Effects of exercise interventions on negative emotions, cognitive performance and drug craving in methamphetamine addiction.

Introduction: Methamphetamine is currently one of the most commonly used addictive substances with strong addiction and a high relapse rate. This systematic review aims to examine the effectiveness of physical activity in improving negative emotions, cognitive impairment, and drug craving in people with methamphetamine use disorder (MUD). Methods: A total of 17 studies out of 133 found from Embase and PubMed were identified, reporting results from 1836 participants from MUD populations. Original research using clearly described physical activity as interventions and reporting quantifiable outcomes of negative mood, cognitive function and drug craving level in people with MUD were eligible for inclusion. We included prospective studies, randomized controlled trials, or intervention studies, focusing on the neurological effects of physical activity on MUD. Results: Taken together, the available clinical evidence showed that physical activity-based interventions may be effective in managing MUD-related withdrawal symptoms. Discussion: Physical exercise may improve drug rehabilitation efficiency by improving negative emotions, cognitive behaviors, and drug cravings. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024530359.

Therapeutic properties, biological effects, antiliver cancer, and anticolon cancer effects of some natural compounds: A biochemical approach.

Natural compounds, such as carotenoids, flavonoids, anthocyanins, or terpenoids, are physiologically active components found in plants (pigments), often known as phytochemicals or phytonutrients. The in vitro cytotoxic and anticolon cancer effects of biologically bavachin, bavachinin, artepillin C, and aromadendrin compounds against SW48, SNU-C1, COLO 205, RKO, LS411N, and SW1417 cancer cell lines were assessed. Results of enzymes and antibacterial, antifungal were in level of micromolar that is good impacts. These natural compounds may be antidiabetic, anticancer, and antibacterial candidates for drug design. IC50 results were obtained between 14-19 and 5-119 µM for α-amylase and α-glucosidase, respectively. Good inhibitor Bavachinin was detected for both enzymes (IC50 for α-amylase: 14.37 µM and IC50 for α-glucosidase: 5.27 µM). The chemical activities of aromadendrin, artepillin C, bavachin, and bavachinin against pancreatic α-amylase and α-glucosidase were assessed by conducting the molecular docking study. The chemical activities of aromadendrin, artepillin C, bavachin, and bavachinin against some of the expressed surface receptor proteins (CD44, CD47, CXCR4, EGFR, folate receptor, HER2, and endothelin receptor) in the mentioned cell lines were investigated using the molecular docking calculations. The results illustrated the atomic-level properties and potential interactions. These chemicals have high binding affinities to the enzymes and proteins, according to the docking scores. In addition, the compounds formed strong contacts with the enzymes and receptors. Thus, these compounds could be potential inhibitors for enzymes and cancer cells.

Kukoamine B Ameliorate Insulin Resistance, Oxidative Stress, Inflammation and Other Metabolic Abnormalities in High-Fat/High-Fructose-Fed Rats.

BACKGROUND: Obesity is characterized by excessive body fat, insulin resistance and dyslipidemia, which increases the chances of developing chronic diseases like type 2 diabetes, cardiovascular diseases, hypertension, nonalcoholic fatty liver diseases, some types of cancers and neurodegenerative diseases. Kukoamine B (Kuk B) is a spermine alkaloid obtained from Lycium chinense, and it has been shown to possess antidiabetic, antioxidant and anti-inflammatory properties. In this study, we evaluated the therapeutic effect of Kuk B on high-fat diet/high-fructose (HFDFr)-induced insulin resistance and obesity in experimental rats. MATERIALS AND METHODS: Rats were fed with either normal rat diet or HFDFr for 10 consecutive weeks. The groups that were fed with HFDFr received Kuk B (25 and 50 mg/kg) from the beginning of the 6th week to the 10th week. After treatment, the effect of Kuk B on body weight, food, water intake, insulin, blood glucose, serum biochemical parameters, hepatic oxidative stress (malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and proinflammatory cytokine (interleukin (IL)-6, interleukin (IL)-1ß and tumor necrosis factor alpha (TNF-α)) levels was determined. Histopathological analysis of the liver tissues was also performed. RESULTS: HFDFr-fed rats showed a significant increase in body weight, fasting blood glucose, insulin, lipid accumulation and liver function enzymes. In addition, HFDFr diet increased hepatic MDA, TNF-α, IL-1ß and IL-6 and decreased hepatic SOD, CAT and GSH-Px activities. On the other hand, Kuk B significantly attenuated body weight, insulin resistance, lipid accumulation, oxidative stress and inflammation. CONCLUSION: These results indicated that Kuk B showed protective effect against HFDFr-induced metabolic disorders by downregulating lipid accumulation, oxidative stress and inflammatory factors.

The landscape and prognostic value of tumor-infiltrating immune cells in gastric cancer.

BACKGROUND: Gastric cancer (GC) is the fourth most frequently diagnosed malignancy and the second leading cause of cancer-associated mortality worldwide. The tumor microenvironment, especially tumor-infiltrating immune cells (TIICs), exhibits crucial roles both in promoting and inhibiting cancer growth. The aim of the present study was to evaluate the landscape of TIICs and develop a prognostic nomogram in GC. MATERIALS AND METHODS: A gene expression profile obtained from a dataset from The Cancer Genome Atlas (TCGA) was used to quantify the proportion of 22 TIICs in GC by the CIBERSORT algorithm. LASSO regression analysis and multivariate Cox regression were applied to select the best survival-related TIICs and develop an immunoscore formula. Based on the immunoscore and clinical information, a prognostic nomogram was built, and the predictive accuracy of it was evaluated by the area under the curve (AUC) of the receiver operating characteristic curve (ROC) and the calibration plot. Furthermore, the nomogram was validated by data from the International Cancer Genome Consortium (ICGC) dataset. RESULTS: In the GC samples, macrophages (25.3%), resting memory CD4 T cells (16.2%) and CD8 T cells (9.7%) were the most abundant among 22 TIICs. Seven TIICs were filtered out and used to develop an immunoscore formula. The AUC of the prognostic nomogram in the TCGA set was 0.772, similar to that in the ICGC set (0.730) and whole set (0.748), and significantly superior to that of TNM staging alone (0.591). The calibration plot demonstrated an outstanding consistency between the prediction and actual observation. Survival analysis revealed that patients with GC in the high-immunoscore group exhibited a poor clinical outcome. The result of multivariate analysis revealed that the immunoscore was an independent prognostic factor. DISCUSSION: The immunoscore could be used to reinforce the clinical outcome prediction ability of the TNM staging system and provide a convenient tool for risk assessment and treatment selection for patients with GC.

MicroRNA-19a regulates the proliferation, migration and invasion of human gastric cancer cells by targeting CUL5.

Gastric cancer is one of the prevalent types of cancers and despite improvements in its treatment, the overall survival is still far from descent. The dearth of efficient biomarkers, chemotherapeutic agents and therapeutic targets form a major hurdle in the treatment of the gastric cancer. Accumulating evidences suggest that MicroRNAs (miRs) may prove important therapeutic targets/agents for the management of cancers including gastric cancer. Herein, we examined the expression of miR-19a by qRT-PCR in gastric cancer and attempted to explore its potential role. It was found that the expression of miR-19a is significantly (p < 0.05) enhanced in the gastric cancer tissues as well as the gastric cancer cell lines. Inhibition of miR-19a in gastric cancer cells suppressed the proliferation migration and invasion of the gastric cancer cells. Bioinformatic analysis revealed CUL5 to be the potential target of miR-19a. Contrary, to the expression of miR-19a, the expression of CUL5 was significantly (p < 0.05) downregulated in all the gastric cancer tissues and cell lines. However, inhibition of miR-19a in SNU-16 gastric cancer cells could cause upsurge of CUL5 expression. Overexpression of CUL-5 was found to exhibit similar effects on the proliferation, migration and invasion of the SNU-16 gastric cancer cells as that of miR-19a suppression. Additionally, overexpression of CUL5 could at least partially abolish the effects of miR-19a suppression on the proliferation, migration and invasion of SNU-16 gastric cancer cells. Finally, overexpression of miR-19a caused inhibition of the xenografted tumors in vivo indicating the potential of miR-19a as therapeutic target for gastric cancer.

Comprehensive evaluation of composite gene features in cancer outcome prediction.

Owing to the heterogeneous and continuously evolving nature of cancers, classifiers based on the expression of individual genes usually do not result in robust prediction of cancer outcome. As an alternative, composite gene features that combine functionally related genes have been proposed. It is expected that such features can be more robust and reproducible since they can capture the alterations in relevant biological processes as a whole and may be less sensitive to fluctuations in the expression of individual genes. Various algorithms have been developed for the identification of composite features and inference of composite gene feature activity, which all claim to improve the prediction accuracy. However, because of the limitations of test datasets incorporated by each individual study and inconsistent test procedures, the results of these studies are sometimes conflicting and unproducible. For this reason, it is difficult to have a comprehensive understanding of the prediction performance of composite gene features, particularly across different cancers, cancer subtypes, and cohorts. In this study, we implement various algorithms for the identification of composite gene features and their utilization in cancer outcome prediction, and perform extensive comparison and evaluation using seven microarray datasets covering two cancer types and three different phenotypes. Our results show that, while some algorithms outperform others for certain classification tasks, no single algorithm consistently outperforms other algorithms and individual gene features.

Gut microbiota dysbiosis and bacterial community assembly associated with cholesterol gallstones in large-scale study.

BACKGROUND: Elucidating gut microbiota among gallstone patients as well as the complex bacterial colonization of cholesterol gallstones may help in both the prediction and subsequent lowered risk of cholelithiasis. To this end, we studied the composition of bacterial communities of gut, bile, and gallstones from 29 gallstone patients as well as the gut of 38 normal individuals, examining and analyzing some 299, 217 bacterial 16S rRNA gene sequences from 120 samples. RESULTS: First, as compared with normal individuals, in gallstone patients there were significant (P < 0.001) increases of gut bacterial phylum Proteobacteria and decreases of three gut bacterial genera, Faecalibacterium, Lachnospira, and Roseburia. Second, about 70% of gut bacterial operational taxonomic units (OTUs) from gallstone patients were detectable in the biliary tract and bacteria diversity of biliary tract was significantly (P < 0.001) higher than that of gut. Third, analysis of the biliary tract core microbiome (represented by 106 bacteria OTUs) among gallstone patients showed that 33.96% (36/106) of constituents can be matched to known bacterial species (15 of which have publicly available genomes). A genome-wide search of MDR, BSH, bG, and phL genes purpotedly associated with the formation of cholesterol gallstones showed that all 15 species with known genomes (e.g., Propionibacterium acnes, Bacteroides vulgates, and Pseudomonas putida) contained at least contained one of the four genes. This finding could potentially provide underlying information needed to explain the association between biliary tract microbiota and the formation of cholesterol gallstones. CONCLUSIONS: To the best of our knowledge, this is the first study to discover gut microbiota dysbiosis among gallstone patients, the presence of which may be a key contributor to the complex bacteria community assembly linked with the presence of cholesterol gallstones. Likewise, this study also provides the first large-scale glimpse of biliary tract microbiota potentially associated with cholesterol gallstones. Such a characterization of the biliary tract core microbiome has potentially important biological and medical implications regarding the role of bacteria in the formation cholesterol gallstones.

The ribonuclease Dis3 is an essential regulator of the developmental transcriptome.

BACKGROUND: Dis3 is ribonuclease that acts directly in the processing, turnover, and surveillance of a large number of distinct RNA species. Evolutionarily conserved from eubacteria to eukaryotes and a crucial component of the RNA processing exosome, Dis3 has been shown to be essential in yeast and fly S2 cells. However, it is not known whether Dis3 has essential functions in a metazoan. This study inquires whether Dis3 is required for Drosophila development and viability and how Dis3 regulates the transcriptome in the developing fly. RESULTS: Using transgenic flies, we show that Dis3 knock down (Dis3KD) retards growth, induces melanotic tumor formation, and ultimately results in 2nd instar larval lethality. In order to determine whether Dis3KD fly phenotypes were a consequence of disrupting developmentally regulated RNA turnover, we performed RNA deep sequencing analysis on total RNA isolated from developmentally staged animals. Bioinformatic analysis of transcripts from Dis3KD flies reveals substantial transcriptomic changes, most notably down-regulation in early expressed RNAs. Finally, gene ontology analysis of this early stage shows that Dis3 regulates transcripts related to extracellular structure and remodelling, neurogenesis, and nucleotide metabolism. CONCLUSIONS: We conclude that Dis3 is essential for early Drosophila melanogaster development and has specific and important stage-specific roles in regulating RNA metabolism. In showing for the first time that Dis3 is required for the development of a multicellular organism, our work provides mechanistic insight into how Dis3-either independent of or associated with the RNA processing exosome-participates in cell type-specific RNA turnover in metazoan development.

Dis3- and exosome subunit-responsive 3' mRNA instability elements.

Eukaryotic RNA turnover is regulated in part by the exosome, a nuclear and cytoplasmic complex of ribonucleases (RNases) and RNA-binding proteins. The major RNase of the complex is thought to be Dis3, a multi-functional 3'-5' exoribonuclease and endoribonuclease. Although it is known that Dis3 and core exosome subunits are recruited to transcriptionally active genes and to messenger RNA (mRNA) substrates, this recruitment is thought to occur indirectly. We sought to discover cis-acting elements that recruit Dis3 or other exosome subunits. Using a bioinformatic tool called RNA SCOPE to screen the 3' untranslated regions of up-regulated transcripts from our published Dis3 depletion-derived transcriptomic data set, we identified several motifs as candidate instability elements. Secondary screening using a luciferase reporter system revealed that one cassette-harboring four elements-destabilized the reporter transcript. RNAi-based depletion of Dis3, Rrp6, Rrp4, Rrp40, or Rrp46 diminished the efficacy of cassette-mediated destabilization. Truncation analysis of the cassette showed that two exosome subunit-sensitive elements (ESSEs) destabilized the reporter. Point-directed mutagenesis of ESSE abrogated the destabilization effect. An examination of the transcriptomic data from exosome subunit depletion-based microarrays revealed that mRNAs with ESSEs are found in every up-regulated mRNA data set but are underrepresented or missing from the down-regulated data sets. Taken together, our findings imply a potentially novel mechanism of mRNA turnover that involves direct Dis3 and other exosome subunit recruitment to and/or regulation on mRNA substrates.

Phosphorylation of Pirh2 by calmodulin-dependent kinase II impairs its ability to ubiquitinate p53.

Although the recently identified Pirh2 protein is known as a p53-induced ubiquitin-protein E3 ligase, which negatively regulates p53, the detailed mechanism underlying the regulation of Pirh2 remains largely unknown. Here, we demonstrate that while Pirh2 is mostly detected in the phosphorylated form in normal tissues, it is predominantly present in the unphosphorylated form in majority of tumor cell lines and tissues examined. Phosphorylated Pirh2 is far more unstable than its unphosphorylated form. We further identified that Calmodulin-dependent kinase II (CaMK II) phosphorylates Pirh2 on residues Thr-154 and Ser-155. Phosphorylation of Pirh2 appears to be regulated through cell cycle-dependent mechanism. CaMK II-mediated Pirh2 phosphorylation abrogates its E3 ligase activity toward p53. Together, our data suggest that phosphorylation of Pirh2 may act as a fine-tuning to maintain the balance of p53-Pirh2 autoregulatory feedback loop, which facilitates the tight regulation of p53 stability and tumor suppression.

Death effector domain DEDa, a self-cleaved product of caspase-8/Mch5, translocates to the nucleus by binding to ERK1/2 and upregulates procaspase-8 expression via a p53-dependent mechanism.

Activation of the apical caspase-8 is crucial to the extrinsic apoptotic pathway. Although the death effector domain (DED) of caspase-8 has been reported to be involved in death-inducing signaling complex formation, the detailed mechanism of how DED functions in regulating apoptosis remains largely unknown. Here, we demonstrate that the prodomain of the caspase-8/Mch5 can be further cleaved between two tandemly repeated DEDs (DEDa-DEDb) at the amino-acid residue Asp129 by caspase-8 itself. The DEDa fragment generated from the endogenous caspase-8 was detected in isolated nucleoli upon treatment with TRAIL (tumor necrosis factor-related apoptosis-inducing ligand). Cleaved DEDa appears to translocate into the nucleus by association with extracellular signal-regulated protein kinases-1/2 (ERK1/2). Elimination of ERK1/2 expression by RNA interference resulted in a significant attenuation of nuclear entry of DEDa and reduced caspase-8-dependent apoptosis. In the nucleus, DEDa interacts with TOPORS, a p53 and topoisomerase I binding protein, and possibly displaces p53 from TOPORS, allowing p53 to stimulate caspase-8 gene expression. In summary, we postulate a positive feedback loop involving DEDa, which enables the continual replenishment of procaspase-8 during apoptosis.