Herbal compound cepharanthine attenuates inflammatory arthritis by blocking macrophage M1 polarization.

OBJECTIVE: Cepharanthine (CEP) is a drug candidate for tumor, viral infection, and some inflammatory diseases, but its effect on rheumatoid arthritis (RA) and the underlying mechanism are incompletely understood. METHODS: CEP was administered intraperitoneally to a collagen-induced arthritis (CIA) model. Joints went radiological and histological examination and serum cytokines were examined with cytometry-based analysis. M1 macrophages were induced from THP-1 cells or mouse bone marrow-derived macrophages with LPS and IFN-γ. Bulk RNA-seq was performed on macrophage undergoing M1-polarizatioin. Western blotting was applied to determine pathways involved in monocyte chemotaxis and polarization. Glycolysis metabolites were measured by chemiluminescence while glycolytic enzymes were examined by quantitative PCR. RESULTS: We found CEP significantly ameliorated synovial inflammation and joint destruction of CIA mice. It downregulated TNF-α levels in serum and in joints. The number of M1 macrophages were reduced in CEP-treated mice. In vitro, CEP inhibited monocyte chemotaxis to MCP-1 by downregulating CCR2 and reducing ERK1/2 signaling. Additionally, CEP suppressed M1 polarization of macrophages induced by LPS and IFN-γ. Genes involved in IFN-γ signaling, IL-6-JAK/STAT3 signaling, glycolysis, and oxidative phosphorylation process were downregulated by CEP. Several enzymes critically involved in glycolytic metabolism were suppressed by CEP, which resulted in reduced citrate in M1-polarizing macrophages. The inhibitory effect of CEP on macrophage polarization might be attributed to the blockage of TLRs-MyD88/IRAK4-IRF5 signaling pathway together with suppression of overactivated glycolytic metabolism in M1-polarizing macrophages. CONCLUSION: CEP attenuated joint inflammation by suppressing monocyte chemotaxis and proinflammatory differentiation. It has the potential to be developed into a complementary or alternative therapy for RA.

Gut microbiome and metabolome analyses reveal the protective effect of special high-docosahexaenoic acid tuna oil on d-galactose-induced aging in mice.

Aging is closely related to altered gut function and its microbiome composition. To elucidate the mechanisms involved in the preventive effect of special high-docosahexaenoic acid tuna oil (HDTO) on senescence, the effects of different doses of HDTO on the gut microbiome and metabolome of d-galactose-induced aging mice were studied. Deferribacteres and Tenericutes and uridine might be used as indicator bacteria and characteristic metabolites to identify aging, respectively. HDTO markedly improved the impaired memory and antioxidant abilities induced by d-galactose. At the phylum level, the abundance of Firmicutes and Tenericutes was significantly increased upon d-galactose induction, while that of Bacteroidetes, Proteobacteria, and Deferribacteres was significantly decreased. At the genus level, the variation mainly presented as an increase in the abundance of the Firmicutes genera Ligilactobacillus, Lactobacillus, and Erysipelothrix, the decrease in the abundance of the Bacteroidetes genera Bacteroides and Alistipes, the Firmicutes genus Dielma, and the Deferribacteres genus Mucispirillum. HDTO supplementation reversed the alterations in the intestinal flora by promoting the proliferation of beneficial flora during the aging process; the metabolic pathways, such as glycine-serine-threonine metabolism, valine-leucine-isoleucine biosynthesis, and some metabolic pathways involved in uridine, were also partially restored. Furthermore, the correlation analysis illustrated an obvious correlation between gut microbiota, its metabolites, and aging-related indices. Moreover, it is worth noting that the metabolic regulation by dietary intervention varied with different HDTO doses and did not present a simple additive effect; indeed, each dose showed a unique modulation mechanism.

Dose effect of high-docosahexaenoic acid tuna oil on dysbiosis in high-fat diet mice.

BACKGROUND: The health benefits of tuna oil, which is different from the fish oil commonly studied, and its higher docosahexaenoic acid (DHA) content, have attracted much scientific attention in recent years. In this study, prepared tuna oil with higher DHA (HDTO) content was employed. It was the first to integrate microbiome and metabolome from a dose-effect perspective to investigate the influence of HDTO on gut dysbiosis and metabolic disorders in diet-induced obese mice. RESULTS: Higher DHA tuna oil was effective in reversing high-fat-diet-induced metabolic disorders and altering the composition and function of gut microbiota, but these effects were not uniformly dose dependent. The flora and metabolites that were targeted to be regulated by HDTO supplementation were Prevotella, Bifidobacterium, Olsenella, glycine, l-aspartate, l-serine, l-valine, l-isoleucine, l-threonine, l-tyrosine, glyceric acid, glycerol, butanedioic acid, and citrate, respectively. Functional pathway analysis revealed that alterations in these metabolic biomarkers were associated with six main metabolic pathways: glycine, serine, and threonine metabolism; glycerolipid metabolism; glyoxylate and dicarboxylate metabolism; alanine, aspartate, and glutamate metabolism; aminoacyl-tRNA biosynthesis, and the citrate cycle (TCA cycle). CONCLUSION: Various doses of HDTO could attenuate endogenous disorders to varying degrees by regulating multiple perturbed pathways to the normal state. This explicit dose research for novel fish oil with high-DHA will provide a valuable reference for those seeking to exploit its clinical therapeutic potential. © 2022 Society of Chemical Industry.

Effects of the Sex Factor on Mouse Iodine Intake: Interactions between the Gut Microbiota Composition and Metabolic Syndromes.

Iodine plays a key role in maintaining thyroid homeostasis, which is influenced by hormones through almost all nucleated cells and is essential for growth and metabolism. The most common kinds of thyroid dysfunction, hypothyroidism and hyperthyroidism, are markedly related to iodine intake. In addition, the prevalence and incidence of hypothyroidism and hyperthyroidism are much higher in women than in men. However, the association between thyroid homeostasis and the gut microbiota is not yet completely clear, especially when comparing women and men. In this study, differences in the gut microbiota compositions, metabolic syndromes, and molecular mechanisms of female and male mice were investigated after iodine supplementation. The gut microbiota in male mice was changed more than that of female mice. The abundances of Muribacium intestinale, Barnesiella, Alloprevotella, Enterococcus, Desulfovibrionaceae, and Clostridium were significantly increased in female mice. This finding indicates that the high risk of thyroid disease in women could be related to the gut microbiota composition.

The gut microbiota mediates the protective effects of anserine supplementation on hyperuricaemia and associated renal inflammation.

Hyperuricaemia is a disease associated with elevated serum uric acid content, which has emerged rapidly in recent decades. The drugs used to treat clinical hyperuricaemia have side effects, and their safety is poor. However, anserine is a natural carnosine derivative that shows an anti-hyperuricaemic effect. A previous study demonstrated that anserine inhibits uric acid synthesis and promotes uric acid excretion, but there is no evidence regarding the effect of anserine from the perspective of the gut microbiota. In this study, the anti-hyperuricaemic and anti-inflammatory effects of anserine were explored in a diet-induced hyperuricaemic mouse model. Anserine alleviated hyperuricaemia and renal inflammation phenotypes, inhibited uric acid biosynthesis, promoted uric acid excretion, and inhibited NLRP3 inflammasome and TLR4/MyD88/NF-κB signalling pathway activation. The results showed that the anti-hyperuricaemic effect of anserine was dependent on the gut microbiota in the germ-free mice experiment. Furthermore, anserine treatment reversed gut microbiota dysbiosis, repaired the intestinal epithelial barrier and increased short-chain fatty acid production. Moreover, the anti-hyperuricaemic effect of anserine was transmissible by transplanting the faecal microbiota from anserine-treated mice, indicating that the protective effects were at least partially mediated by the gut microbiota. Thus, we identified a new and safe prebiotic material to alleviate hyperuricaemia and provided ideas for the development of oligopeptides.

Apostichopus japonicus Oligopeptide Induced Heterogeneity in the Gastrointestinal Tract Microbiota and Alleviated Hyperuricemia in a Microbiota-Dependent Manner.

SCOPE: This study aims to investigate the protective effect of Apostichopus japonicus oligopeptide (AJOP) on hyperuricemia, demonstrate the modulation of the gastrointestinal tract (GIT) microbiota, and clarify the underlying microbiota-dependent mechanism. METHODS AND RESULTS: Hyperuricemic mice treated with AJOP and subjected to corresponding fecal microbiota transplantation (FMT) are used to observe the beneficial effects of AJOP and microbiota. Gene transcriptions are measured using quantitative real-time PCR. The GIT (stomach, colon, cecum, and feces) microbiota is analyzed by 16S rDNA sequencing and the short-chain fatty acids are detected using GC-MS. Dietary administration of AJOP significantly alleviates hyperuricemia, regulates uric acid metabolism, inhibites the activation of the NLRP3 inflammasome and NF-κB-related signaling pathway, and restores m6A methylation levels. In addition, substantial heterogeneity is observed in GIT microbiota. Furthermore, FMT effectively alleviates hyperuricemia in mice by selectively regulating the corresponding pathways associated with AJOP treatment, indicating that the mechanism underlying the protective effects of AJOP is partly microbiota-dependent. CONCLUSION: This study demonstrates that AJOP exerts a protective effect on hyperuricemic mice by regulating uric acid metabolism, resulting in substantial heterogeneity among the GIT microbiota, thus mediating the beneficial effects in a microbiota-dependent manner.

Novel high-docosahexaenoic-acid tuna oil supplementation modulates gut microbiota and alleviates obesity in high-fat diet mice.

Studies have documented the benefits of fish oil in different diseases because of its high n-3 polyunsaturated fatty acid content. However, these studies mostly used commercially available fish oil supplements with a ratio of 18/12 for eicosapentaenoic acid and docosahexaenoic acid (DHA). However, increasing DHA content for this commonly used ratio might bring out a varied metabolic effect, which have remained unclear. Thus, in this study, a novel tuna oil (TO) was applied to investigate the effect of high-DHA content on the alteration of the gut microbiota and obesity in high-fat diet mice. The results suggest that high-DHA TO (HDTO) supplementation notably ameliorates obesity and related lipid parameters and restores the expression of lipid metabolism-related genes. The benefits of TOs were derived from their modification of the gut microbiota composition and structure in mice. A high-fat diet triggered an increased Firmicutes/Bacteroidetes ratio that was remarkably restored by TOs. The number of obesity-promoting bacteria-Desulfovibrio, Paraeggerthella, Terrisporobacter, Millionella, Lachnoclostridium, Anaerobacterium, and Ruminiclostridium-was dramatically reduced. Desulfovibrio desulfuricans, Alistipes putredinis, and Millionella massiliensis, three dysbiosis-related species, were especially regulated by HDTO. Regarding the prevention of obesity, HDTO outperforms the normal TO. Intriguingly, HDTO feeding to HFD-fed mice might alter the arginine and proline metabolism of intestinal microbiota.

Protective effects of tuna meat oligopeptides (TMOP) supplementation on hyperuricemia and associated renal inflammation mediated by gut microbiota.

Recently, interest in using whole food-derived mixtures to alleviate chronic metabolic syndrome through potential synergistic interactions among different components is increasing. In this study, the effects and mechanisms of tuna meat oligopeptides (TMOP) on hyperuricemia and associated renal inflammation were investigated in mice. Dietary administration of TMOP alleviated hyperuricemia and renal inflammation phenotypes, reprogramed uric acid metabolism pathways, inhibited the activation of NLRP3 inflammasome and TLR4/MyD88/NF-κB signaling pathways, and suppressed the phosphorylation of p65-NF-κB. In addition, TMOP treatments repaired the intestinal epithelial barrier, reversed the gut microbiota dysbiosis and increased the production of short-chain fatty acids. Moreover, the antihyperuricemia effects of TMOP were transmissible by transplanting the fecal microbiota from TMOP-treated mice, indicating that the protective effects were at least partially mediated by the gut microbiota. Thus, for the first time, we clarify the potential effects of TMOP as a whole food derived ingredient on alleviating hyperuricemia and renal inflammation in mice, and additional efforts are needed to confirm the beneficial effects of TMOP on humans.

Alterations of the Brain Proteome and Gut Microbiota in d-Galactose-Induced Brain-Aging Mice with Krill Oil Supplementation.

Brain aging is commonly associated with neurodegenerative disorders, but the ameliorative effect of krill oil and the underlying mechanism remain unclear. In this study, the components of krill oil were measured, and the antiaging effects of krill oil were investigated in mice with d-galactose (d-gal)-induced brain aging via proteomics and gut microbiota analysis. Krill oil treatment decreased the expression of truncated dopamine- and cAMP-regulated phosphoproteins and proteins involved in the calcium signaling pathway. In addition, the concentrations of dopamine were increased in the serum (p < 0.05) and brain (p > 0.05) due to the enhanced expressions of tyrosine-3-monooxygenase and aromatic l-amino acid decarboxylase. Moreover, krill oil alleviated gut microbiota dysbiosis, decreased the abundance of bacteria that consume the precursor tyrosine, and increased the abundance of Lactobacillus spp. and short-chain fatty acid producers. This study revealed the beneficial effect of krill oil against d-gal-induced brain aging and clarified the underlying mechanism through proteomics and gut microbiota analysis.

Different host-specific responses in thyroid function and gut microbiota modulation between diet-induced obese and normal mice given the same dose of iodine.

Iodine is an important trace element involved in thyroid hormone biosynthesis, while diet-induced obesity is reported to disturb the trace element metabolic balance. Herein, we studied the host-specific responses involved in modulating thyroid function and gut microbiota in obese mice after the iodine treatment and analyzed the possible causes for these responses. Obesity in the mice was induced by a high-fat diet, and the obese and normal mice were treated with the same iodine dosage (18 µg/kg/day) continuously for 8 weeks. Iodine treatment in the obese mice showed a weight-reducing effect, increased the thyroid hormone concentrations, altered the transcriptions of genes involved in thyroid hormone biosynthesis, and modulated the gut microbiota with an increased abundance of pathogenic bacteria and decreased the proportion of beneficial bacteria. However, completely different or even opposite response profiles were observed in the normal hosts. Our work indicated that obesity may exacerbate the risk of thyroid disease with a relatively safe dose of iodine, and individual differences should be considered with trace element supplementation.

Lipase-catalyzed selective enrichment of omega-3 polyunsaturated fatty acids in acylglycerols of cod liver and linseed oils: Modeling the binding affinity of lipases and fatty acids.

Present study employed molecular modeling method to elucidate the binding affinity of lipases with fatty acids of different chain lengths; and investigated the effects of lipases positional and fatty acids specificity on omega-3 polyunsaturated fatty acids (ω-3 PUFAs) enrichment in cod liver and linseed oils. Among the lipases studied, molecular modeling showed the active sites of Candida rugosa lipase (CRL) had a low C-Docker interactive energy for saturated (SFA) and monounsaturated (MUFA) fatty acids which predicted CRL to have highest preferences to selectively hydrolyze resulting in efficient enrichment of ω-3 PUFAs. Verification experiments showed the SFA and MUFA in the acylglycerol fraction includes monoacylglcyerols (MAG), diacyglycerols (DAG), and triacylglycerols (TAG) of CRL-hydrolyzed cod liver oil decreased from the initial 25.21 to 16.88% and 45.25 to 32.17%, respectively. In addition, CRL-hydrolyzed cod liver oil demonstrated 88.36% of ω-3 PUFAs enrichment. The regio-distribution of fatty acids in CRL-hydrolyzed cod liver oil were not significantly different than that of cod liver oil indicating the ω-3 PUFAs enrichment was due to fatty acids selectivity and not positional selectivity of CRL.

Euphorbia factor L2 alleviates lipopolysaccharide-induced acute lung injury and inflammation in mice through the suppression of NF-κB activation.

Acute respiratory distress syndrome threatens public health with high morbidity and mortality due to ineffective intervention whereby lipopolysaccharide (LPS) induced acute lung injury (ALI) in mice provides a research model. The seeds of Euphorbia lathyris L. have a long history of usage in Traditional Chinese Medicine. Euphorbia factors L1-L11, extracted from this herb, have been reported to have anti-inflammation and anti-cancer effects. Here, we report the preventive and therapeutic potential of Euphorbia factor L2 (EFL2) on LPS-induced ALI in mice, where EFL2 attenuated pathological alterations in the lung and improved survival. Significant suppression of the recruitment and transmigration of inflammatory cells, specifically neutrophils, by 40 mg/kg of EFL2 was observed. EFL2 exerted potent anti-inflammatory effects by decreasing the levels of interleukin-1ß (IL-1 ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF- α), interleukin-8 (IL-8) and myeloperoxidase (MPO) in the lung and bronchioalveolar lavage fluid. Consistent with the findings in vivo, EFL2 also showed robust inhibitory effects on the production of IL-1 ß, IL-6, TNF- α and IL-8 released from LPS-stimulated RAW264.7 cells in vitro. Interestingly, this effect appeared to be mediated by EFL2's inhibition of NF-κB signaling activation, but not the MAPK pathway. Not only phosphorylation of IKK α/ß and IκBα was down-regulated, p65 translocation and its DNA-binding activity were also significantly suppressed by EFL2. Moreover, overexpression of p65 reversed the inhibitory effect of EFL2 in LPS-induced NF-κB activation and cytokines production. The observed anti-inflammatory bioactivity of EFL2 indicates its potential as a drug development candidate, particularly for LPS-mediated disorders of inflammation.

Modulation of gut microbiota by dietary supplementation with tuna oil and algae oil alleviates the effects of D-galactose-induced ageing.

Previous studies have shown that dietary supplementation with tuna oil and algae oil can alleviate the effects of ageing on learning and memory in mouse models, but the mechanism of this effect remains unknown. This study aimed to determine whether dietary oil supplementation alters the composition of the gut microbiota during the prevention of age-related effects on cognition. Ageing mice received dietary oil supplementation continuously for 12 weeks. The supplementation was found to improve the animals' learning and cognition, and this effect was most marked in the TO200AO400 group, which received a 1:2 mixture of tuna oil and algae oil at 600 mg kg-1 day-1. Next-generation sequencing of the 16S rRNA gene present in faecal samples showed that the gut microbiota varied in the groups that received different oil treatments; the TO200AO400 treatment most closely restored the composition of the D-galactose-altered gut microbiota to that of the control. Moreover, 83 altered operational taxonomic units (OTUs) responsive to dietary oil supplementation were identified; five of these differed in one or more parameters associated with host ageing. In conclusion, this study confirmed the effect of dietary oil supplementation on the alleviation of age-related decline in cognitive function and showed that oil supplementation results in alterations in the composition of the gut microbiota. Further research will be needed to elucidate the causal relationship between the reversal of age-related cognitive decline and gut microbiota modulation and to explore the potential of gut microbial communities as a diagnostic biomarker and a therapeutic target in ageing.

Dietary Apostichopus japonicus Alleviates Diabetes Symptoms and Modulates Genes Expression in Kidney Tissues of db/db Mice.

The effects of Apostichopus japonicus enzymatic hydrolysate on the regulation of dyslipidemia, pathoglycemia, and transcription changes in kidney tissues of db/db mice were evaluated. In this study, the symptoms of diabetes in db/db mice were alleviated after 10 weeks of treatments with low (db/db + LD group) and high dose (db/db + HD group) of Apostichopus japonicus enzymatic hydrolysate, and the high dose treatment showed a better antidiabetic effect. Compared with the db/db group, the fasting blood glucose levels (36.84 ± 7.82 vs 25.18 ± 6.84 mmol/L, P < 0.01), the urine glucose levels (45.44 ± 3.93 vs 22.66 ± 5.58 mmol/L, P < 0.01), and the serum insulin sensitivity index (-4.65 ± 0.43 vs -4.74 ± 0.75, P > 0.05) in the db/db + HD group were decreased, whereas the fasting plasma insulin (3.12 ± 1.08 vs 5.54 ± 1.82 µg/L, P < 0.01) and the serum insulin resistance index (5.01 ± 2.02 vs 5.96 ± 2.49, P < 0.05) were increased. Subsequently, the kidney transcription profiles were measured in the db/db group and db/db + HD group via microarray, and the results show that Apostichopus japonicus hydrolysate induced differential expression of 77 genes. Among these genes, the down-regulation of genes ntrK1 and ptpN5 played vital roles, as this effect induced the further down-regulation of neurotrophin tyrosine kinase, protein tyrosine phosphatase, and other transcription factors, which are involved in the classical mitogen-activated protein kinases (MAPK) and p38MAPK signaling pathways. The inhibited MAPK and p38MAPK signaling pathways are involved in glycometabolism and the control of lipid metabolism, and they regulate the occurrence and development of diabetic nephropathy.

Microbial diversity and composition in different gut locations of hyperlipidemic mice receiving krill oil.

Low-dose (LD, 100 mg kg-1 day-1), moderate-dose (MD, 200 mg kg-1 day-1), and high-dose (HD, 600 mg kg-1 day-1) krill oil treatments have a stepwise, enhanced effect on alleviating hyperlipidemia, and 16S rRNA sequencing of the fecal samples demonstrates that krill oil treatment alters microbial communities. Feces may not represent all microbial communities in the gastrointestinal (GI) tract. Therefore, in this study, the stored ileal and colon samples collected from LD and HD groups were sequenced, and the location-specific modulations of microbial communities were observed after krill oil treatments. The 16S rRNA sequencing of the ileal samples showed that the LD and HD groups have similar patterns between control and high-fat diet (HFD) treatments, and six most abundant genera and 40 operational taxonomic units that respond to krill oil treatment were identified. However, the 16S rRNA sequencing of the colon samples showed that LD krill oil shifts the structure from the HFD to that of the control, whereas the HD group was distributed between the control and HFD groups. The corresponding most abundant genera and responsive OTUs totaled 4 and 45, respectively. In conclusion, different gastrointestinal tract locations contain different microbial communities. These results will help to provide a comprehensive understanding of the role of dietary krill oil in modulating the gut microbiota and alleviating hyperlipidemia.

Modulation of the gut microbiota by the mixture of fish oil and krill oil in high-fat diet-induced obesity mice.

Previous studies confirmed that dietary supplements of fish oil and krill oil can alleviate obesity in mice, but the underlying mechanism remains unclear. This study aims to discern whether oil treatment change the structure of the gut microbiota during the obesity alleviation. The ICR mice received high-fat diet (HFD) continuously for 12 weeks after two weeks of acclimatization with a standard chow diet, and the mice fed with a standard chow diet were used as the control. In the groups that received HFD with oil supplementation, the weight gains were attenuated and the liver index, total cholesterol, triglyceride and low-density lipoprotein cholesterol were reduced stepwise compared with the HFD group, and the overall structure of the gut microbiota, which was modulated in the HFD group, was shifted toward the structure found in the control group. Moreover, eighty-two altered operational taxonomic units responsive to oil treatment were identified and nineteen of them differing in one or more parameters associated with obesity. In conclusion, this study confirmed the effect of oil treatment on obesity alleviation, as well as on the microbiota structure alterations. We proposed that further researches are needed to elucidate the causal relationship between obesity alleviation and gut microbiota modulation.

Dietary krill oil enhances neurocognitive functions and modulates proteomic changes in brain tissues of d-galactose induced aging mice.

The effects of dietary krill oil on neurocognitive functions and proteomic changes in brain tissues of d-galactose-induced aging mice were evaluated. Dietary krill oil enhanced the neurocognitive functions of aging mice with a significant (P < 0.05) decrease in escape latency and an increase in the number of times of crossing over the hidden platform during the Morris water maze test. Krill oil was also found to protect against oxidative damage, lipid peroxidation and neurodegenerative diseases. Oxidative stress biomarkers of aging mice administered with krill oil showed significant (P < 0.05) improvement with an increase in serum superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels; there were insignificant changes in the serum malondialdehyde (MDA) level. In terms of proteomic changes, krill oil resulted in upregulation of the Celsr3 and Ppp1r1b gene expression, which contribute to brain development, learning and memory behavior processes. In particular, the Ppp1r1b gene is associated with the inhibition of dopamine releases, which decreases the motivation for learning.