Green Tea Extract Containing Piper retrofractum Fruit Ameliorates DSS-Induced Colitis via Modulating MicroRNA-21 Expression and NF-κB Activity

The aim of the present study was to examine the effect of green tea extract containing Piper retrofractum fruit (GTP) on dextran-sulfate-sodium (DSS)-induced colitis, the regulatory mechanisms of microRNA (miR)-21, and the nuclear factor-κB (NF-κB) pathway. Different doses of GTP (50, 100, and 200 mg/kg) were administered orally once daily for 14 days, followed by GTP with 3% DSS for 7 days. Compared with the DSS-treated control, GTP administration alleviated clinical symptoms, including the disease activity index (DAI), colon shortening, and the degree of histological damage. Moreover, GTP suppressed miR-21 expression and NF-κB activity in colon tissue of DSS-induced colitis mice. The mRNA levels of inflammatory mediators, such as tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), were downregulated by GTP. Colonic nitric oxide (NO) and prostaglandin E2 (PGE2) production, and myeloperoxidase (MPO) activity were also lowered by GTP. Taken together, our results revealed that GTP inhibits DSS-induced colonic inflammation by suppressing miR-21 expression and NF-κB activity, suggesting that it may be used as a potential functional material for improving colitis.     

Different Dose of Sucrose Consumption Divergently Influences Gut Microbiota and PPAR-γ/MAPK/NF-κB Pathway in DSS-Induced Colitis Mice

Sugar reduction and sugar control are advocated and gaining popularity around the world. Sucrose, as the widely consumed ingredient in our daily diet, has been reported a relation to gastrointestinal diseases. However, the role of sucrose in inflammatory bowel disease remains controversial. Hence, our study aimed to elucidate the potential role of three doses of sucrose on DSS-induced colitis in C57BL/6 mice and the underlying mechanisms. The results showed that low-dose sucrose intervention alleviated colitis in mice, reducing the expression of inflammatory cytokines and repairing mucosal damages. In contrast, high-dose sucrose intervention exacerbated colitis. Furthermore, three doses of sucrose administration markedly altered gut microbiota composition. Notably, the low-dose sucrose restored microbial dysfunction and enhanced the production of short chain fatty acids (SCFAs). Specifically, the abundance of SCFAs-producing bacteria Faecalibaculum, Bacteroides, and Romboutsia were increased significantly in the LOW group. Consistently, PPAR-γ, activated by SCFAs, was elevated in the LOW group, thereby inhibiting the MAPK/NF-κB pathway. Together, our study demonstrates the differential effects of sucrose on colitis at different doses, providing a scientific basis for measuring and modifying the safe intake level of sugar and providing favorable evidence for implementing sugar reduction policies.     

The Mechanisms of the Anti-Inflammatory and Anti-Apoptotic Effects of Omega-3 Polyunsaturated Fatty Acids during Methotrexate-Induced Intestinal Damage in Cell Line and in a Rat Model

Background: The aim of this study was to examine the anti-inflammatory and anti-apoptotic patterns of omega-3 polyunsaturated fatty acids (n-3 PUFAs) during methotrexate (MTX) induced intestinal damage in cell culture and in a rat model. Methods: Non-treated and treated with MTX HT 29 and HCT116cells were exposed to increasing doses of n-3 PUFAs and cell viability was evaluated using PrestoBlue^® assay. Male Sprague-Dawley rats were divided into 4 experimental groups: Control rats, CONTR+n-3 PUFA rats that were treated with oral n-3 PUFA, MTX rats were treated with MTX given IP, and MTX+n-3 PUFA rats were treated with oral n-3 PUFA before and following injection of MTX. Intestinal mucosal parameters and mucosal inflammation, enterocyte proliferation and apoptosis, TNF-α in mucosal tissue and plasma (ELISA), NF-κB, COX-2, TNF-α, Fas, FasL, Fadd, Bid, Bax and Bcl-2gene and protein levels were determined 72 h following MTX injection. Results: Exposure of HT 29 and HCT116cells to n-3 PUFA attenuated inhibiting effects of MTX on cell viability. MTX-n-3 PUFA rats demonstrated a lower intestinal injury score and enhanced intestinal repair. A significant decrease in enterocyte apoptosis in MTX+n-3 PUFA rats was accompanied by decreased TNF-α, FAS, FasL, FADD and BID mRNA levels. Decreased NF-κB, COX-2 and TNF-α levels in mucosa was accompanied by a decreased number of IELs and macrophages. Conclusions: n-3 PUFAs inhibit NF-κB/COX-2 induced production of pro-inflammatory cytokines and inhibit cell apoptosis mainly by extrinsic pathway in rats with MTX-induced intestinal damage.     

γ-Oryzanol Enhances Adipocyte Differentiation and Glucose Uptake

Recent studies show that brown rice improves glucose intolerance and potentially the risk of diabetes, although the underlying molecular mechanisms remain unclear. One of the phytochemicals found in high concentration in brown rice is γ-oryzanol (Orz), a group of ferulic acid esters of phytosterols and triterpene alcohols. Here, we found that Orz stimulated differentiation of 3T3-L1 preadipocytes and increased the protein expression of adipogenic marker genes such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and CCAAT/enhanced binding protein alpha (C/EBPα). Moreover, Orz significantly increased the glucose uptake in insulin-resistant cells and translocation of glucose transporter type 4 (GLUT4) from the cytosol to the cell surface. To investigate the mechanism by which Orz stimulated cell differentiation, we examined its effects on cellular signaling of the mammalian target of rapamycin complex 1 (mTORC1), a central mediator of cellular growth and proliferation. The Orz treatment increased mTORC1 kinase activity based on phosphorylation of 70-kDa ribosomal S6 kinase 1 (S6K1). The effect of Orz on adipocyte differentiation was dependent on mTORC1 activity because rapamycin blocks cell differentiation in Orz-treated cells. Collectively, our results indicate that Orz stimulates adipocyte differentiation, enhances glucose uptake, and may be associated with cellular signaling mediated by PPAR-γ and mTORC1.     

Resveratrol Increases Nephrin and Podocin Expression and Alleviates Renal Damage in Rats Fed a High-Fat Diet

Resveratrol is well known for its anti-inflammation and anti-oxidant properties, and has been shown to be effective in alleviating the development of obesity. The purpose of this investigation was to analyze the effect of resveratrol on renal damage in obese rats induced by a high-fat diet (HFD) and its possible mechanisms. Male Sprague-Dawley rats were divided into three groups: control, HFD, and HFD plus resveratrol (treated with 100 mg/kg/day resveratrol). Body weight, serum and urine metabolic parameters, and kidney histology were measured. Meanwhile, the activities of nuclear factor-κB (NF-κB) and superoxide dismutase (SOD), the content of malondialdehyde (MDA), and the protein levels of tumor necrosis factor (TNF-α), monocyte chemotactic protein-1 (MCP-1), nephrin and podocin in kidney were detected. Our work showed that resveratrol alleviated dyslipidemia and renal damage induced by HFD, decreased MDA level and increased SOD activity. Furthermore, the elevated NF-κB activity, increased TNF-α and MCP-1 levels, and reduced expressions of nephrin and podocin induced by HFD were significantly reversed by resveratrol. These results suggest resveratrol could ameliorate renal injury in rats fed a HFD, and the mechanisms are associated with suppressing oxidative stress and NF-κB signaling pathway that in turn up-regulate nephrin and podocin protein expression.     

Fucoxanthin alters the apelin-13/APJ pathway in certain organs of γ-irradiated mice

Apelin-13 and APJ are implicated in different key physiological processes. This work aims at exploring the radioprotective effect of fucoxanthin (FX) on γ-radiation (RAD)-induced changes in the apelin-13/APJ pathway, which causes damage in the liver, kidney, lung and spleen of mice. Mice were administered FX (10 mg kg^–1 day^–1, i.p) and exposed to γ-radiation (2.5 Gy week^–1) for four consecutive weeks. The treatment of irradiated mice by FX resulted in a significant amendment in protein expression of the apelin-13/APJ/NF-κB signalling pathway concurrently with reduced hypoxia (hypoxia-inducible factor-1α), suppressed oxidative stress marker (malondialdehyde), enhanced antioxidant defence mechanisms (reduced glutathione and glutathione peroxidase), a modulated inflammatory response [interleukin-6 (IL-6), monocyte chemoattractant protein-1, IL-10 and α-7-nicotinic acetylcholine receptor) and ameliorated angiogenic regulators [matrix metalloproteinase (MMP-2), MMP-9 and tissue inhibitor of metalloproteinase-1), as well as the tissue damage indicator (lactate dehydrogenase) in organ tissues. In addition, there were significant improvement in serum inflammatory markers tumour necrosis factor-α, IL-10, IL-1β and C-reactive protein compared with irradiated mice. The histopathological investigation of the FX + RAD organ tissues support the biochemical findings where the improvements in the tissues’ architecture were obvious when compared with those of RAD. FX was thus shown to have a noticeable radioprotective action mediated through its regulatory effect on the apelin-13/APJ/NF-κB signalling pathway attributed to its antioxidant and anti-inflammatory activity that was reflected in different physiological processes. It could be recommended to use FX in cases of radiation exposure to protect normal tissues.     

Alginate Oligosaccharides Ameliorate DSS-Induced Colitis through Modulation of AMPK/NF-κB Pathway and Intestinal Microbiota

Alginate oligosaccharides (AOS) are shown to have various biological activities of great value to medicine, food, and agriculture. However, little information is available about their beneficial effects and mechanisms on ulcerative colitis. In this study, AOS with a polymerization degree between 2 and 4 were found to possess anti-inflammatory effects in vitro and in vivo. AOS could decrease the levels of nitric oxide (NO), IL-1β, IL-6, and TNFα, and upregulate the levels of IL-10 in both RAW 264.7 and bone-marrow-derived macrophage (BMDM) cells under lipopolysaccharide (LPS) stimulation. Additionally, oral AOS administration could significantly prevent bodyweight loss, colonic shortening, and rectal bleeding in dextran sodium sulfate (DSS)-induced colitis mice. AOS pretreatment could also reduce disease activity index scores and histopathologic scores and downregulate proinflammatory cytokine levels. Importantly, AOS administration could reverse DSS-induced AMPK deactivation and NF-κB activation in colonic tissues, as evidenced by enhanced AMPK phosphorylation and p65 phosphorylation inhibition. AOS could also upregulate AMPK phosphorylation and inhibit NF-κB activation in vitro. Moreover, 16S rRNA gene sequencing of gut microbiota indicated that supplemental doses of AOS could affect overall gut microbiota structure to a varying extent and specifically change the abundance of some bacteria. Medium-dose AOS could be superior to low- or high-dose AOS in maintaining remission in DSS-induced colitis mice. In conclusion, AOS can play a protective role in colitis through modulation of gut microbiota and the AMPK/NF-kB pathway.     

Prevention of Ulcerative Colitis in Mice by Sweet Tea (Lithocarpus litseifolius) via the Regulation of Gut Microbiota and Butyric-Acid-Mediated Anti-Inflammatory Signaling

Sweet tea (Lithocarpus litseifolius [Hance] Chun) is a new resource for food raw materials, with plenty of health functions. This study aimed to investigate the preventive effect and potential mechanism of sweet tea extract (STE) against ulcerative colitis (UC). Briefly, BABL/c mice were treated with STE (100 and 400 mg/kg) for 2 weeks to prevent 3% dextran sulfate sodium (DSS)-induced UC. It was found that STE supplementation significantly prevented DSS-induced UC symptoms; suppressed the levels of pro-inflammatory mediators, such as myeloperoxidase and tumor necrosis factor-α; increased the levels of anti-inflammatory cytokines; and up-regulated the expression of tight junction proteins (Zonula occludens-1 and Occludin). STE also altered the gut microbiota profile of UC mice by increasing Bacteroidetes, Lactobacillus, Akkermansia, Lachnospiraceae_NK4A136_group, and Alistipes and inhibiting Firmicutes, Proteobacteria, and Helicobacter, accompanied by a significant increase in the content of butyric acid. Moreover, STE increased the expression of G-protein-coupled receptor (GPR) 43 and GPR109A and inhibited the expression of histone deacetylase 3 (HDAC3) and nuclear factor-κB p65 (NF-κB p65) in the colon. In conclusion, this study indicated that STE has a good preventive effect on UC by regulating gut microbiota to activate butyrate-GPR-mediated anti-inflammatory signaling and simultaneously inhibit HDAC3/NF-κB inflammatory signaling.     

Anti-Obesity and Antidiabetic Effects of Nelumbinis Semen Powder in High-Fat Diet-Induced Obese C57BL/6 Mice

Nelumbinis Semen (NS, the seeds of Nelumbo nucifera) extract is a traditional Korean medicine with anti-oxidant activity. The present study examined the anti-obesity and antidiabetic effects of NS powder in high-fat diet (HFD)-induced obese C57BL/6 mice. Mice (n = 8/group) were fed a normal diet (CON), HFD, HFD containing 5% NS powder (HFD-NS5%), or HFD containing 10% NS powder (HFD-NS10%) for 12 weeks. Food intake was relatively higher in groups HFD-NS5% and HFD-NS10%, while the food efficiency ratio was highest in group HFD (p < 0.05). HFD-NS5% reduced the body weight (−39.1%) and fat weight (−26.6%), including epididymal fat and perirenal fat, and lowered the serum triglyceride levels (−20.6%) compared with HFD. Groups HFD-NS5% and HFD-NS10% showed hepatoprotective properties, reducing the serum ALT levels (p < 0.05) and fat globules (size and number) in the liver compared with group HFD. HFD-NS5% and HFD-NS10% regulated the blood glucose, improved the glucose intolerance, and showed a 12.5% and 15.0% reduction in the area under the curve (AUC) of intraperitoneal glucose tolerance test (IPGTT), and a 26.8% and 47.3% improvement in homeostatic model assessment insulin resistance (HOMA-IR), respectively, compared with HFD (p < 0.05). Regarding the expressions of genes related to anti-obesity and antidiabetes, there was a 1.7- and 1.3-fold increase in PPAR-α protein expression, 1.4- and 1.6-fold increase in PPAR-γ protein expression, and 0.7- and 0.6-fold decrease in TNF-α protein expression, respectively, following HFD-NS5% and HFD-NS10% treatments, compared with HFD, and GLUT4 protein expression increased relative to CON (p < 0.05). These results comprehensively provide the fundamental data for NS powder’s functional and health-promoting benefits associated with anti-obesity and antidiabetes.     

The Nutraceutical N-Palmitoylethanolamide (PEA) Reveals Widespread Molecular Effects Unmasking New Therapeutic Targets in Murine Varicocele

Varicocele is an age-related disease with no current medical treatments positively impacting infertility. Toll-like receptor 4 (TLR4) expression is present in normal testis with an involvement in the immunological reactions. The role of peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor, in fertility is still unclear. N-Palmitoylethanolamide (PEA), an emerging nutraceutical compound present in plants and animal foods, is an endogenous PPAR-α agonist with well-demonstrated anti-inflammatory and analgesics characteristics. In this model of mice varicocele, PPAR-α and TLR4 receptors’ roles were investigated through the administration of ultra-micronized PEA (PEA-um). Male wild-type (WT), PPAR-α knockout (KO), and TLR4 KO mice were used. A group underwent sham operation and administration of vehicle or PEA-um (10 mg/kg i.p.) for 21 days. Another group (WT, PPAR-α KO, and TLR4 KO) underwent surgical varicocele and was treated with vehicle or PEA-um (10 mg/kg i.p.) for 21 days. At the end of treatments, all animals were euthanized. Both operated and contralateral testes were processed for histological and morphometric assessment, for PPAR-α, TLR4, occludin, and claudin-11 immunohistochemistry and for PPAR-α, TLR4, transforming growth factor-beta3 (TGF-β3), phospho-extracellular signal-Regulated-Kinase (p-ERK) 1/2, and nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) Western blot analysis. Collectively, our data showed that administration of PEA-um revealed a key role of PPAR-α and TLR4 in varicocele pathophysiology, unmasking new nutraceutical therapeutic targets for future varicocele research and supporting surgical management of male infertility.     

Effects of d-α-tocopherol supplements on lipid metabolism in a high-fat diet-fed animal model

High-fat diet up-regulates either insulin resistance or triglycerides, which is assumed to be related to the expression of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ. The beneficial effects of vitamin E on insulin resistance are well known; however, it is not clear if vitamin E with a high-fat diet alters the expression of PPAR-α and PPAR-γ. We investigated the effects of d-α-tocopherol supplementation on insulin sensitivity, blood lipid profiles, lipid peroxidation, and the expression of PPAR-α and PPAR-γ in a high-fat (HF) diet-fed male C57BL/6J model of insulin resistance. The animals were given a regular diet (CON; 10% fat), a HF diet containing 45% fat, or a HF diet plus d-α-tocopherol (HF-E) for a period of 20 weeks. The results showed that the HF diet induced insulin resistance and altered the lipid profile, specifically the triglyceride (TG) and total cholesterol (TC) levels (P < 0.05). In this animal model, supplementation with d-α-tocopherol improved insulin resistance as well as the serum levels of TG and very-low-density lipoprotein-cholesterol (VLDL-C) (P < 0.05). Moreover, the treatment decreased the levels of malondialdehyde (MDA) in the serum and liver while increasing hepatic PPAR-α expression and decreasing PPAR-γ expression. In conclusion, the oral administration of d-α-tocopherol with a high-fat diet had positive effects on insulin resistance, lipid profiles, and oxidative stress through the expression of PPAR-α and PPAR-γ in a high-fat diet-fed male mice.     

Simultaneous Pretreatment of Aspirin and Omega-3 Fatty Acid Attenuates Nuclear Factor-κB Activation in a Murine Model with Ventilator-Induced Lung Injury

Ventilator-induced lung injury (VILI) is an important critical care complication. Nuclear factor-κB (NF-κB) activation, a critical signaling event in the inflammatory response, has been implicated in the tracking of the lung injury. The present study aimed to determine the effect of simultaneous pretreatment with enteral aspirin and omega-3 fatty acid on lung injury in a murine VILI model. We compared the lung inflammation after the sequential administration of lipopolysaccharides and mechanical ventilation between the pretreated simultaneous enteral aspirin and omega-3 fatty acid group and the non-pretreatment group, by quantifying NF-κB activation using an in vivo imaging system to detect bioluminescence signals. The pretreated group with enteral aspirin and omega-3 fatty acid exhibited a smaller elevation of bioluminescence signals than the non-pretreated group (p = 0.039). Compared to the non-pretreated group, the pretreatment group with simultaneous enteral aspirin and omega-3 fatty acid showed reduced expression of the pro-inflammatory cytokine, tumor necrosis factor-α, in bronchoalveolar lavage fluid (p = 0.038). Histopathological lung injury scores were also lower in the pretreatment groups compared to the only injury group. Simultaneous pretreatment with enteral administration of aspirin and omega-3 fatty acid could be a prevention method for VILI in patients with impending mechanical ventilation therapy.     

In vitro biological evaluation of 100 selected methanol extracts from the traditional medicinal plants of Asia

BACKGROUND/OBJECTIVES

In Asia, various medicinal plants have been used as the primary sources in the health care regimen for thousands of years. In recent decades, various studies have investigated the biological activity and potential medicinal value of the medicinal plants. In this study, 100 methanol extracts from 98 plant species were evaluated for their biological activities.

MATERIALS/METHODS

The research properties, including 1,1-diphenyl-2-pic-rylhydrazyl (DPPH) radical scavenging activity, α-glucosidase and α-tyrosinase inhibitory effects, anti-inflammatory activity, and anticancer activity were evaluated for the selected extracts.

RESULTS

Fifteen of the extracts scavenged more than 90% of the DPPH radical. Among the extracts, approximately 20 extracts showed a strong inhibitory effect on α-glucosidase, while most had no effect on α-tyrosinase. In addition, 52% of the extracts showed low toxicity to normal cells, and parts of the extracts exhibited high anti-inflammatory and anticancer activities on the murine macrophage cell (RAW 264.7) and human colon cancer cell (HT-29) lines, respectively.

CONCLUSIONS

Our findings may contribute to further nutrition and pharmacological studies. Detailed investigations of the outstanding samples are currently underway.     

Consumption of Polyphenol-Rich Zingiber Zerumbet Rhizome Extracts Protects against the Breakdown of the Blood-Retinal Barrier and Retinal Inflammation Induced by Diabetes

The present study investigates the amelioration of diabetic retinopathy (DR) by Zingiber zerumbet rhizome ethanol extracts (ZZRext) in streptozotocin-induced diabetic rats (STZ-diabetic rats). ZZRext contains high phenolic and flavonoid contents. STZ-diabetic rats were treated orally with ZZRext (200, 300 mg/kg per day) for three months. Blood-retinal barrier (BRB) breakdown and increased vascular permeability were found in diabetic rats, with downregulation of occludin, and claudin-5. ZZRext treatment effectively preserved the expression of occludin, and claudin-5, leading to less BRB breakdown and less vascular permeability. Retinal histopathological observation showed that the disarrangement and reduction in thickness of retinal layers were reversed in ZZRext-treated diabetic rats. Retinal gene expression of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, vascular endothelial growth factor, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were all decreased in ZZRext-treated diabetic rats. Moreover, ZZRext treatment not only inhibited the nuclear factor κB (NF-κB) activation, but also downregulated the protein expression of p38 mitogen-activated protein kinase (MAPK) in diabetic retina. In conclusion, the results suggest that the retinal protective effects of ZZRext occur through improved retinal structural change and inhibiting retinal inflammation. The antiretinopathy property of ZZRext might be related to the downregulation of p38 MAPK and NF-κB signal transduction induced by diabetes.     

Inosine Pretreatment Attenuates LPS-Induced Lung Injury through Regulating the TLR4/MyD88/NF-κB Signaling Pathway In Vivo

Inosine is a type of purine nucleoside, which is considered to a physiological energy source, and exerts a widely range of anti-inflammatory efficacy. The TLR4/MyD88/NF-κB signaling pathway is essential for preventing host oxidative stresses and inflammation, and represents a promising target for host-directed strategies to improve some forms of disease-related inflammation. In the present study, the results showed that inosine pre-intervention significantly suppressed the pulmonary elevation of pro-inflammatory cytokines (including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)), malondialdehyde (MDA), nitric oxide (NO), and reactive oxygen species (ROS) levels, and restored the pulmonary catalase (CAT), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and myeloperoxidase (MPO) activities (p < 0.05) in lipopolysaccharide (LPS)-treated mice. Simultaneously, inosine pre-intervention shifted the composition of the intestinal microbiota by decreasing the ratio of Firmicutes/Bacteroidetes, elevating the relative abundance of Tenericutes and Deferribacteres. Moreover, inosine pretreatment affected the TLR4/MyD88/NF-κB signaling pathway in the pulmonary inflammatory response, and then regulated the expression of pulmonary iNOS, COX2, Nrf2, HO-1, TNF-α, IL-1β, and IL-6 levels. These findings suggest that oral administration of inosine pretreatment attenuates LPS-induced pulmonary inflammatory response by regulating the TLR4/MyD88/NF-κB signaling pathway, and ameliorates intestinal microbiota disorder.