Electroacupuncture ameliorates AOM/DSS-induced mice colorectal cancer by inhibiting inflammation and promoting autophagy via the SIRT1/miR-215/Atg14 axis.

Colorectal cancer (CRC) is one of the most common tumors of the digestive tract, with the third-highest incidence and the second-highest mortality rate among all malignant tumors worldwide. However, treatment options for CRC remain limited. As a complementary therapy, acupuncture or electro-acupuncture (EA) has been widely applied in the treatment of various inflammation-related diseases, such as obesity, ulcerative colitis and tumors. Although numerous pre-clinical and clinical studies have investigated the beneficial effects of acupuncture on CRC, the mechanism underlying the therapeutic action of EA is largely unknown. Evidence from previous studies has revealed that SIRT1 participates in CRC progression by activating autophagy-related miRNAs. Using azoxymethane/dextran sulfate sodium- (AOM/DSS-) induced colorectal cancer model in mice, we explored whether EA treatment can inhibit inflammation and promote autophagy via the SIRT1/miR-215/Atg14 axis. Our results showed that EA notably alleviated the CRC in mice, by decreasing the tumor number and DAI scores, inflammation, and increasing body weight of mice. Besides, EA increased the expression of SIRT1 and autophagy. Further experiments showed that SIRT1 overexpression downregulated miR-215, and promoted the expression of Atg14, whereas SIRT1 knockdown induced opposite results. In conclusion, EA can ameliorate AOM/DSS-induced CRC through regulating the SIRT1-mediated miR-215/Atg14 axis by suppressing inflammation and promoting autophagy in mice. These findings reveal a potential molecular mechanism underlying the anti-CRC effect of EA indicating that EA is a promising therapeutic candidate for CRC.

Research progress on acupuncture treatment in central nervous system diseases based on NLRP3 inflammasome in animal models.

Central nervous system (CNS) disorders exhibit complex neurophysiological and pathological mechanisms, which seriously affect the quality of life in patients. Acupuncture, widely accepted as complementary and alternative medicine, has been proven to exert significant therapeutic effects on CNS diseases. As a part of the innate immune system, NLRP3 inflammasome contributes to the pathogenesis of CNS diseases via regulating neuroinflammation. To further explore the mechanisms of acupuncture regulating NLRP3 inflammasome in CNS diseases, our study focused on the effects of acupuncture on neuroinflammation and the NLRP3 inflammasome in vascular dementia, Alzheimer's disease, stroke, depression, and spinal cord injury. This study confirmed that the activation of NLRP3 inflammasome promotes the development of CNS diseases, and inhibiting the activation of NLRP3 inflammasome is a potential key target for the treatment of CNS diseases. In addition, it is concluded that acupuncture alleviates neuroinflammation by inhibiting the activation of the NLRP3 inflammasome pathway, thereby improving the progression of CNS diseases, which provides a theoretical basis for acupuncture to attenuate neuroinflammation and improve CNS diseases.

Relationship between acupuncture and transient receptor potential vanilloid: Current and future directions.

Acupuncture is a common complementary and alternative therapy around the world, but its mechanism remains still unclear. In the past decade, some studies indicated that transient receptor potential vanilloid (TRPV) channels play a great role in the response of acupuncture stimulation. In this article, we discussed the relationship between acupuncture and TRPV channels. Different from inhibitors and agonists, the regulation of acupuncture on TRPV channels is multi-targeted and biphasic control. Acupuncture stimulation shows significant modulation on TRPV1 and TRPV4 at the autonomic nervous system (ANS) including central and peripheral nervous systems. On the contrary, the abundant expression and functional participation of TRPV1 and TRPV4 were specific to acupuncture stimulation at acupoints. The enhancement or inhibition of TRPV channels at different anatomical levels will affect the therapeutic effect of acupuncture. In conclusion, TRPV channels help to understand the principle of acupuncture stimulation, and acupuncture also provides a potential approach to TRPV-related trials.

Electroacupuncture Pretreatment Exhibits Lung Protective and Anti-Inflammation Effects in Lipopolysaccharide-Induced Acute Lung Injury via SIRT1-Dependent Pathways.

To investigate the effect of electroacupuncture (EA) on acute lung injury (ALI), a lipopolysaccharide (LPS) induced ALI mouse model was used in this study. Before receiving intratracheal LPS instillation, mice were given EA at ST36 for 7 days as a long-term treatment or one time as a short-term treatment. Lung histopathological examination, lung injury scores, lung wet/dry (W/D) ratio, and inflammatory cytokines included proinflammation factors such as TNF-α, IL-1ß, and IL-6 and anti-inflammation factors such as IL-4 and IL-10 in serum and bronchoalveolar lavage fluid (BALF) were detected at the end of experiment. The results show that EA pretreatment ameliorated the lung damage and inflammatory response by LPS. In addition, we found that SIRT1 and its deacetylation of NF-κB were promoted after EA pretreatment in lung tissues. Meanwhile, the expression of angiotensin-converting enzyme 2 (ACE2) is also enhanced by EA pretreatment. Thus, the present findings suggest that EA could be a potential therapy of ALI.

Network Pharmacology and Molecular Docking-Based Investigation: Prunus mume Against Colorectal Cancer via Silencing RelA Expression.

Colorectal cancer (CRC) is one of the most pervasive cancers in the human disease spectrum worldwide, ranked the second most common cause of cancer death by the end of 2020. Prunus mume (PM) is an essential traditional Chinese medicine for the adjuvant treatment of solid tumors, including CRC. In the current study, we utilize means of network pharmacology, molecular docking, and multilayer experimental verification to research mechanism. The five bioactive compounds and a total of eight critical differentially expressed genes are screened out using the bioinformatics approaches of Cytoscape software, String database, Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathways, and molecular docking. RelA has been proven to be highly expressed in CRC. Experiments in vitro have shown that kaempferol, the main active component of PM, dramatically inhibited the growth, migration, and invasion of CRC cells, and experiments in vivo have shown that PM effectively delays CRC formation and improves the survival cycle of mice. Further analysis shows that PM inhibits the CRC progression by down-regulating the expression level of RelA, Bax, caspase 3, caspase 9, and EGFR in CRC. PM and its extract are potentially effective therapeutics for the treatment of CRC via the RelA/nuclear factor κB signaling pathway.

HDAC3 deteriorates colorectal cancer progression via microRNA-296-3p/TGIF1/TGFß axis.

BACKGROUND: The mechanism of histone deacetylase 3 (HDAC3) in colorectal cancer (CRC) has already been discussed. However, the feedback loop of HDAC3/microRNA (miR)-296-3p and transforming growth factor ß-induced factor 1 (TGIF1) in CRC has not been explained clearly. Thus, the mainstay of this study is to delve out the mechanism of this axis in CRC. METHODS: To demonstrate that HDAC3 regulates the miR-296-3p/TGIF1/TGFß axis and is involved in CRC progression, a series of cell biological, molecular and biochemical approaches were conducted from the clinical research level, in vitro experiments and in vivo experiments. These methods included RT-qPCR, Western blot assay, cell transfection, MTT assay, EdU assay, flow cytometry, scratch test, Transwell assay, dual luciferase reporter gene assay, chromatin immunoprecipitation, nude mouse xenograft, H&E staining and TUNEL staining. RESULTS: Higher HDAC3 and TGIF1 and lower miR-296-3p expression levels were found in CRC tissues. HDAC3 was negatively connected with miR-296-3p while positively correlated with TGIF1, and miR-296-3p was negatively connected with TGIF1. Depleted HDAC3 elevated miR-296-3p expression and reduced TGIF1 expression, decreased TGFß pathway-related proteins, inhibited CRC proliferation, invasion, and migration in vitro and slowed down tumor growth and induction of apoptosis in vivo, which were reversed by miR-296-3p knockdown. Restored miR-296-3p suppressed TGIF1 and reduced TGFß pathway-related proteins, inhibited CRC proliferation, invasion, and migration in vitro and slowed down tumor growth and induction of apoptosis in vivo, which were reversed by TGIF1 overexpression. CONCLUSION: This study illustrates that down-regulation of HDAC3 or TGIF1 or up-regulation of miR-296-3p discourages CRC cell progression and slows down tumor growth, which guides towards a novel direction of CRC treatment.

Prediction of protein crotonylation sites through LightGBM classifier based on SMOTE and elastic net.

Lysine crotonylation is an important protein post-translational modification, which plays an important role in the process of chromosome organization and nucleic acid metabolism. Recognition of crotonylation sites is important to understand the function and mechanism of proteins. Traditional experimental methods are time-consuming and expensive, and can't predict crotonylation sites quickly and accurately. Therefore, this paper proposes a novel crotonylation sites prediction method called LightGBM-CroSite. First, binary encoding (BE), position weight amino acid composition (PWAA), encoding based on grouped weight (EBGW), k nearest neighbors (KNN), pseudo-position specific scoring matrix (PsePSSM) are used to extract features of protein sequences and obtain the original feature space. Second, the elastic net is used to remove redundant information and select the optimal feature subset. Third, the synthetic minority oversampling technique (SMOTE) is used to balance the samples. Finally, the balanced feature vectors are input into LightGBM to predict the crotonylation sites. According to the result of jackknife test, the Accuracy (ACC), Matthew's correlation coefficient (MCC) and area under ROC curve (AUC) are 98.99%, 0.9798 and 0.9996, respectively. Compared with other state-of-the-art methods, the results show that our method has a better model performance on the crotonylation sites prediction. The source code and all datasets are available at https://github.com/QUST-AIBBDRC/LightGBM-CroSite/.

Improving protein-protein interactions prediction accuracy using XGBoost feature selection and stacked ensemble classifier.

Protein-protein interactions (PPIs) are involved with most cellular activities at the proteomic level, making the study of PPIs necessary to comprehending any biological process. Machine learning approaches have been explored, leading to more accurate and generalized PPIs predictions. In this paper, we propose a predictive framework called StackPPI. First, we use pseudo amino acid composition, Moreau-Broto, Moran and Geary autocorrelation descriptor, amino acid composition position-specific scoring matrix, Bi-gram position-specific scoring matrix and composition, transition and distribution to encode biologically relevant features. Secondly, we employ XGBoost to reduce feature noise and perform dimensionality reduction through gradient boosting and average gain. Finally, the optimized features that result are analyzed by StackPPI, a PPIs predictor we have developed from a stacked ensemble classifier consisting of random forest, extremely randomized trees and logistic regression algorithms. Five-fold cross-validation shows StackPPI can successfully predict PPIs with an ACC of 89.27%, MCC of 0.7859, AUC of 0.9561 on Helicobacter pylori, and with an ACC of 94.64%, MCC of 0.8934, AUC of 0.9810 on Saccharomyces cerevisiae. We find StackPPI improves protein interaction prediction accuracy on independent test sets compared to the state-of-the-art models. Finally, we highlight StackPPI's ability to infer biologically significant PPI networks. StackPPI's accurate prediction of functional pathways make it the logical choice for studying the underlying mechanism of PPIs, especially as it applies to drug design. The datasets and source code used to create StackPPI are available here: https://github.com/QUST-AIBBDRC/StackPPI/.

Crosstalk between Acupuncture and NF-κB in Inflammatory Diseases.

Acupuncture has been used in China for thousands of years and concerned as a typical alternative medicine in inflammatory diseases nowadays. The nuclear factor-κB (NF-κB) transcription factor is an important regulator of inflammation. In this article, we discuss the role of acupuncture in NF-κB pathways and also present the acupoints selection, acupuncture administration, and related inflammation diseases and models from previous studies to bring readers close to a more complete understanding of the mechanisms between acupuncture and NF-κB in inflammatory diseases.

The Prognostic Value of Autophagy-Related Markers Bclin-1 and LC-3 in Colorectal Cancers: A Systematic Review and Meta-analysis.

OBJECTIVE: At present, the relationship between autophagosomes and the prognosis of various cancers has become a subject of active investigation. A series of studies have demonstrated the correlation between autophagy microtubule-associated protein light chain 3 (LC-3), Beclin-1, and colorectal cancer (CRC). Since autophagy has dual regulatory roles in tumors, the results of this correlation are also uncertain. Hence, we summarized the relationship between Beclin-1, LC-3, and CRC using systematic reviews and meta-analysis to clarify their prognostic significance in it. METHODS: PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched online up to April 1, 2019. The quality of the involving studies was assessed against the Newcastle-Ottawa Scale (NOS). Pooled hazard ratio (HR) and 95% confidence interval (CI) in a fixed or random effects model were used to assess the strength of correlation between Beclin-1, LC-3, and CRC. RESULTS: A total of 9 articles were collected, involving 2,297 patients. Most literatures scored more than 6 points, suggesting that the quality of our including research was acceptable. Our finding suggested that the expression of Beclin-1 was not associated with overall survival (HR = 0.68, 95% CI (0.31-1.52), P=0.351). Nonetheless, LC-3 expression exerted significant impact on OS (HR = 0.51, 95% CI (0.35-0.74), P < 0.05). Subgroup analysis exhibited that Beclin-1 expression was associated with OS at TNM stage III (HR = 0.04, 95% CI = 0.02-0.08, P < 0.05), surgical treatment (HR = 1.53, 95% CI (1.15-2.02), P=0.003), and comprehensive treatment (HR = 0.27 95% CI (0.08-0.92), P=0.036), respectively. Similarly, the results showed the increased LC-3 expression in CRC was related to OS in multivariate analyses (HR = 0.44, 95% CI (0.34-0.57), P < 0.05), stages (HR = 0.51, 95% CI (0.35-0.74), P < 0.05), and comprehensive treatment (HR = 0.44, 95% CI (0.34-0.57), P < 0.05). CONCLUSIONS: Autophagy-related proteins of LC-3 might be an important marker of CRC progression. However, since the number of the original studies was limited, more well-designed, large-scale, high-quality studies are warranted to provide more convincing and reliable information.

Lycorine Induces autophagy-associated apoptosis by targeting MEK2 and enhances vemurafenib activity in colorectal cancer.

Lycorine is a powerful anti-cancer agent against various cancer cell lines with minor side effects. However, the detailed mechanisms of its effects in colorectal cancer (CRC) remain unclear. In this study, we investigated the function and mechanism of lycorine against CRC both in vitro and in vivo. Molecular docking modeling was used to identify potential inhibitory targets of lycorine in CRC. Cell viability was measured using the Cell Counting Kit-8 assay, and apoptosis was measured using flow cytometry. Autophagosomes were examined using transmission electron microscopy and confocal microscopy. HCT116-derived xenografts were constructed to analyze the effect of lycorine in CRC in vivo. Using the CDOCKER algorithm, we determined that lycorine has four interactions with the conserved domain of mitogen-activated protein kinase kinase 2 (MEK2). This prediction was further confirmed by the degradation of phosphorylated MEK2 and its downstream targets after lycorine treatment, and MEK2 overexpression abolished lycorine-induced autophagy-associated apoptosis. Additionally, we revealed that the combination of vemurafenib and lycorine had better effects in CRC models in vitro and in vivo than monotherapy. Our findings identified lycorine as an effective MEK2 inhibitor and suggested that the combination of lycorine and vemurafenib could be used to treat CRC.

[Electroacupuncture improves inflammatory reaction and insulin sensitivity in insulin-resistant obese rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on inflammatory reaction and insulin sensitivity in insulin-resistant obese (OIR) rats. METHODS: Thirteen male Wistar rats were randomly selected as the control group and fed with common diet. The other 39 rats were fed with high-fat diet for 8 weeks to establish OIR model and then randomized into model, EA and sham EA groups. EA (2 Hz, 1 mA) was applied to unilateral "Zusanli" (ST36), "Fenglong" (ST40), "Zhongwan" (CV12) and "Guanyuan" (CV4) for 15 min, once every other day for 8 weeks, and sham EA was applied to unilateral 4 control spots about 5 mm lateral to the aforementioned 4 acupoints after shallowly inserting acupuncture needles, but without electric current output. After 8 weeks' intervention, the body weight was recorded and the glucose infusion rate (GIR) measured using hyperinsulinemic-euglycemic clamp technique. At the 6th week of intervention, glucose contents of intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tole-rance test (IPITT) were measured. The levels of serum insulin (INS) and inflammatory factors as C-reactive protein (CRP), IL-6 and TNF-α were measured by using ELISA at the end of the treatment. The expression levels of IL-6, TNF-α, monocyte chemoattractant protein-1(MCP-1), IL-10 and IL-1ß proteins and mRNAs in the abdominal adipose tissues were detected by Western blot and quantitative real time-PCR, separately. The CD68 expression (displaying infiltration of macrophages) of adipose tissue was detected using immunohistochemistry. RESULTS: After modeling, the contents of glucose of IPGTT at 30, 60 and 120 min and those of IPITT at 15, 30, 60 and 120 min, serum INS, CRP, IL-6 and TNF-α, as well as the expression levels of IL-6, TNF-α, IL-1ß and MCP-1 proteins and mRNAs and CD68 protein were significantly increased (P<0.01, P<0.05), while the levels of GIR and IL-10 protein and mRNA were obviously decreased in the model group in comparison with those of the control group (P<0.01), suggesting an increase of inflammation and a decline of INS sensitivity. Following the interventions, the increased contents of glucose of IPGTT and IPITT, serum INS, CRP, IL-6 and TNF-α, expression levels of IL-6, TNF-α, IL-1ß and MCP-1 proteins and mRNAs and CD68 protein, and the decreased levels of GIR and IL-10 protein and mRNA were evidently reversed in the EA group compared with the model group (P<0.01, P<0.05) rather than those in the sham EA group (P>0.05). CONCLUSION: EA can reduce the level of inflammation and improve insulin sensitivity in OIR rats.

Association Between the Polymorphism in miR-605 and Cancer Susceptibility: a PRISMA-Compliant Meta-Analysis.

Background: MicroRNAs (miRNAs) play important roles in cancer development. miR-605 was reported in several studies and showed potential as a prognostic biomarker. However, the association between miR-605 and the risk of cancer remained controversial in previous studies. Therefore, this meta-analysis was carried out to elaborate the association between polymorphism in miR-605 and cancer susceptibility. Methods: PubMed, Embase, Ovid Medline, and CNKI were searched for eligible studies through up to April 2018. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were derived from a random effects model. Statistical analysis was performed using STATA10.0 software or Review Manager 5.3 software. Results: A total of 8 eligible studies consisting of 2,462 cases and 3,716 controls were included in this meta-analysis. The ORs and 95% CIs in the 4 genetic models were (GA+GG vs. AA: OR = 0.97, 95% CI: 0.97, 1.19; GG vs. GA+AA: OR = 1.09, 95% CI: 0.81, 1.47; GG vs. AA: OR = 1.19, 95% CI: 0.77, 1.82; GA vs. AA: OR = 0.94, 95% CI: 0.77, 1.15). When stratified by cancer type and race, the results showed that polymorphism in miR-605 (rs2043556) is a protective factor for cancer in Asian population. But rs2043556 could increase the susceptibility of head and neck squamous cell carcinoma (NSCC) in the dominant genotype model. The results of subgroup analysis of race (Asian: GA+GG vs. AA: OR = 0.86, 95% CI: 0.75, 1.00; GA vs. AA: OR = 0.82, 95% CI: 0.72, 0.92) and of cancer type (NSCC: GA+GG vs. AA: OR = 1.36, 95% CI: 1.14, 1.61). Conclusions: The current meta-analysis demonstrated that the rs2043556 may decrease susceptibility in Asian populations, especially allelic-G may be a protective factor for cancer in carriers.

Electroacupuncture: A Feasible Sirt1 Promoter Which Modulates Metainflammation in Diet-Induced Obesity Rats.

It is generally accepted that metainflammation, a state of chronic and low-grade inflammation in obesity, plays a great role in metabolic disorder like insulin resistance. To gain further insight into the mechanism of metainflammation and find feasible therapy of obesity, diet-induced obesity (DIO) rats model and Electroacupuncture (EA) treatment were established in this trail. The results indicated that rising Lee's index, hyperlipidemia, insulin resistance, and increasing inflammation factors including NF-κB, TNF-α, and Macrophages 1 were determined in DIO rats while EA is exhibiting an effective intervention. Furthermore, to clarify this phenomenon and provide new recognition of alternative medicine for the treatment of metainflammation, we found that EA activating Sirt1 and Sirt1-dependent deacetylation of histone (H3K9) was the key of modulation. It should be noted that, while possible, the activating of Sirt1 could lead to deacetylation of NF-κB also. In this study, the deacetylation of NF-κB depended on higher level of Sirt1 than H3K9, which suggested that the deacetylation via Sirt1 in metainflammation could be specific and programmed.

Association between -174G>C polymorphism in the IL-6 promoter region and the risk of obesity: A meta-analysis.

BACKGROUND: Many researchers have suggested that the -174G>C polymorphism in the interleukin-6 (IL-6) promoter region contributes to the risk of obesity; however, this hypothesis is still inconclusive. Therefore, we conducted a meta-analysis to combine the data from several studies to arrive at a conclusion regarding the association between -174G>C polymorphism and the risk of obesity. METHODS: The PubMed and Embase databases were searched up to February 20, 2018. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using a random-effects model. Subgroup analysis and sensitivity were also performed. RESULTS: Ten eligible studies involving 7210 cases were performed to identify the association strength. The association strength was measured by the ORs and 95% CIs. By pooling the eligible studies, we found a significant association between the -174G>C polymorphism and obesity risk (C vs G: OR = 1.37; 95% CI, 1.08-1.74; Pheterogeneity < .01). Overall, individuals with the variant CC (OR = 1.58; 95% CI, 1.09-2.28; Pheterogeneity < 0.01) and GC/CC (OR = 1.61; 95% CI, 1.13-2.29; Pheterogeneity < .01) were associated with a significantly increased risk of obesity. CONCLUSION: The meta-analysis results suggested that the polymorphism -174G>C in the IL-6 promoter region was associated with a significantly increased risk of obesity.

Predicting protein submitochondrial locations by incorporating the pseudo-position specific scoring matrix into the general Chou's pseudo-amino acid composition.

Mitochondrion is important organelle of most eukaryotes and play an important role in participating in various life activities of cells. However, some functions of mitochondria can only be achieved in specific submitochondrial location, the study of submitochondrial locations will help to further understand the biological function of protein, which is a hotspot in proteomics research. In this paper, we propose a new method for protein submitochondrial locations prediction. Firstly, the features of protein sequence are extracted by combining Chou's pseudo-amino acid composition (PseAAC) and pseudo-position specific scoring matrix (PsePSSM). Then the extracted feature information is denoised by two-dimensional (2-D) wavelet denoising. Finally, the optimal feature vectors are input to the SVM classifier to predict the protein submitochondrial locations. We obtained the ideal prediction results by jackknife test and compared with other prediction methods. The results indicate that the proposed method is significantly better than the existing research results, which can provide a new method to predict protein locations in other organelles. The source code and all datasets are available at https://github.com/QUST-BSBRC/PseAAC-PsePSSM-WD/ for academic use.