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CTNNB1, encoding β-catenin protein, is the most frequently altered proto-oncogene in hepatic neoplasms. In this study, we studied the significance and pathological mechanism of CTNNB1 gain-of-function mutations in hepatocarcinogenesis. Activated β-catenin not only triggered hepatic tumorigenesis but also exacerbated Tp53 deletion or hepatitis B virus infection-mediated liver cancer development in mouse models. Using untargeted metabolomic profiling, we identified boosted de novo pyrimidine synthesis as the major metabolic aberration in β-catenin mutant cell lines and livers. Oncogenic β-catenin transcriptionally stimulated AKT2, which then phosphorylated the rate-limiting de novo pyrimidine synthesis enzyme CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase) on S1406 and S1859 to potentiate nucleotide synthesis. Moreover, inhibition of β-catenin/AKT2-stimulated pyrimidine synthesis axis preferentially repressed β-catenin mutant cell proliferation and tumor formation. Therefore, β-catenin active mutations are oncogenic in various preclinical liver cancer models. Stimulation of β-catenin/AKT2/CAD signaling cascade on pyrimidine synthesis is an essential and druggable vulnerability for β-catenin mutant liver cancer.

Lead (Pb) exposure can cause central nervous system (CNS) damage. The process of Pb neurotoxicity is accompanied by the microglia activation. In addition, microglia activation was observed under the intervention of high‐fat diets (HFD). This study was designed to investigate the effect of Pb on the cognitive function of mice with HFD, with focus on the microglia activation in brain. Male C57BL/6J mice, 8 weeks of age, were randomly divided into control, HFD, Pb, and HFD + Pb groups. The results showed that HFD following Pb exposure could exacerbate the learning and memory impairment in mice. Pb exposure could promote microglia activation and increase the expression of M1 microglia marker and decrease the expression of M2 microglia marker in the hippocampus of mice with HFD. Our finding suggested that Pb exposure may aggravate CNS damage by promoting M1 polarization and inhibiting M2 polarization of hippocampal microglia in HFD mice. [ABSTRACT FROM AUTHOR]

Cardiac fibroblast (CF) proliferation and activation play important roles in cardiac fibrosis and diastolic dysfunction (DD), which are involved in fibrosis-associated cardiovascular diseases. A previous study showed that ivabradine, a specific heart rate (HR)-lowering agent, significantly ameliorated DD in diabetic db/db mice by reducing HR. Herein, we attempted to determine whether ivabradine has antifibrotic and cardioprotective effects in diabetic mice by directly suppressing CF proliferation and activation, independent of a reduction in HR. We found that knockdown of c-Jun N-terminal kinase (JNK) or p38 mitogen-activated protein kinase (MAPK), or treatment with ivabradine, reduced JNK and p38 MAPK phosphorylation and the protein expression of proliferating cell nuclear antigen, collagen I, collagen III, tissue inhibitor of matrix metalloproteinase 2, and α-smooth muscle actin, accompanied with upregulation of matrix metalloproteinase 2 both in high glucose-treated neonatal rat CFs and left ventricular CFs isolated from db/db mice. However, zatebradine (a HR-lowering agent) did not have these effects in vitro or in vivo. In addition, cardiac fibrosis and DD were ameliorated in db/db mice that were intravenously administered lentiviruses carrying short hairpin RNAs targeting JNK and p38 MAPK or administered ivabradine. Taken together, these findings demonstrate that the ivabradine-induced amelioration of cardiac fibrosis, and DD in db/db mice may be at least in part attributable to the suppression of CF proliferation and activation, through the inhibition of JNK and p38 MAPK. [ABSTRACT FROM AUTHOR]

Ulcerative Colitis (UC) is a chronic inflammation disease, and the incidence of UC is increasing recently. Both clinical trials and animal experiments show that moxibustion is a complementary and alternative treatment for UC. Previous studies showed that moxibustion can improve UC by regulating the balance of Tregs and Th17 (Sun et al., 2017). Treg cells is one subset of CD4 + T cells that exert the immunosuppressive function. CD39 and CD73, expressed on the surface of Tregs, hydrolyze ATP to AMP and are further involved in the immunosuppressive function of Tregs. In this study, we investigated the effect of moxibustion on CD39 + Tregs and CD73 + Tregs in dextran sulfate sodium (DSS) induced UC mice. The A2a receptor (A2aR), one of the targets of adenosine, was also detected. The results showed that moxibustion could increase the expression of CD39, CD73, and A2aR in colonic tissue and improve the proportion of CD39 + Tregs and CD73 + Tregs in peripheral blood, inguinal draining lymph nodes and spleen in the UC model. Additionally, A2aR agonists enhanced the cell viability of colonic epithelial cells and inhibit the production of cytokines IL-6 and TNF- α in vitro, which may further influence the pathway of ATP purine signal metabolism and alleviates the gut inflammation of UC mice. Taken together, this study provides supplemental evidence to reveal the immune related mechanism of moxibustion in the treatment of UC. [ABSTRACT FROM AUTHOR]

Objectives. To study how thermal energy is converted after moxibustion at local skin from the view of mitochondrial respiratory chain and its key regulatory elements of sirtuins 1 (SIRT1) and sirtuins 3 (SIRT3). Methods. Two moxibustion temperatures usually used in clinical practice (38°C and 46°C) were applied to Zusanli (ST36) acupoint for 30 minutes in C57BL/6J mice. Local skin samples were harvested at 30 min and 72 h after moxibustion intervention, respectively. The activity of mitochondrial respiratory chain complexes I–V was detected by spectrophotometry. The expression of SIRT1 and SIRT3 protein was detected by immunofluorescence staining or western blot. Results. Moxibustion at 38°C triggered more significant increase of mitochondrial respiratory chain complexes I–V expression. However, the protein expression of SIRT1 and SIRT3 at 46°C showed more obvious enhancement. In addition, the effect of mitochondrial respiratory chain complexes I–V activity on local skin of ST36 acupoint was more obvious at 30 min after moxibustion, while the expression of SIRT1 and SIRT3 protein was more significant at 72 h after moxibustion. Conclusion. Mitochondrial respiratory chain and its key regulatory element proteins SIRT1 and SIRT3 play important role in the initial process of thermal energy conversion stimulated by different moxibustion temperatures in local skin. [ABSTRACT FROM AUTHOR]

Purpose/Aim: Pulmonary fibrosis (PF) is characterized by the progressive and ultimately fatal accumulation of fibroblasts and extracellular matrix in the lung that distorts its architecture and compromises its function. Objective: The present study investigated the potential protective effects of schisandrin B (Sch B) on the Wingless/Integrase-1 (Wnt) signaling pathway in attenuating inflammation and oxidative stress in ICR mice. Methods: Sixty healthy ICR mice were randomly divided into the following groups: control group, bleomycin (BLM) group, Sch B low dose (Sch B-L) group, Sch B medium dose (Sch B-M) group, Sch B high dose (Sch B-H) group, and dexamethasone (DXM) group. The expression of transforming growth factor (TGF)-β1 was examined by ELISA. In addition, the levels of superoxide dismutase (SOD), hydroxyproline (HYP), and the total antioxidant capacity (T-AOC) were determined. The protein and mRNA levels of matrix metalloproteinase 7 (MMP7) and β-catenin in mice were analyzed by western blot and quantitative real -quantitative time PCR (qRT-PCR), respectively. Results: Lung tissues from the BLM group exhibited significantly more inflammatory changes and a significantly greater number of collagen fibers than lung tissues from the control group. In addition, the lung tissues from these BLM-treated mice exhibited slightly increased MMP7 and β-catenin protein expression. Lung tissues from the Sch B-H group exhibited fewer inflammatory changes and fewer collagen fibers than lung tissues from the BLM group. Furthermore, the lung tissues from the Sch B-H mice exhibited decreased HYP and TGF-β1 levels, but increased SOD and T-AOC levels. Conclusions: The present study provided evidence that Sch B may be a potential therapeutic agent for the treatment of PF. [ABSTRACT FROM AUTHOR]

Previous studies have confirmed that acupuncture and moxibustion is an effective way for treating ulcerative colitis (UC). However, the exact mechanism is unclear yet. In this study, DSS-induced UC mice were treated by electroacupuncture and moxibustion, and the genome of intestinal flora was subsequently detected by high-throughput sequencing in order to explore the detailed mechanism in terms of intestinal flora. The results indicated that the alpha diversity indices and beta diversity of intestinal flora were improved by electroacupuncture and moxibustion treatments, especially by the moxibustion treatment. These treatments inhibited Streptococcus, Odoribacter, and Allobaculum whereas it facilitated Lactobacillus on genus level. Further correlation analysis showed that the alpha diversity indices were positively correlated with the percentage of Treg cells in CD4+ cells but negatively correlated with the percentage of Th17 in CD4+ cells. These data indicated that both electroacupuncture and moxibustion can promote the intestinal flora diversity, providing a new view to understand the relationship between host and microbiome when using some external therapies. [ABSTRACT FROM AUTHOR]

Highlights • Treadmill exercise efficiently enhances learning and memory in APP/PS1 mice. • Treadmill exercise improves mitochondrial ultrastructure and functions in the hippocampus of APP/PS1 mice. • Treadmill exercise increased mitochondrial fusion and inhibited mitochondrial fission in the hippocampus of APP/PS1 mice. Abstract Mitochondrial dysfunction is widely recognized as an early event in the pathogenesis of Alzheimer's disease (AD). Defects in mitochondrial fusion and fission have been proposed to lead to learning and memory impairments in AD. The current study aimed to investigate whether exercise-improved learning and memory were associated with improves in mitochondrial function by increased mitochondrial fusion and decreased mitochondrial fission. APP/PS1 transgenic mice were divided into transgenic sedentary (ADC, n = 15) and transgenic exercise (ADE, n = 15) groups. Wild-type mice were also separated into sedentary (WTC, n = 15) and exercise (WTE, n = 15) groups. The WTE and ADE mice were subjected to treadmill exercise for 12 weeks. In this study, learning and memory were significantly decreased in ADC mice compared with those in WTC mice, whereas exercise improved learning and memory in APP/PS1 transgenic mice. Meanwhile, ADC mice displayed defective mitochondrial function as evidenced by a significant increase in swollen mitochondria and vacuoles, loss of mitochondrial cristae, and decreased ATP levels, as well as an imbalance in mitochondrial fusion and fission as evidenced by significantly increased Drp1 and Mff and decreased Mfn1, Mfn2, and Opa1 in the hippocampus. Interestingly, exercise mitigated mitochondrial dysfunction as evidenced by a significant reduction in swollen mitochondria and vacuoles and increased mitochondrial cristae and ATP levels in ADE mice. Coincidentally, exercise promoted the balance of mitochondrial fusion and fission as evidenced by a significantly decreased Drp1 and Mff and increased Mfn1, Mfn2, and Opa1 in the hippocampus. These findings suggest that treadmill exercise efficiently enhances learning and memory in AD by improving mitochondrial dysfunction in APP/PS1 transgenic mice. [ABSTRACT FROM AUTHOR]

Aim. To investigate the relationship between the effects of electroacupuncture/moxibustion and the balance of Th17/Treg in treating ulcerative colitis (UC) and to preliminary compare the effects of the above two methods. Methods. DSS-induced UC mice were treated by electroacupuncture and moxibustion. Disease activity index (DAI) was scored; intestinal pathological structure and ultrastructure were observed. The levels of IL-2, IL-6, IL-10, IL-17A, IL-17F, and TGF-β in plasma were measured by ELISA. The percentages of Treg and Th17 in spleen lymphocytes were analyzed by flow cytometry. Also, the expressions of TLR2, TLR4, RORγt, and FOXP3 in the distal colon were detected by immunohistochemistry or western blot. Results. Both electroacupuncture and moxibustion can relieve UC. These effects are further supported by ELISA results. In addition, the ratio of Treg and Th17 in spleen lymphocytes and the expression of TLR2 and TLR4 are significantly improved. Also, the expression of RORγt and FOXP3 in distal colon were improved. Besides, the effect of moxibustion is better than that of electroacupuncture on TLR2, TLR4, and FOXP3 expression (P<0.05). Conclusion. Both electroacupuncture and moxibustion may ameliorate UC by regulating the balance of Th17/Treg. Whether moxibustion has better efficacy than electroacupuncture needs further study. [ABSTRACT FROM AUTHOR]

Abstract: The IPSE/alpha-1 gene (IL-4-inducing principle of Schistosoma mansoni eggs) is a major secreted glycoprotein of S. mansoni eggs that has a potent IL-4-inducing effect. To test the hypothesis that the immune evasion mechanism can be used to overcome the xenograft immune response, the IPSE/alpha-1 gene was transferred into pig fibroblasts, and the transgenic cells were transplanted into KM mice by subcutaneously injecting 105cells per mouse. Cytokine levels were measured to examine the immune response polarization by real-time PCR and ELISA. Mice injected with pig fibroblasts containing a pIRES2-EGFP expression vector were used as a control group. In this group, both cellular and humoral immune responses were activated to reject the grafts alongside increases in all measured cytokine levels. In contrast, the experimental group injected with cells constitutively expressing the IPSE/alpha-1 gene demonstrated a significant decrease in Th1 response cytokines and a significant increase in Th2 response cytokines compared with the control group. These results imply that constitutive IPSE/alpha-1 expression can shift the Th1/Th2 balance of xenograft rejections toward the Th2 response while suppressing the Th1 response. In conclusion, IPSE/alpha-1 could influence the polarization of immune responses during xenograft rejection and suppress the Th1 response. Therefore, this parasitic immune evasion mechanism could be helpful in overcoming xenograft rejection. [Copyright &y& Elsevier]

Artemisia ordosica Krasch. (AOK) has been used for rheumatic arthritis, cold headache, sore throat, etc. in traditional Chinese/Mongolian medicine and is used for nasosinusitis by local Mongolian "barefoot" doctors. Up to now, their mechanisms are still unclear. To evaluate the in vivo anti-inflammatory and allergic rhinitis (AR) alleviating effect as well as in vitro antimicrobial activities of AOK extracts to verify its ethno-medicinal claims. Crude extracts (methanol/95%-ethanol/ethyl acetate) of AOK root/stem/leaf and fractions (petroleum ether/ethyl acetate/n-butanol/aqueous) of AOK root extract were prepared. Xylene-induced ear swelling model in mouse and ovalbumin (OVA)-induced AR model in guinea pig were established. Ear swelling degrees of mice were measured. The numbers of rubbing movement and sneezes of guinea pigs were counted to evaluate the symptoms of AR. The serum levels of histamine, INF-γ, IL-2/4/10, and VCAM-1 were measured by ELISA assay. The histological changes of nasal mucosa were investigated by light microscope after H&E staining. Antimicrobial activities of AOK extracts were also tested. LC-MS/MS analysis was performed to characterize the constituents of active extract and molecular docking was conducted to predict the biological mechanism. In ear-swelling model, extract (100.00 mg/kg) from the ethyl acetate layer of 95% ethanol (100.00 mg/kg) showed better swelling inhibition in mice than positive control (dexamethasone, 191.91 mg/kg). In AR model, extract from the ethyl acetate layer of 95% ethanol significantly alleviated the AR symptoms in guinea pigs, decreased the serum levels of histamine, INF-γ, IL-2/4/10, and VCAM-1, and reduced the infiltration of eosinophil in nasal mucosa. For Staphylococcus aureus , the ethyl acetate extract of AOK stem showed the highest inhibition (MIC=1.25 mg/mL), for Escherichia coli , n-butanol layer of 95% ethanol extract of AOK root showed the highest inhibition (MIC=15.00 mg/mL), for Candida glabrata , 95%-ethyl acetate extract of AOK leaf showed the best inhibition (MIC=0.064 mg/mL), while ethyl acetate and n-butanol layers showed similar inhibition on MRSA (MIC=7.50 mg/mL). LC-MS/MS characterization showed that dicaffeoylquinic acids account for more than 30% of ethyl acetate layer of AOK extract. Dicaffeoylquinic acids bind with histamine-1 receptor with high affinities and interesting modes. Extracts from AOK had interesting anti-inflammatory activity in mice, alleviating effect against OVA-induced AR in guinea pigs, and antimicrobial activities in vitro , which support the ethno-medicinal use of it. The main constituents in ethyl acetate layer of AOK root extract are dicaffeoylquinic acids and could bind with histamine-1 receptor well. These findings highlighted the importance of natural product chemistry study of AOK. Image 1 [ABSTRACT FROM AUTHOR]

• Methamphetamine (METH) induced conditioned place preference (CPP) in mice. • L-THP attenuated METH-induced CPP in mice. • METH induced upregulation of ERK phosphorylation in nucleus accumbens (NAc) and prefrontal cortex (PFc) of mice. • L-THP decreased the high expression of ERK phosphorylation induced by METH in NAc and PFc of mice. Levo-tetrahydropalmatine (L-THP) is the main active ingredient of traditional Chinese herbal medicine Corydalis and Stephania , which have been used for sedative, neuroleptic, and analgesic purposes. Previous studies have demonstrated that L-THP has antagonistic activation on dopamine receptors. Despite its effectiveness on treating drug addiction, L-THP's underlying molecular mechanisms in modulating methamphetamine (METH) reward behavior remain unclear. In order to clarify the mechanisms behind, we designed an experiment of conditioned place preference (CPP) to investigate the effects of L-THP on METH-induced CPP in mice. We then dissected the underlying molecular mechanisms of L-THP in modulating METH-induced CPP by evaluating accompanying changes in expression of phosphorylated extracellular signal-regulated kinase (p-ERK) in reward-relevant brain regions, including nucleus accumbens (NAc), prefrontal cortex (PFc), caudate putamen (CPu), and hippocampus (Hip), which may mediate the effects of L-THP on METH-induced CPP. The results showed that 1.0 mg/kg METH could induce obvious CPP in mice; 10.0 mg/kg L-THP could significantly attenuate METH-induced CPP in mice, though it could not induce CPP or conditioned place aversion by itself. Moreover, the levels of p-ERK in NAc and PFc of the METH group were significantly higher than that of the saline group. Although there was no evident difference between the levels of p-ERK of the L-THP group with that of the saline group, the levels of p-ERK in NAc and PFc of the M + T group were significantly lower than that of the METH group. There was no striking difference among the levels of p-ERK in CPu and Hip of all experimental groups. Our research suggested that NAc and PFc function as circuits contributing to METH addiction, and the activation of the ERK phosphorylation plays an important role in the mechanisms of METH addiction. Besides, L-THP significantly decreased ERK phosphorylation's high expression induced by METH, which suggested that the inhibitory effect of L-THP on modulating METH reward behavior may be related to the suppression of ERK phosphorylation in NAc and PFc of mice. In conclusion, L-THP could suppress the reward properties of METH, therefore, it may be a promising candidate for the treatment of METH addiction. [ABSTRACT FROM AUTHOR]