cells treated with MK-4. These results suggest that MK-4 may modulate bile acid synthesis. To our knowledge, this is the first report showing the effect of MK-4 in hPXR mice.
Nonalcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease, can progress to hepatic steatosis, inflammation, and advanced fibrosis, increasing the risk of cirrhosis. ...Resveratrol, a natural polyphenol with antioxidant and anti-inflammatory properties, is beneficial in treating multiple metabolic diseases. Gnetin C, a resveratrol derivative obtained from Melinjo seed extract (MSE), shares similar health-promoting properties. We investigated the role of gnetin C in preventing NAFLD in a mouse model and compared it with resveratrol. Male C57BL/6J mice were fed a control diet (10% calories from fat), a high-fat choline-deficient (HFCD) diet (46% calories from fat) and HFCD diet supplemented with gnetin C (150 mg/kg BW·day−1) or resveratrol (150 mg/kg BW·day−1) for 12 weeks. Gnetin C supplementation reduced body and liver weight, and improved blood glucose levels and insulin sensitivity. Both gnetin C- and resveratrol reduced hepatic steatosis, with gnetin C also decreasing liver lipid content. Gnetin C and resveratrol ameliorated HFCD diet-induced hepatic fibrosis. The mRNA expression results, and western blot analyses showed that gnetin C and, to some extent, resveratrol downregulated fibrosis markers in the TGF-β1 signaling pathway, indicating a possible safeguarding mechanism against NAFLD. These results suggest that gnetin C supplementation may protect against lipid deposition and hepatic fibrosis.
Fermented rice bran (FRB) is known to protect mice intestines against dextran sodium sulfate (DSS)-induced inflammation; however, the restoration of post-colitis intestinal homeostasis using FRB ...supplementation is currently undocumented. In this study, we observed the effects of dietary FRB supplementation on intestinal restoration and the development of fibrosis after DSS-induced colitis. DSS (1.5%) was introduced in the drinking water of mice for 5 days. Eight mice were sacrificed immediately after the DSS treatment ended. The remaining mice were divided into three groups, comprising the following diets: control, 10% rice bran (RB), and 10% FRB-supplemented. Diet treatment was continued for 2 weeks, after which half the population of mice from each group was sacrificed. The experiment was continued for another 3 weeks before the remaining mice were sacrificed. FRB supplementation could reduce the general observation of colitis and production of intestinal pro-inflammatory cytokines. FRB also increased intestinal mRNA levels of anti-inflammatory cytokine, tight junction, and anti-microbial proteins. Furthermore, FRB supplementation suppressed markers of intestinal fibrosis. This effect might have been achieved via the canonical Smad2/3 activation and the non-canonical pathway of Tgf-β activity. These results suggest that FRB may be an alternative therapeutic agent against inflammation-induced intestinal fibrosis.
The pregnane X receptor (PXR) is the key regulator of our defense mechanism against foreign substances such as drugs, dietary nutrients, or environmental pollutants. Because of increased health ...consciousness, the use of dietary supplements has gradually increased, and most of them can activate PXR. Therefore, an analysis of the interaction between drugs and nutrients is important because altered levels of drug-metabolizing enzymes or transporters can remarkably affect the efficiency of a co-administered drug. In the present study, we analyzed the effect of vitamin K-mediated PXR activation on drug metabolism-related gene expression in intestine-derived LS180 cells via gene expression studies and western blotting analyses. We demonstrated that menaquinone 4 (MK-4), along with other vitamin Ks, including vitamin K1, has the potential to induce MDR1 and CYP3A4 gene expression. We showed that PXR knockdown reversed MK-4-mediated stimulation of these genes, indicating the involvement of PXR in this effect. In addition, we showed that the expression of MDR1 and CYP3A4 genes increased synergistically after 24 h of rifampicin and MK-4 co-treatment. Our study thus elucidates the importance of drug–nutrient interaction mediated via PXR.
The objective of this study was to evaluate the effects of supplementing a yeast culture (YC; Saccharomyces cerevisiae) on rumen fermentation, nutrient utilization, and milk production in dairy cows. ...Six Holstein cows were subjected to two dietary treatments in a crossover design. The treatments were control (no yeast culture) and yeast culture (fed at 30 g/head per day). Rumen pH and protozoal counts were similar between both treatments, although the concentration of rumen ammonia-N tended to be lower with YC treatment. Moreover, YC treatment did not affect the concentration of total short-chain fatty acids in the rumen, but tended to reduce the molar proportion of acetic acid (A), while significantly increasing that of propionic acid (P). Therefore, the A/P ratio decreased significantly after 5 hr of YC feeding as compared with the control. The treatments had no effect on the blood plasma concentrations of glucose, urea-N, and non-esterified fatty acids. However, YC treatment resulted in a significantly higher concentration of plasma free lysine, along with higher concentrations of isoleucine, arginine, and total free amino acids. Dry matter intake and milk yield were similar between both treatments, though the percentage of milk protein tended to be higher with YC treatment. In addition, YC treatment did not affect the milk fatty acid composition and somatic cell counts. Overall, the yeast culture had a subtle effect on ruminal fermentation. The higher plasma concentrations of some essential amino acids indicated the positive effect of YC supplementation on the availability of amino acids for milk protein synthesis in the mammary gland of dairy cows.
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