Therapeutic role of ursodeoxycholic acid in colitis-associated cancer via gut microbiota modulation.

Inflammatory bowel disease (IBD) is a predisposing factor for colitis-associated cancer (CAC). The association between bile acids and the gut microbiota has been demonstrated in colon neoplasia; however, the effect of ursodeoxycholic acid (UDCA) on gut microbiota alteration in development of colitis and CAC is unknown. Our analysis of publicly available datasets demonstrated the association of UDCA treatment and accumulation of Akkermansia. UDCA-mediated alleviation of DSS-induced colitis was microbially dependent. UDCA treatment significantly upregulated Akkermansia colonization in a mouse model. Colonization of Akkermansia was associated with enhancement of the mucus layer upon UDCA treatment as well as activation of bile acid receptors in macrophages. UDCA played a role in CAC prevention and treatment in the AOM-DSS and ApcMin/+-DSS models through downregulation of inflammation and accumulation of Akkermansia. This study suggests that UDCA intervention could reshape intestinal gut homeostasis, facilitating colonization of Akkermansia and preventing and treating colitis and CAC.

Soybean glycinin and ß-conglycinin damage the intestinal barrier by triggering oxidative stress and inflammatory response in weaned piglets.

PURPOSE: Soybean glycinin (11S) and ß-conglycinin (7S) are major antigenic proteins in soybean and can induce a variety of allergic reactions in the young animals. This study aimed to investigate the effect of 7S and 11S allergens on the intestine of piglets. METHODS: Thirty healthy 21-day-old weaned "Duroc × Long White × Yorkshire" piglets were randomly divided into three groups fed with the basic diet, the 7S supplemented basic diet, or the 11S supplemented basic diet for 1 week. Allergy markers, intestinal permeability, oxidative stress, and inflammatory reactions were detected, and we observed different sections of intestinal tissue. The expressions of genes and proteins related to NOD-like receptor thermal protein domain associated protein 3 (NLRP-3) signaling pathway were detected by IHC, RT-qPCR, and WB. RESULTS: Severe diarrhea and decreased growth rate were observed in the 7S and 11S groups. Typical allergy markers include IgE production and significant elevations of histamine and 5-hydroxytryptamine (5-HT). More aggressive intestinal inflammation and barrier dysfunction were observed in the experimental weaned piglets. In addition, 7S and 11S supplementation increased the levels of 8-hydroxy-2 deoxyguanosine (8-OHdG) and nitrotyrosine, triggering oxidative stress. Furthermore, higher expression levels of NLRP-3 inflammasome ASC, caspase-1, IL-1ß, and IL-18 were observed in the duodenum, jejunum, and ileum. CONCLUSION: We confirmed that 7S and 11S damaged the intestinal barrier of weaned piglets and may be associated with the onset of oxidative stress and inflammatory response. However, the molecular mechanism underlying these reactions deserves further study.

Soybean Antigen Protein-Induced Intestinal Barrier Damage by Trigging Endoplasmic Reticulum Stress and Disordering Gut Microbiota in Weaned Piglets.

Endoplasmic reticulum (ER) stress is a crucial factor in the pathogenesis of intestinal diseases. Soybean antigenic proteins (ß-conglycinin and soy glycinin) induce hypersensitivity reactions and intestinal barrier damage. However, whether this damage is associated with ER stress, autophagy, and the gut microbiome is largely unclear. Therefore, in this study, we aimed to investigate the effect of dietary supplementation with soy glycinin (11S glycinin) and ß-conglycinin (7S glycinin) on intestinal ER stress, autophagy, and flora in weaned piglets. Thirty healthy 21-day-old weaned "Duroc × Long White × Yorkshire" piglets were randomly divided into three groups and fed a basic, 7S-supplemented, or 11S-supplemented diet for one week. The results indicated that 7S/11S glycinin disrupted growth performance, damaged intestinal barrier integrity, and impaired goblet cell function in piglets (p < 0.05). Moreover, 7S/11S glycinin induced ER stress and blocked autophagic flux in the jejunum (p < 0.05) and increased the relative abundance of pathogenic flora (p < 0.01) and decreased that of beneficial flora (p < 0.05). In conclusion, 7S/11S glycinin induces intestinal ER stress, autophagic flux blockage, microbiota imbalance, and intestinal barrier damage in piglets.

Epigallocatechin-3-gallate activates the AMP-activated protein kinase signaling pathway to reduce lipid accumulation in canine hepatocytes.

Epigallocatechin-3-gallate (EGCG) plays a crucial role in hepatic lipid metabolism. However, the underlying regulatory mechanism of hepatic lipid metabolism by EGCG in canine is unclear. Primary canine hepatocytes were treated with EGCG (0.01, 0.1, or 1 µM) and BML-275 (an AMP-activated protein kinase [AMPK] inhibitor) to study the effects of EGCG on the gene and protein expressions associated with AMPK signaling pathway. Data showed that treatment with EGCG had greater activation of AMPK, as well as greater expression levels and transcriptional activity of peroxisome proliferator activated receptor-α (PPARα) along with upregulated messenger RNA (mRNA) abundance and protein abundance of PPARα-target genes. EGCG decreased the expression levels and transcriptional activity of sterol regulatory element-binding protein 1c (SREBP-1c) along with downregulated mRNA abundance and protein abundance of SREBP-1c target genes. Of particular interest, exogenous BML-275 could reduce or eliminate the effects of EGCG on lipid metabolism in canine hepatocytes. Furthermore, the content of triglyceride was significantly decreased in the EGCG-treated groups. These results suggest that EGCG might be a potential agent in preventing high-fat diet-induced lipid accumulation in small animals.

Endoscopic treatment of pouch inlet and afferent limb strictures: stricturotomy vs. balloon dilation.

BACKGROUND: Strictures are common complications after ileal pouch surgery. The aim of this study is to evaluate the efficacy and safety of endoscopic stricturotomy vs. endoscopic balloon dilation (EBD) in the treatment of pouch inlet strictures. METHODS: All consecutive ulcerative colitis patients with the diagnosis of pouch inlet or afferent limb strictures treated in our Interventional Inflammatory Bowel Disease Unit (i-IBD) from 2008 to 2017 were extracted. The primary outcomes were surgery-free survival and post-procedural complications. RESULTS: A total of 200 eligible patients were included in this study, with 40 (20.0%) patients treated with endoscopic stricturotomy and 160 (80.0%) patients treated with EBD. Symptom improvement was recorded in 11 (42.3%) patients treated with endoscopic stricturotomy and 16 (13.2%) treated with EBD. Subsequent surgery rate was comparable between the two groups (9 [22.5%] vs. 33 [20.6%], P = 0.80) during a median follow-up of 0.6 years (interquartile range [IQR] 0.4-0.8) vs. 3.6 years (IQR 1.1-6.2) in patients receiving endoscopic stricturotomy and EBD, respectively. The overall surgery-free survival seems to be comparable as well (P = 0.12). None of the patients in the stricturotomy group developed pouch failure, while 9 patients (5.6%) had pouch failure in the balloon dilation group (P = 0.17). Procedural bleeding was seen in three occasions (4.7% per procedure) in patients receiving endoscopic stricturotomy and perforation was seen in three occasions (0.8% per procedure) in patients receiving EBD (P = 0.02). In multivariable analysis, an increased length of the stricture (hazard ratio [HR] 1.4, 95% confidence interval [CI] 1.0-1.8) and concurrent pouchitis (HR 2.5, 95% CI 1.0-5.7) were found to be risk factors for the requirement of surgery. CONCLUSION: Endoscopic stricturotomy and EBD were both effective in treating patients with pouch inlet or afferent limb strictures, EBD had a higher perforation risk while endoscopic stricturotomy had a higher bleeding risk.

Lycopene attenuates zearalenone-induced oxidative damage of piglet sertoli cells through the nuclear factor erythroid-2 related factor 2 signaling pathway.

Zearalenone (ZEA) has an estrogenic effect and often causes reproductive damage. Pigs are particularly sensitive to it. Lycopene (LYC) is a type of fat-soluble natural carotenoid that has antioxidant, anti-inflammatory, anti-cancer, anti-cardiovascular and detoxifying effects. In this study, piglet sertoli cells (SCs) were used as research objects to investigate the mechanism of ZEA induced damage to piglet SCs and to evaluate the protective effect of LYC on ZEA induced toxic damage to piglet SCs. The results showed that ZEA damaged the cell structure and inhibited the expression of nuclear factor erythroid-2 related factor 2 (Nrf2) in the nucleus, which down-regulated the relative mRNA expression of heme oxygenase 1 (HO-1) and glutathione peroxidase 1 (GPX1) and decreased the activity of HO-1, glutathione peroxidase (GSH-Px) and total superoxide dismutase (T-SOD), resulting in an increase in malondialdehyde (MDA) and reactive oxygen species (ROS) content. ZEA downregulated the relative mRNA and protein expression of bcl-2 in piglet SCs, promoted cell apoptosis, and upregulated the relative mRNA and protein expression of LC3, beclin-1, and bax. After 3 h LYC-pretreatment, ZEA was added for mixed culture. The results of pretreatment with LYC showed that LYC could alleviate the cytotoxicity of ZEA to porlets SCs. Compared with ZEA group, improved the cell survival rate, promoted the expression of Nrf2 in the nucleus, upregulated the relative mRNA expression of HO-1 and GPX1, increased the activity of antioxidant enzymes, and reduced the levels of MDA and ROS. Moreover, after pretreatment with LYC, the mRNA expression of bcl-2 was upregulated, the apoptosis rate was decreased, the relative mRNA and protein expressions of LC3, beclin-1 and bax were downregulated, and autophagy was alleviated. In conclusion, LYC alleviated the oxidative damage of SCs caused by ZEA by promoting the expression of Nrf2 pathway and decreased autophagy and apoptosis.

Autophagy protects PC12 cells against deoxynivalenol toxicity via the Class III PI3K/beclin 1/Bcl-2 pathway.

Deoxynivalenol (DON) is a major mycotoxin from the trichothecene family of mycotoxins produced by Fusarium fungi. It can cause a variety of adverse effects on human and farm animal health. Here, we determined the effect of DON on the Class III phosphatidylinositol 3-kinase (PIK3C3)/beclin 1/B cell lymphoma-2 (Bcl-2) pathway in PC12 cells and the relationship between autophagy and apoptosis. The effects of DON were evaluated based on the apoptosis ratio; the typical indicators of autophagy, including cellular morphology, acridine orange- and monodansylcadaverine-labeled vacuoles, green fluorescent protein-microtubule associated protein 1 light chain 3 (LC3) localization, and LC3 immunofluorescence; and the expression of key autophagy-related genes and proteins, that is, PIK3C3, beclin 1, Bcl-2, LC3, and p62. The relationship between autophagy and apoptosis was analyzed by western blot analysis and flow cytometry. DON-induced PC12 cell morphological changes and autophagy significantly. PIK3C3, beclin 1, and LC3 increased in tandem with the DON concentration used; Bcl-2 and p62 expression decreased as DON concentrations increased. Moreover, the PIK3C3/beclin 1/Bcl-2 signaling pathway played a role in DON-induced autophagy. Our findings suggest that DON can induce autophagy by activating the PIK3C3/beclin 1/Bcl-2 signaling pathway and that autophagy may play a positive role in reducing DON-induced apoptosis.

Tea polyphenols attenuate liver inflammation by modulating obesity-related genes and down-regulating COX-2 and iNOS expression in high fat-fed dogs.

BACKGROUND: Tea polyphenols (TPs) attenuate obesity related liver inflammation; however, the anti-obesity effects and anti-inflammatory mechanisms are not clearly understood. This study aimed to determine whether the anti-obesity and anti-inflammatory TPs mechanisms associated with cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression levels, and obesity-related gene response in dogs. RESULTS: Dogs fed TPs displayed significantly decreased (p < 0.01) mRNA expression of tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1ß), and interleukin-6 (IL-6) compared to dogs that consumed high-fat diet (HFD) alone. TPs significantly (p < 0.01) inhibited COX-2 and iNOS expression level, and decreased liver fat content and degeneration. CONCLUSION: These results suggested that TPs act as a therapeutic agent for obesity, liver inflammation, and fat degeneration via COX-2 and iNOS inhibition, with TNF-α, IL-1ß, and IL-6 involvement.

Mechanism of deoxynivalenol-induced neurotoxicity in weaned piglets is linked to lipid peroxidation, dampened neurotransmitter levels, and interference with calcium signaling.

Deoxynivalenol（DON） has broad toxicity in livestock, but we know little about its neurotoxic mechanisms. We investigated DON neurotoxicity in the cerebral cortex, cerebellum, and hippocampus of "Duroc × Landrace × Yokshire" piglets. Control piglets were fed a basal diet, while those in low- and high-treatment groups were fed diets with 1.3 mg/kg and 2.2 mg/kg DON, respectively. After a 60 d trial, scanning electron microscopy revealed the destruction of hippocampal cell ultrastructure. As DON concentrations increased, oxidative damage also increased in the cerebral cortex, cerebellum, and hippocampus. Norepinephrine and 5-hydroxytryptamine concentrations tended to increase, whereas dopamine and γ-aminobutyric acid concentrations decreased. We also observed an increase in calcium concentration, relative mRNA expression of calcium/calmodulin-dependent protein kinase II (CaMKII), and CaMKII phosphorylation. However, calmodulin (CaM) mRNA and protein content decreased. Overall, our results suggest that DON acts through the Ca2+/CaM/CaMKII signaling pathway to influence cerebral lipid peroxidation and neurotransmitter levels.

[Early stage mechanical adaptability and osteogenic differentiation of mouse bone marrow derived mesenchymal stem cell under micro-vibration stimulation environment].

This study investigated the early mechanical adaptability and osteogenic differentiation of mouse bone marrow mesenchymal stem cells (M-BMSCs) under micro-vibration stimulation (MVS). M-BMSCs were stimulated by MVS in vitro, cell proliferation, alkaline phosphatase (ALP) activity assay, and cytoskeleton were measured, and cell apoptosis was observed by flow cytometry. Early osteoblast-associated genes, runt-related transcription factor 2 (Runx2), Collagen Ⅰ (Col-Ⅰ) and ALP, were observed by RT-PCR and the activation of extracellular regulated protein kinases 1/2 (ERK1/2) was determined by Western blotting. The results showed that MVS had no significant effect on the proliferation of M-BMSCs. The early apoptosis was induced by mechanical stimulation (for one day), but the apoptosis was decreased after cyclic stimulation for 3 days. At the same time, MVS significantly accelerated the expression of F-actin protein in cytoskeleton, the synthesis of ALP and the ERK1/2 pathway, also up-regulated the expressions of Runx2, Col-Ⅰ and ALP genes. This study indicates that MVS could regulate cellular activity, alter early adaptive structure and finally promote the early osteogenic differentiation of M-BMSCs.

The malignant role of exosomes in the communication among colorectal cancer cell, macrophage and microbiome.

Colorectal cancer (CRC) is a complex and heterogeneous malignant cancer characterized by its high prevalence and poor prognosis. Among different etiologies, impairment of immune surveillance and dysbiosis are important events to mediate the invasion and metastasis of CRC. Although aberrant distribution of macrophages and microbiota exhibits distinct properties to modulate the malignant behaviors of CRC, the crosstalk among macrophages, microbiomes and tumor cells remains unclear. Exosomes are intercellular messengers carrying different cargo to regulate the biological and pathologic changes of recipient cells. CRC-derived exosomes can educate macrophages and facilitate the angiogenesis and establishment of premetastatic niche. Meanwhile, exosomes from macrophages and microbiome can regulate the tumor microenvironment for tumor progression and dissemination. The aim of this review is to highlight the innovative role of exosomes in the pathogenesis of CRC. Theoretical elaboration of the underlying mechanism provides valuable treating targets of CRC.

Glucagon attenuates lipid accumulation in cow hepatocytes through AMPK signaling pathway activation.

The ketotic cows displayed hepatic lipid metabolic disorder and high blood concentration of glucagon. Importantly, adenosine monophosphate-activated protein kinase (AMPK) signaling pathway plays an important role in the hepatic lipid homeostasis. Therefore, the aim of this study was to investigate the effect of glucagon on AMPK pathway and its underlying mechanism on lipid metabolism in cow hepatocytes. Cow hepatocytes were cultured and treated with glucagon and AMPK inhibitor (BML-275). The results showed that glucagon significantly promoted the expression of glucagon receptor and increased the phosphorylation level and activity of AMPKα. Activated AMPKα increased the expression level and transcriptional activity of peroxisome proliferator-activated receptor α, which further increased the expression of fatty acid oxidation genes and lipid oxidation. Furthermore, activated AMPKα inhibited the expression level and transcriptional activity of sterol regulatory element binding protein-1c and carbohydrate response element binding protein, which decreased the expression of lipogenic genes, thereby decreasing lipid synthesis. In addition, glucagon also increased the expression of very-low-density lipoprotein (VLDL) assembly to export intracellular triglycerides (TG). Consequently, the content of intracellular TG was significantly decreased in cow hepatocytes. These results indicate that glucagon activates the AMPK signaling pathway to increase lipid oxidation and VLDL assembly and decrease lipid synthesis in cow hepatocytes, thereby reducing liver fat accumulation.

Pro-endometriotic niche in endometriosis.

Endometriosis is a complex and heterogeneous disorder of unknown aetiology. This benign disease possesses special biological behaviours that mimic those of malignant tumours. A pro-endometriotic niche established by an existing lesion is a supportive micro-environment for the progression of endometriosis. After the accumulation of cells by an existing lesion, these components display distinct characteristics that impair immune surveillance. Subsequent retrograde menstruation of endometrial stromal cells into the pro-endometriotic niche facilitates endometriotic progression from early initiation to an advanced lesion. This study aimed to highlight the innovative role of the pro-endometriotic niche in endometriosis, and to provide valuable treatment targets for endometriosis.

Uric acid transporters BCRP and MRP4 involved in chickens uric acid excretion.

BACKGROUND: Breast cancer resistance protein (BCRP) and multidrug resistance protein 4 (MRP4) are involved in uric acid excretion in humans and mice. Despite evidence suggesting that renal proximal tubular epithelial cells participate in uric acid excretion in chickens, the roles of BCRP and MRP4 therein remain unclear. This study evaluated the relationship between BCRP and MRP4 expression and renal function in chickens. RESULTS: Sixty laying hens were randomly divided into four treatment groups: a control group (NC) fed a basal diet; a sulfonamide-treated group (SD) fed the basal diet and supplemented with sulfamonomethoxine sodium via drinking water (8 mg/L); a fish meal group (FM) fed the basal diet supplemented with 16% fishmeal; and a uric acid injection group (IU) fed the basal diet and intraperitoneally injected with uric acid (250 mg/kg body weight). The results showed that serum uric acid, creatinine, and blood urea nitrogen levels were significantly higher in the SD and IU, but not FM, than in the NC groups. Renal tubular epithelial cells in the SD and IU groups were damaged. Liver BCRP and MRP4 mRNA and protein levels were significantly decreased in the SD and IU groups, but slightly increased in the FM group. In the SD group, BCRP and MRP4 were significantly increased in the ileum and slightly increased in the kidney. In the FM group, BCRP and MRP4 were significantly increased in the kidney and slightly increased in the ileum. In the IU group, BCRP and MRP4 were significantly increased in the kidney and ileum. BCRP and MRP4 expression in the jejunum was not affected by the treatments. CONCLUSION: Together, these results demonstrate that BCRP and MRP4 are involved in renal and intestinal uric acid excretion in chickens and that BCRP is positively related to MRP4 expression. Further, impairment of renal function results in an increase in serum uric acid as well as a compensatory increase in BCRP and MRP4 in the ileum; however, under normal renal function, renal BCRP and MRP4 are the main regulators of uric acid excretion.

Rutin protects against lipopolysaccharide-induced mastitis by inhibiting the activation of the NF-κB signaling pathway and attenuating endoplasmic reticulum stress.

Rutin, found widely in traditional Chinese medicine materials, is used to treat eye swelling and pain, hypertension, and hyperlipidemia. In the present study, a mouse mastitis model induced by lipopolysaccharide (LPS) was established to explore rutin's inhibitory mechanism on mastitis via nuclear factor kappa B (NF-κB) inflammatory signaling and the relationship between NF-κB signaling and endoplasmic reticulum (ER) stress. Mice were divided into six groups: Control group, LPS model group, LPS + rutin (25, 50, and 100 mg/kg) and LPS + dexamethasone (DEX) group. DEX, rutin, and PBS (control and LPS groups) were administered 1 h before and 12 h after perfusion of LPS. After LPS stimulation for 24 h, to evaluate rutin's therapeutic effect on mastitis, the mammary tissues of each group were collected to detect histopathological injury, tumor necrosis factor alpha (TNF-α), interleukin (IL)-1ß, and IL-6 mRNA and protein levels; and glucose-regulated protein, 78 kDa (GRP78) protein levels. The protein and mRNA levels of TNF-α, IL-1ß, and IL-6 in the LPS + rutin group were significantly lower than those in the LPS model group. Similarly, p50/p105, phosphorylated (p)-p65/p65 and p-inhibitor of nuclear factor kappa b kinase subunit beta (p-IKKß)/IKKß ratios in the LPS + rutin group (50 mg/kg) and LPS + rutin group (100 mg/kg) decreased significantly. GRP78 protein expression was significantly higher in LPS + rutin group (100 mg/kg). The structure of mammary tissue became gradually more intact and vacuolization of acini decreased as the rutin concentration increased. The nuclear quantity of p65 in the LPS + rutin group decreased significantly in a rutin dose-dependent manner. Rutin had an anti-inflammatory effect in the LPS-induced mouse mastitis model, manifested by inhibition of NF-κB pathway activation and attenuation of ER stress.

Villainous role of estrogen in macrophage-nerve interaction in endometriosis.

Endometriosis is a complex and heterogeneous disorder with unknown etiology. Dysregulation of macrophages and innervation are important factors influencing the pathogenesis of endometriosis-associated pain. It is known to be an estrogen-dependent disease, estrogen can promote secretion of chemokines from peripheral nerves, enhancing the recruitment and polarization of macrophages in endometriotic tissue. Macrophages have a role in the expression of multiple nerve growth factors (NGF), which mediates the imbalance of neurogenesis in an estrogen-dependent manner. Under the influence of estrogen, co-existence of macrophages and nerves induces an innovative neuro-immune communication. Persistent stimulation by inflammatory cytokines from macrophages on nociceptors of peripheral nerves aggravates neuroinflammation through the release of inflammatory neurotransmitters. This neuro-immune interaction regulated by estrogen sensitizes peripheral nerves, leading to neuropathic pain in endometriosis. The aim of this review is to highlight the significance of estrogen in the interaction between macrophages and nerve fibers, and to suggest a potentially valuable therapeutic target for endometriosis-associated pain.

Cadmium pyrithione suppresses tumor growth in vitro and in vivo through inhibition of proteasomal deubiquitinase.

The ubiquitin-proteasome system (UPS) is indispensable to the protein quality control in eukaryotic cells. Due to the remarkable clinical success of using proteasome inhibitors for clinical treatment of multiple myeloma, it is anticipated that targeting the UPS upstream of the proteasome step be an effective strategy for cancer therapy. Deubiquitinases (DUB) are proteases that remove ubiquitin from target proteins and therefore regulate multiple cellular processes including some signaling pathways altered in cancer cells. Thus, targeting DUB is a promising strategy for cancer drug discovery. Previously, we have reported that metal complexes, such as copper and gold complexes, can disrupt the UPS via suppressing the activity of 19S proteasome-associated DUBs and/or of the 20S proteasomes, thereby inducing cancer cell death. In this study, we found that cadmium pyrithione (CdPT) treatment led to remarkable accumulation of ubiquitinated proteins in cultured cancer cells and primary leukemia cells. CdPT potently inhibited the activity of proteasomal DUBs (USP14 and UCHL5), but slightly inhibited 20S proteasome activity. The anti-cancer activity of CdPT was associated with triggering apoptosis via caspase activation. Moreover, treatment with CdPT inhibited proteasome function and repressed tumor growth in animal xenograft models. Our results show that cadmium-containing complex CdPT may function as a novel proteasomal DUB inhibitor and suggest appealing prospects for cancer treatment.

Treatment of inflammatory bowel disease via green tea polyphenols: possible application and protective approaches.

Inflammatory bowel disease (IBD) is a collection of inflammatory conditions of colon and small intestine which affect millions of individuals worldwide and the prevalence amount is on the rise. The organ failure as well as loss of tissue function is because of the inflammatory reaction which is the major contributor of tissue healing leading to lifelong debilitation. To stop the tough consequences of inflammation every patient pursues alternative therapy to relieve symptoms. Green tea polyphenols (GTPs) play significant roles in down regulating signaling pathways because GTPs exert effective antioxidant properties and regulate Toll-like receptor 4 (TLR4) expression via certain receptor, inhibited endotoxin-mediated tumor necrosis factor alpha (TNF-α) production by blocking transcription nuclear factor-kappa B (NF-kB) activation and upstream of mediated I kappa B kinase complex pathway activities, as well as intrusion with the flow of cytokines and synthesis of cyclooxygenase-2 (COX-2). This article highlights the green approach regarding the defensive effects of GTP review-related studies concerning the contrary effects and the key therapeutic targets application of GTPs in biomedical field to treat inflammatory bowel disease (IBD) and its complications. .

Macrophage and nerve interaction in endometriosis.

Dysregulation of the immune system in endometriotic milieus has been considered to play a pivotal role in the pathogenesis of endometriosis. Macrophage recruitment and nerve fiber infiltration are the two major characteristics of this aberrant immune environment. First, the recruitment of macrophages and their polarization phenotype within the endometriotic lesion have been demonstrated to facilitate the development and maintenance of endometriosis. M1 phenotype of macrophages has the capacity to secrete multiple cytokines for inflammatory response, while M2 macrophage possesses an opposite property that can mediate the process of immunosuppression and neuroangiogenesis. Upon secretion of multiple abnormal signal molecules by the endometriotic lesion, macrophages could alter their location and phenotype. These changes facilitate the accommodation of the aberrant microenvironment and the exacerbation of disease progression. Second, the infiltration of nerve fibers and their abnormal distribution are proved to be involved in the generation of endometriosis-associated pain and inflammatory response. An imbalance in sensory and sympathetic innervation and the abnormal secretion of different cytokines could mediate neurogenesis and subsequent peripheral neuroinflammation in endometriosis. Although endometriosis creates an inflammatory milieu promoting macrophage infiltration and an imbalanced innervation, interaction between macrophages and nerve fibers in this process remains unknown. The aim of this review is to highlight the role of macrophage and nerve interaction in endometriosis, where macrophage recruitment and neurogenesis can be the underlying mechanism of neuroinflammation and pathogenesis of endometriosis.

High levels of acetoacetate and glucose increase expression of cytokines in bovine hepatocytes, through activation of the NF-κB signalling pathway.

Elevated levels of blood interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) increase insulin resistance and result in inflammation. It is not clear whether elevated blood level of acetoacetate (ACAC) and decreased blood level of glucose, which are the predominant characteristics of clinical biochemistry in ketotic dairy cows, increase proinflammatory cytokines and subsequent inflammation. The objective of this study was to test the hypothesis that ACAC and glucose activate the NF-κB signalling pathway to regulate cytokines expression in bovine hepatocytes. Bovine hepatocytes were cultured with ACAC (0-4.8 mm) and glucose (0-5.55 mm) with or without NF-κB inhibitor PDTC for 24 h. The secretion and mRNA levels of cytokines were determined by enzyme-linked immunosorbent assay (ELISA) and real-time fluorescence quantitative polymerase chain reaction (qRT-PCR). The NF-κB signalling pathway activation was evaluated by western blotting. Results showed that the secretion and expression of IL-1ß, IL-6 and TNF-α increased in an ACAC dose-dependent manner. Additionally, there was an increase in the secretion and mRNA expression of these three cytokines in glucose treatment group, which increased significantly when the glucose concentrations exceed 3.33 mm. Furthermore, both ACAC and glucose upregulated NF-κB p65 protein expression and IκBα phosphorylation levels. However, these effects were reduced by PDTC. These results demonstrate that elevated levels of ACAC and glucose increase the synthesis and expression of proinflammatory factors by activating NF-κB signalling pathway in hepatocytes, which may contribute to inflammation injury in ketotic dairy cows.