Recent advances in the involvement of epigenetics in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a typical systemic autoimmune disease that manifests as skin rash, arthritis, lymphadenopathy, and multiple organ lesions. Epigenetics, including DNA methylation, histone modification, and non-coding RNA regulation, mainly affect the function and characteristics of cells through the regulation of gene transcription or translation. Increasing evidence indicates that there are a variety of complex epigenetic effects in patients with SLE, which interfere with the differentiation and function of T, and B lymphocytes, monocytes, and neutrophils, and enhance the expression of SLE-associated pathogenic genes. This paper summarizes our currently knowledge regarding pathogenesis of SLE, and introduces current advances in the epigenetic regulation of SLE from three aspects: immune function, inflammatory response, and lupus complications. We propose that epigenetic changes could be used as potential biomarkers and therapeutic targets of SLE.

The active fraction of Garcinia yunnanensis suppresses the progression of colorectal carcinoma by interfering with tumorassociated macrophage-associated M2 macrophage polarization in vivo and in vitro.

Colorectal cancer (CRC) is the third most common solid tumor worldwide and has shown resistance to several immunotherapies, particularly immune checkpoint blockade therapy, which is effective in many other types of cancer. Our previous studies indicated that the active fraction of Garcinia yunnanensis (YTE-17), had potent anticancer activities by regulating multiple signaling pathways. However, knowledge regarding the mechanism and effect of YTE-17 in the prevention of CRC is limited. This study tested the effects of YTE-17 on colon cancer development in vivo by using two murine models: the carcigenic azoxymethane/dextran sulfate sodium (AOM/DSS)-induced CRC model and a genetically induced model using ApcMin/+ mice. Here, the tumor load, tumor number, histology, and even some oncogenes were used to evaluate the effect of YTE-17. The intragastric administration of YTE-17 for 12 weeks significantly decreased CRC incidence, tumor number and size, immunity, and some tumor-associated macrophage (TAM) markers, including CD206, Arg-1, IL-10, and TGF-ß. Importantly, the macrophages depletion by clodronate (CEL) also played a role in reducing the tumor burden and inhibiting tumor development, which were not affected by YTE-17 in the ApcMin/+ mice. Moreover, the YTE-17 treatment attenuated CRC cell growth in a co-culture system in the presence of macrophages. Consistently, YTE-17 effectively reduced the tumor burden and macrophage infiltration and enhanced immunity in the AOM/DSS and ApcMin/+ colon tumor models. Altogether, we demonstrate that macrophages in the microenvironment may contribute to the development and progression of CRC cells and propose YTE-17 as a new potential drug option for the treatment of CRC.

YYFZBJS ameliorates colorectal cancer progression in ApcMin/+ mice by remodeling gut microbiota and inhibiting regulatory T-cell generation.

BACKGROUND: Progression of Colorectal cancer (CRC) is influenced by single or compounded environmental factors. Accumulating evidence shows that microbiota can influence the outcome of cancer immunotherapy. T cell, one of the main populations of effector immune cells in antitumor immunity, has been considered as a double-edged sword during the progression of CRC. Our previous studies indicate that traditional Chinese herbs (TCM) have potential anticancer effects in improving quality of life and therapeutic effect. However, little is known about the mechanism of TCM formula in cancer prevention. METHODS: Here, we used C57BL/6 J ApcMin/+ mice, an animal model of human intestinal tumorigenesis, to investigate the gut bacterial diversity and their mechanisms of action in gastrointestinal adenomas, and to evaluate the effects of Yi-Yi-Fu-Zi-Bai-Jiang-San (YYFZBJS) on of colon carcinogenesis in vivo and in vitro. Through human-into-mice fecal microbiota transplantation (FMT) experiments from YYFZBJS volunteers or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. RESULTS: We report herein, YYFZBJS treatment blocked tumor initiation and progression in ApcMin/+ mice with less change of body weight and increased immune function. Moreover, diversity analysis of fecal samples demonstrated that YYFZBJS regulated animal's natural gut flora, including Bacteroides fragilis, Lachnospiraceae and so on. Intestinal tumors from conventional and germ-free mice fed with stool from YYFZBJS volunteers had been decreased. Some inflammation' expression also have been regulated by the gut microbiota mediated immune cells. Intestinal lymphatic, and mesenteric lymph nodes (MLN), accumulated CD4+ CD25+ Foxp3 positive Treg cells were reduced by YYFZBJS treatment in ApcMin/+ mice. Although YYFZBJS had no inhibition on CRC cell proliferation by itself, the altered Tregs mediated by YYFZBJS repressed CRC cancer cell growth, along with reduction of the phosphorylation of ß-catenin. CONCLUSIONS: In conclusion, we demonstrated that gut microbiota and Treg were involved in CRC development and progression, and we propose YYFZBJS as a new potential drug option for the treatment of CRC. Video abstract.

Prediction of the use of mobile device interfaces in the progressive aging process with the model of Fitts' law.

PURPOSE: As the population ages, so do the potential users of technology, and older adults' behaviors when using mobile device interfaces are becoming increasingly important. A representative model for detecting older adults' behaviors and performance on the use of mobile device interfaces is needed to provide individualized designs. This research aimed to investigate the applicability of the broadly used model of Fitts' law to detect the progressive changes in the use of mobile device interfaces in older adults. The effect of experience with using technology on performance on a Fitts task was also examined. METHOD: A sample of 135 older adults was recruited to test the application of Fitts' model to the use of technology by older adult users. Each participant was asked to finish tasks at 9 levels of difficulty, from easy to difficult, in a multidirectional tapping task. Analysis of variance was employed to examine the effect of age on performance on the Fitts task, movement time, and the standard deviation of movement time. Stepwise regression was used to investigate how well age and technology use could predict performance on the Fitts task. RESULT: Performance on the Fitts task was sensitive to the gradual changes in abilities with aging. Rather than the amount of experience in using technology, age was the stronger predictor of older adults' performance on the Fitts task. Additionally, compared with the younger groups, the users above 80 years old demonstrated significantly higher behavioral variation during the use of mobile device interfaces. CONCLUSION: This research confirmed that Fitts' law is applicable to the evaluation of the effects of aging on the use of mobile device interfaces. Adults above the age of 80 years should be a major focus for special individualized interface design. This finding can inform future designers and researchers in the development of individualized interface designs for older adult users to enhance their user experiences of mobile device technology. RELEVANCE TO INDUSTRY: Future designers and researchers can apply the finding on Fitts' law in this research to develop user-friendly interface designs for mobile technology for older adults and thereby improve their user experiences to enhance their independence and quality of life through the use of technology.

Dihydromyricetin reverses MRP2-mediated MDR and enhances anticancer activity induced by oxaliplatin in colorectal cancer cells.

Dihydromyricetin (DMY), extracted from the Chinese herbal medicine Ampelopsis grossedentata, possesses antitumor potential in different types of human cancer cells. Hence, its effects on drug resistance and molecular mechanisms in colorectal cancer (CRC) are still unknown. In our present study, we observed that DMY enhanced the chemosensitivity to oxaliplatin (OXA). DMY increased OXA-induced apoptosis and reduced 5(6)-carboxy-2',7'-dichlorofluorescein accumulation in OXA-resistant CRC HCT116/L-OHP cells. Our mechanistic study suggested that DMY treatment inhibited multidrug resistance protein 2 (MRP2) expression levels and promoter activity, indicating that DMY reduced not only MRP2 transcriptional and translational levels but also its function. Additional experiments indicated that the nuclear translocation of nuclear factor-erythroid 2 p45 related factor 2, a MRP2 regulator, was also inhibited by DMY. In summary, our study provided the first direct evidence that the inhibitory effects of DMY on MRP2 expression in OXA-resistant CRC cells were closely associated with the inhibition of nuclear factor-erythroid 2 p45 related factor 2 signaling. DMY could be a potential candidate for CRC chemotherapy.

Evodiamine Suppresses ABCG2 Mediated Drug Resistance by Inhibiting p50/p65 NF-κB Pathway in Colorectal Cancer.

Evodiamine (Evo), extracted from the Chinese herbal medicine Evodia rutaecarpa, has cytotoxic effects on different types of human cancer cells. However, its effects on drug resistance and their molecular mechanism and therapeutic target in colorectal cancer are not well understood. In the present study, we observed that Evo inhibited cell growth and induced apoptosis in adose-and time-dependent manner in HCT-116/L-OHP cells. Moreover, Evo treatment reduced Rhodamine 123 accumulation and ATPase activity in HCT-116/L-OHP cells, indicating that Evo decreased the efflux function in HCT-116/L-OHP cells. Interestingly, phosphorylation of NF-κB pathway, particularly p50/p65, was also inhibited by Evo treatment. Furthermore the effect of Evo in reversing drug resistance and suppressing phosphorylation of NF-κB pathway were attenuated after treatment with the NF-κB activator (LPS). Additionally, Evo inhibited the tumor growth in a colorectal MDR cancer xenograft model and down regulated p-NF-κB level in vivo. Our study provided the first direct evidence that Evo can attenuate multidrug resistance by blocking p-NF-κB signaling pathway in human colorectal cancer. Evo could be a potential candidate for cancer chemotherapy.

ZiBu PiYin recipe prevents diabetes-associated cognitive decline in rats: possible involvement of ameliorating mitochondrial dysfunction, insulin resistance pathway and histopathological changes.

BACKGROUND: Disturbance in energy metabolism, as a key factor in diabetes-associated cognitive decline (DACD), has become a promising therapeutic target of Chinese medicine ZiBu PiYin Recipe (ZBPYR). However, it is still not clear how ZBPYR affects the mitochondrial function in DACD rats' brains, which is considered as the crucial cell organelle to supply energy for the brain. METHODS: Type 2 diabetes mellitus (T2DM) rat models were established by using high fat diet and streptozotocin (STZ) (30 mg/kg, ip). The evaluation of insulin sensitivity was performed by oral glucose tolerance and insulin tolerance test. After 7 weeks, the T2DM rats were treated with vehicle or ZBPYR for 11 weeks and morris water maze (MWM) test were used to evaluate memory function. The ultra structural changes of prefrontal cortex (PFC) and hippocampus were examined by transmission electron microscopy (TEM). The mitochondrial membrane potential (ΔΨm) and reactive oxygen species (ROS) were measured with JC-1 and DCFDA assay. The levels of insulin proteins were quantified by Western Blot analysis and the markers of histopathological changes were detected by immunohistochemistry. RESULTS: ZBPYR could alleviate learning and memory impairment of DACD rats. TEM showed that ZBPYR prevented mitochondrial ultra-structural alterations and number changes in the PFC and hippocampus of the DACD rats. In addition, ZBPYR significantly increased ΔΨm and lowered the levels of ROS. Further investigation indicated that ZBPYR suppressed the release of cytochrome c from mitochondria, strengthened insulin signaling and inhibited GSK3ß over-expression. These positive effects were associated with reduced Aß1-42 deposition and restored expression levels of microtubule-associated protein MAP2. CONCLUSION: ZBPYR showed excellent protective effect against DACD via ameliorating mitochondrial dysfunction, insulin resistance and histopathological changes.

Resveratrol suppresses epithelial-to-mesenchymal transition in colorectal cancer through TGF-ß1/Smads signaling pathway mediated Snail/E-cadherin expression.

BACKGROUND: Resveratrol extracted from grape has been an ideal alternative drug in the therapy of different cancers including colorectal cancer (CRC). Since the underlying mechanisms of resveratrol on the invasion and metastasis of CRC have not been fully elucidated, and epithelial-to-mesenchymal transition (EMT) is a key process associated with the progression of CRC, here we aimed to investigate the potential mechanism of resveratrol on the inhibition of TGF-ß1-induced EMT in CRC LoVo cells. METHODS: We investigated the anticancer effect of resveratrol against LoVo cells in vitro and in vivo. In vivo, the impact of resveratrol on invasion and metastasis was investigated by mice tail vein injection model and mice orthotopic transplantation tumor model. In vivo imaging was applied to observe the lungs metastases, and hemaoxylin-eosin (HE) staining was used to evaluate metastatic lesions. In vitro, impact of resveratrol on the migration and invasion of LoVo cells was evaluated by transwell assay. Inhibition effect of resveratrol on TGF-ß-induced EMT was examined by morphological observation. Epithelial phenotype marker E-cadherin and mesenchymal phenotype marker Vimentin were detected by western blot and immunofluorescence. Promoter activity of E-cadherin was measured using a dual-luciferase assay kit. mRNA expression of Snail and E-cadherin was measured by RT-PCR. RESULTS: We demonstrated that, resveratrol inhibited the lung metastases of LoVo cells in vivo. In addition, resveratrol reduced the rate of lung metastases and hepatic metastases in mice orthotopic transplantation. In vitro, TGF-ß1-induced EMT promoted the invasion and metastasis of CRC, reduced the E-cadherin expression and elevated the Vimentin expression, and activated the TGF-ß1/Smads signaling pathway. But resveratrol could inhibit the invasive and migratory ability of LoVo cells in a concentration-dependent manner, increase the expression of E-cadherin, repress the expression of Vimentin, as well as the inhibition of TGF-ß1/Smads signaling pathway. Meanwhile, resveratrol reduced the level of EMT-inducing transcription factors Snail and the transcription of E-cadherin during the initiation of TGF-ß1-induced EMT. CONCLUSIONS: Our new findings provided evidence that, resveratrol could inhibit EMT in CRC through TGF-ß1/Smads signaling pathway mediated Snail/E-cadherin expression, and this might the potential mechanism of resveratrol on the inhibition of invasion and metastases in CRC.

Verbascoside promotes apoptosis by regulating HIPK2-p53 signaling in human colorectal cancer.

BACKGROUND: We investigated the role of the HIPK2-p53 signaling pathway in tumorigenesis and resistance to the drug Verbascoside (VB) in colorectal cancer (CRC), using in vivo and in vitro experiments. METHODS: Primary human CRC samples and normal intestinal tissues from patients were analyzed for HIPK2 expression by immunohistochemistry (IHC) and its expression was correlated against patients' clinicopathological characteristics. Human CRC HCT-116 cells were implanted in BALB/c nude mice; mice with xenografted tumors were randomly administrated vehicle (control), 20, 40, or 80 mg/mL VB, or 1 mg/mL fluorouracil (5-FU). HIPK2, p53, Bax, and Bcl-2 expression in these tumors were determined by IHC. In vitro effects of VB on CRC cell proliferation and apoptosis were measured by CCK-8 assay and flow cytometry; HIPK2, p53, p-p53, Bax, and Bcl-2 were measured by western blot. RESULTS: IHC analysis for 100 human CRC tumor samples and 20 normal intestinal tissues, showed HIPK2 expression to inversely correlate with Dukes stage and depth of invasion in CRC (P<0.05). In vivo, the inhibition rates of 20, 40, and 80 mg/mL VB on CRC xenograft tumor weight were 42.79%, 53.90%, and 60.99%, respectively, and were accompanied by increased expression of HIPK2, p53, and Bax, and decreased Bcl-2 expression in treated tumors. In vitro, VB significantly inhibited proliferation of CRC cell lines HCT-116, HT-29, LoVo, and SW620, in a time- and dose-dependent manner. The apoptosis rates of 25, 50, and 100 µM VB on HCT-116 cells were 10.83±1.28, 11.25±1.54, and 20.19±2.87%, and on HT-29 cells were 18.92±6.12, 21.57±4.05, and 25.14±6.73%, respectively. In summary, VB treatment significantly enhanced the protein expression of pro-apoptotic HIPK2, p53, p-p53, Bax, and decreased anti-apoptotic Bcl-2 expression in CRC cells. CONCLUSIONS: HIPK2 protein modulates the phosphorylation status of p53, and levels of Bax and Bcl-2 in CRC. We also found that VB effectively activated the HIPK2-p53 signaling pathway, resulting in increased CRC cell apoptosis.

Zuo Jin Wan reverses P-gp-mediated drug-resistance by inhibiting activation of the PI3K/Akt/NF-κB pathway.

BACKGROUND: Zuo-Jin-Wan (ZJW), a traditional Chinese medicine formula, has been identified to be effective against drug resistance in cancer. In the present study, we investigated the effect of ZJW on acquired oxaliplatin-resistant and the PI3K/Akt/NF-κB pathway in vitro. METHODS: We tested the dose-response relationship of ZJW on reversing drug-resistance by CCK-8 assay and flow cytometry analysis in vitro. The protein expression of P-gp, MRP-2, LRP, and ABCB1 mRNA expression level were evaluated by Western blot and quantitative RT-PCR. The activities of PI3K/Akt/NF-κB pathway were also examined with or without ZJW, including Akt, IκB, p65 and their phosphorylation expression. RESULTS: We found that ZJW significantly enhanced the sensitivity of chemotherapeutic drugs and increased oxaliplatin (L-OHP)-induced cell apoptosis in a time- and dose-dependent manner. Moreover, both ZJW and a PI3K specific inhibitor (LY294002) suppressed phosphorylation of Akt (Ser473) and NF-κB, which is necessary in the activation of the PI3K/Akt/NF-κB pathway. The effect of ZJW in reversing drug-resistance and suppressing phosphorylation of Akt (Ser473) and NF-κB were weakened after treatment with a PI3K/Akt activator in HCT116/L-OHP cells. CONCLUSIONS: Our study has provided the first direct evidence that ZJW reverses drug-resistance in human colorectal cancer by blocking the PI3K/Akt/NF-κB signaling pathway, and could be considered as a useful drug for cancer therapy.

Potential pharmacological mechanisms of tanshinone IIA in the treatment of human neuroblastoma based on network pharmacological and molecular docking Technology.

Tanshinone IIA (Tan-IIA) is the main bioactive component of Chinese herbal medicine salvia miltiorrhiza (Danshen). Sodium sulfonate of Tan-IIA is widely used in the treatment of cardiovascular and cerebrovascular diseases. Tan-IIA also has inhibitory effects on tumor cells such as gastric cancer, but its therapeutic effect and mechanism on human neuroblastoma have not been evaluated, so its pharmacological mechanism is systematically evaluated by the combined method of network pharmacology and molecular docking. PharmMapper and SwissTargetPrediction predicted 331 potential Tan-IIA-related targets, and 1,152 potential neuroblastoma-related targets were obtained from GeneCards, DisGeNET, DrugBank, OMIM and Therapeutic Target databases (TTD), 107 common targets for Tan-IIA and neuroblastoma. Through gene ontology (GO) functional annotation, Kyoto Encyclopedia of Genes and Genomesa (KEGG) pathway enrichment, protein-protein interaction (PPI) network and cytoHubba plug-in, 10 related signal pathways (Pathways in cancer, PI3K-Akt signaling pathway, Prostate cancer, etc.) and 10 hub genes were identified. The results of molecular docking showed that Tan-IIA could interact with 10 targets: GRB2, SRC, EGFR, PTPN1, ESR1, IGF1, MAPK1, PIK3R1, AKT1 and IGF1R. This study analyzed the related pathways and targets of Tan-IIA in the treatment of human neuroblastoma, as well as the potential anticancer and anti-tumor targets and related signaling pathways of Tan-IIA, which provides a reference for us to find and explore effective drugs for the treatment of human neuroblastoma.

YTE-17 inhibits colonic carcinogenesis by resetting antitumor immune response via Wnt5a/JNK mediated metabolic signaling.

The density and composition of lymphocytes infiltrating colon tumors serve as predictive factors for the clinical outcome of colon cancer. Our previous studies highlighted the potent anti-cancer properties of the principal compounds found in Garcinia yunnanensis (YTE-17), attributing these effects to the regulation of multiple signaling pathways. However, knowledge regarding the mechanism and effect of YTE-17 in the prevention of colorectal cancer is limited. In this study, we conducted isobaric tags for relative and absolute quantification (iTRAQ) analysis on intestinal epithelial cells (IECs) exposed YTE-17, both in vitro and invivo, revealing a significant inhibition of the Wnt family member 5a (Wnt5a)/c-Jun N-terminal kinase (JNK) signaling pathway. Subsequently, we elucidated the influence and mechanism of YTE-17 on the tumor microenvironment (TME), specifically focusing on macrophage-mediated T helper 17 (Th17) cell induction in a colitis-associated cancer (CAC) model with Wnt5a deletion. Additionally, we performed the single-cell RNA sequencing (scRNA-seq) on the colonic tissue from the Wnt5a-deleted CAC model to characterize the composition, lineage, and functional status of immune mesenchymal cells during different stages of colorectal cancer (CRC) progression. Remarkably, our findings demonstrate a significant reduction in M2 macrophage polarization and Th17 cell phenotype upon treatment with YTE-17, leading to the restoration of regulatory T (Treg)/Th17 cell balance in azoxymethane (AOM)/dextran sodium sulfate (DSS) model. Furthermore, we also confirmed that YTE-17 effectively inhibited the glycolysis of Th17 cells in both direct and indirect co-culture systems with M2 macrophages. Notably, our study shed light on potential mechanisms linking the non-canonical Wnt5a/JNK signaling pathway and well-established canonical ß-catenin oncogenic pathway in vivo. Specifically, we proposed that Wnt5a/JNK signaling activity in IECs promotes the development of cancer stem cells with ß-catenin activity within the TME, involving macrophages and T cells. In summary, our study undergoes the potential of YTE-17 as a preventive strategy against CRC development by addressing the imbalance with the immune microenvironment, thereby mitigating the risk of malignancies.

Latent profiles of academic resilience in undergraduate nursing students and their association with resilience and self-efficacy.

AIM: This study aimed to investigate the heterogeneity of academic resilience among nursing students using latent profile analysis and its associated influencing factors. BACKGROUND: Nursing students experience higher levels of stress compared to their peers in other professions, and the cultivation of academic resilience plays a pivotal role in their ability to effectively cope with this stress. Academic resilience not only facilitates success in the face of academic adversity but also contributes to the promotion of mental well-being among nursing students. However, the current research on the academic resilience of nursing students has predominantly focused on a scale-centered total score approach, disregarding individual variability, and hindering the development to inform personalized interventions for enhancing academic resilience. DESIGN: A cross-sectional study. METHODS: A convenience sampling method was used to collect a total of 644 nursing students from two medical schools in Guangzhou City. The participants were recruited through an online survey conducted from January to March 2023. The questionnaires consisted of a general information form, the Chinese version of the Academic Resilience Scale-30 (C-ARS-30), the 10-item Connor Davidson Resilience Scale (CD-RISC-10), and the General Self-Efficacy Scale (GSES). Latent profile analysis was used to identify distinct categories of academic resilience among nursing students, and influencing factors were examined through ordinal logistic regression analysis. RESULTS: The academic resilience levels of nursing students can be divided into three potential categories: 'low academic resilience' (13.0%), 'moderate academic resilience' (70.0%), and 'high academic resilience' (17.0%). Level of grade, GPA, self-reported physical health level, resilience and self-efficacy were significantly influenced the different categories of academic resilience of nursing students (P<0.05). CONCLUSIONS: The majority of undergraduate nursing students were placed in the moderate academic resilience group, however, educational institutions should pay special attention to nursing students demonstrating low levels. Regular assessments of academic resilience are recommended, and personalized interventions should be tailored to address specific academic resilience characteristics across different grades of nursing students. Strategies aimed at enhancing academic resilience among nursing students may include improvements in GPA performance, attention to physical health, and the reinforcement of resilience and self-efficacy.

Nicotine up-regulated 4-1BBL expression by activating Mek-PI3K pathway augments the efficacy of bone marrow-derived dendritic cell vaccination.

PURPOSE: To explore the role of 4-1BBL in nicotine-treated immature dendritic cells (imDCs) mediated anti-tumor effects. METHODS: Bone marrow-derived imDCs were stimulated with nicotine and 4-1BBL expression was determinated by flow cytometry, Western blot and RT-PCR respectively. Then, the roles of 4-1BBL in nicotine-augmented DCs-dependent T cell proliferation, CTL priming and anti-tumor effects were investigated by BrdU cell proliferation assay, enzyme-linked immunospot assay and in vivo preventive effect on tumor development, respectively. Finally, using relative kinase inhibitors, the mechanism of 4-1BBL up-regulation by nicotine stimulation and the roles of Mek-PI3K signal pathways in nicotine-augmented DCs-dependent T cell proliferation were explored by Western blot and BrdU cell proliferation assay, respectively. RESULTS: Firstly, nicotine could up-regulate 4-1BBL expression in both protein and mRNA levels. Secondly, the effects of nicotine-augmented DCs-dependent T-cell proliferation, CTL priming and anti-tumor effects could be significantly abolished by blocking CD80, CD86 and 4-1BBL activity, respectively. Thirdly, the combined blockages of CD80/CD86, CD80/4-1BBL, CD86/4-1BBL or CD80/CD86/4-1BBL signals could decrease 53.2 %, 29.6 %, 27.9 % and 54.5 % nicotine-enhanced T cell proliferation, respectively. Importantly, nicotine-induced 4-1BBL up-regulation could be decreased by the usage of Mek-PI3K pathway kinase inhibitors. The pre-treatment of Mek-p38-PI3K kinase inhibitors could obviously abolish nicotine-augmented DCs-dependent T cell proliferation. CONCLUSIONS: CD80/CD86 and 4-1BBL are critical for nicotine augmented DCs-mediated anti-tumor effects. 4-1BBL and CD80/CD86 could be considered as potential candidates for preventive and therapeutic tumor vaccination.

A Chinese herbal formula, Yi-Qi-Fu-Sheng, inhibits migration/invasion of colorectal cancer by down-regulating MMP-2/9 via inhibiting the activation of ERK/MAPK signaling pathways.

BACKGROUND: A Chinese herbal formula, Yi-Qi-Fu-Sheng (YQFS), has long been employed clinically to treat cancer patients. We aimed to determine its effectiveness as a treatment method for colorectal cancer. We investigated the therapeutic effects of YQFS on colorectal cancer, as well as the underlying mechanisms, which have not previously been explored. METHODS: First, YQFS was extracted and chemically characterized. We then tested the effects of YQFS on proliferation and migration by MTT and transwell migration assays in vitro. Mouse xenograft models of colorectal cancer were established by inoculation with HCT-116 cells, and mice received one of three oral doses (200, 400 and 800 mg/kg/day) to evaluate the effects of YQFS extract. Metalloproteinase-2/9 (MMP-2/9) expression in mice was evaluated by gelatin zymography assay. Apoptosis was evaluated by flow cytometry (FCM) analysis in vitro and by TUNEL assay in vivo. ERK and p-ERK expression were evaluated by western blot analysis at the protein level in vitro, and by quantitative RT-PCR at mRNA level in vivo. RESULTS: Our results show that YQFS significantly inhibits colorectal cancer cell proliferation and induces apoptosis and cell cycle arrest at the G1- and S-phase in HCT-116 cells. Furthermore, YQFS effectively retards tumor cell migration and invasion by inhibiting metalloproteinase-2/9 (MMP-2/9) expression, both in vitro and in vivo. Moreover, YQFS had an inhibitory effect on tumor growth in vivo, and induced apoptosis through the inhibition of the ERK1/2 pathway both in vitro and in vivo. CONCLUSION: These findings demonstrate that YQFS extract has an anti-tumor effect in colorectal cancer, which could be attributed to ERK1/2-dependent inhibition of MMP-2/9 expression.

The effect of Chinese Jinzhida recipe on the hippocampus in a rat model of diabetes-associated cognitive decline.

BACKGROUND: To investigate the effects of treatment with Multi component Chinese Medicine Jinzhida (JZD) on behavioral deficits in diabetes-associated cognitive decline (DACD) rats and verify our hypothesis that JZD treatment improves cognitive function by suppressing the endoplasmic reticulum stress (ERS) and improving insulin signaling transduction in the rats' hippocampus. METHODS: A rat model of type 2 diabetes mellitus (T2DM) was established using high fat diet and streptozotocin (30 mg/kg, ip). Insulin sensitivity was evaluated by the oral glucose tolerance test and the insulin tolerance test. After 7 weeks, the T2DM rats were treated with JZD. The step-down test and Morris water maze were used to evaluate behavior in T2DM rats after 5 weeks of treatment with JZD. Levels of phosphorylated proteins involved in the ERS and in insulin signaling transduction pathways were assessed by Western blot for T2DM rats' hippocampus. RESULTS: Compared to healthy control rats, T2DM rats initially showed insulin resistance and had declines in acquisition and retrieval processes in the step-down test and in spatial memory in the Morris water maze after 12 weeks. Performance on both the step-down test and Morris water maze tasks improved after JZD treatment. In T2DM rats, the ERS was activated, and then inhibited the insulin signal transduction pathways through the Jun NH2-terminal kinases (JNK) mediated. JZD treatment suppressed the ERS, increased insulin signal transduction, and improved insulin resistance in the rats' hippocampus. CONCLUSIONS: Treatment with JZD improved cognitive function in the T2DM rat model. The possible mechanism for DACD was related with ERS inducing the insulin signal transduction dysfunction in T2DM rats' hippocampus. The JZD could reduce ERS and improve insulin signal transduction and insulin resistance in T2DM rats' hippocampus and as a result improved the cognitive function.

[Influence of sensor spectral parameters on the simulation of hypespectral data based on the spectral reconstruction approach].

Data simulation has been widely used in various applications of remote sensing, especially in design of new type sensors, test of new developed algorithms and other associated applications. However, change of parameters of sensor and its system can affect the accuracy of data simulations. Based on spectral reconstruction, the present study employs convolution of spectral response function (SRF) of four bands-blue, green, red, and infrared red within the wide field of view multispectral imager to analyze the impact central wavelength and bandwidth have on the accuracy of spectral reconstruction. The results show that root mean square error (RMSE) caused by central wavelength displacement is less than 0.025, while RMSE caused by bandwidth shift is less than 0.012, indicating the good accuracy of data simulations. Apparently, central wavelength and bandwidth have impact on accuracy of spectral reconstruction to some extent. Therefore, hyperspectral reconstruction depending on central wavelength and bandwidth is conducive for users to further understand hyperspectral imaging system, to find the main factor(s) influencing system performance, to better simulate hyperspectral data and to broaden the application range of remotely sensed data.

ZiBuPiYin recipe ameliorates diabetes-associated cognitive decline by improving neuronal mitochondrial function in chronic psychologically stressed zucker diabetic fatty rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Zibu Piyin Recipe (ZBPYR) is a traditional Chinese medicine compound composed of 12 kinds of Chinese herbal medicines including red ginseng and yam. Long-term basic and clinical applications have proved that ZBPYR can prevent and treat cognitive dysfunction. Previous studies showed that chronic psychological stress can increase the risk of type 2 diabetes mellitus (T2DM), and lead to cognitive decline. Mitochondrial dysfunction plays a key role in chronic psychological stress-induced diabetes mellitus. While the mechanism of mitochondrial dysfunction and insulin resistance in diabetes-associated cognitive decline (DACD) is unclear. AIM OF THE STUDY: Our previous research found that a ZiBuPiYin recipe (ZBPYR) has significant pharmacological effects against DACD. The present study investigated changes in mitochondrial dysfunction in the brain and the mechanism of insulin resistance and mitochondrial damage to explore the relationship between neuronal mitochondrial dysfunction and insulin resistance in chronic psychologically stressed DACD rats. MATERIALS AND METHODS: Zucker diabetic fatty (ZDF) rats with spontaneous T2DM and rats with diabetic cognitive impairment that was induced by chronic psychological stress were used in in vivo experiments. PC12 cells that were damaged by rotenone were used for the in vitro experiment. RESULTS: The findings indicated that the number of mitochondria decreased, morphology and membrane potential were damaged, and reactive oxygen species increased in the cortex and hippocampus in psychologically stressed DACD rats. Protein kinase Cß2 (PKCß2) activation and insulin resistance were markedly induced by chronic psychological stress, together with decreases in peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and mitochondrial fusion protein 2 (Mfn2). Furthermore, ZBPYR exerted protective effects both in in vivo and in vitro. CONCLUSION: Mitochondrial damage and insulin resistance were observed in the brain in chronic psychologically stressed DACD rats. The ZBPYR significantly improved brain mitochondrial damage and insulin resistance in chronic psychologically stressed DACD rats. These results provide novel insights for the development of ZBPYR as a traditional Chinese medicine for the treatment of chronic psychological stress and DACD.

Exosomes derived from MDR cells induce cetuximab resistance in CRC via PI3K/AKT signaling­mediated Sox2 and PD­L1 expression.

The anti-EGFR antibody cetuximab is used as a first-line targeted therapeutic drug in colorectal cancer. It has previously been reported that the efficacy of the EGFR antibody cetuximab is limited by the emergence of acquired drug resistance. In our previous study the transmissibility effect of exosomes from drug resistant tumor cells to sensitive tumor cells was identified. It can therefore be hypothesized that drug resistant cells might affect neighboring and distant cells via regulation of exosome composition and behavior. However, the mechanism of exosomes in KRAS-wild-type colorectal cancer (CRC) remains unknown. In the present study, functional analysis of overall survival post-diagnosis in patients with KRAS wild-type and those with mutant CRC was performed using human CRC specimens. Furthermore, it was demonstrated that multidrug resistance (MDR) cancer cell-derived exosomes were potentially a key factor, which promoted cetuximab-resistance in CRC cells and reduced the inhibitory effect of cetuximab in CRC xenograft models. The Cell Counting Kit-8 and colony formation assays were performed to assess the effects of exosomes derived from CRC/MDR cells on cetuximab resistance. Sphere formation assay results demonstrated that exosomes derived from CRC/MDR cells altered the self-renewal and multipotential ability of stem-cell-associated markers and facilitated resistance to cetuximab in cetuximab-sensitive cells. Furthermore, exosomes derived from CRC/MDR cells decreased sensitivity to cetuximab via the activation of PI3K/AKT signaling, which promoted Sox2 and programmed death-ligand 1 (PD-L1) mRNA and protein expression according to reverse transcription-quantitative PCR, western blotting and immunohistochemistry analyses, as well as apoptosis resistance both in vitro and in vivo according to a TUNEL assay. In conclusion, the results of the present study demonstrated that exosomes derived from CRC/MDR cells may promote cetuximab resistance in KRAS wild-type cells via activation of the PI3K/AKT signaling pathway-mediated expression of Sox2 and PD-L1, which will be useful for investigating a potential clinical target in predicting cetuximab resistance.