Self-adaptive pyroptosis-responsive nanoliposomes block pyroptosis in autoimmune inflammatory diseases.

Nanoliposomes have a broad range of applications in the treatment of autoimmune inflammatory diseases because of their ability to considerably enhance drug transport. For their clinical application, nanoliposomes must be able to realize on-demand release of drugs at disease sites to maximize drug-delivery efficacy and minimize side effects. Therefore, responsive drug-release strategies for inflammation treatment have been explored; however, no specific design has been realized for a responsive drug-delivery system based on pyroptosis-related inflammation. Herein, we report a pioneering strategy for self-adaptive pyroptosis-responsive liposomes (R8-cardiolipin-containing nanoliposomes encapsulating dimethyl fumarate, RC-NL@DMF) that precisely release encapsulated anti-pyroptotic drugs into pyroptotic cells. The activated key pyroptotic protein, the N-terminal domain of gasdermin E, selectively integrates with the cardiolipin of liposomes, thus forming pores for controlled drug release, pyroptosis, and inflammation inhibition. Therefore, RC-NL@DMF exhibited effective therapeutic efficacies to alleviate autoimmune inflammatory damages in zymosan-induced arthritis mice and dextran sulfate sodium-induced inflammatory bowel disease mice. Our novel approach holds great promise for self-adaptive pyroptosis-responsive on-demand drug delivery, suppressing pyroptosis and treating autoimmune inflammatory diseases.

Period2 is associated with immune cell infiltration and is a potential diagnostic and prognostic marker for hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) health challenge worldwide. Many studies showed that circadian rhythms play a critical role in tumor development. This study aimed to investigate the role of the circadian gene period2 (PER2) in HCC development and explore the possible mechanisms involved. Methods: From fresh HCC tissues and paired paracancerous tissues, we measured PER2 mRNA and protein expression levels and calculated the correlations between PER2 expression and clinicopathological parameters in patients with HCC. We used transcriptome data from The Cancer Genome Atlas to mine the PER2 gene, including single gene difference analysis, single gene co-expression analysis, gene set enrichment analysis, immune infiltration analysis, and methylation analysis to explore its role and mechanism in HCC occurrence and development. Results: PER2 expression levels were significantly lower in HCC tissues than in the paired paracancerous tissues. PER2 expression in HCC significantly correlated with neural invasion, Child-Pugh classification, and China liver cancer staging stage in HCC patients. The differentially expressed genes associated with PER2 were significantly enriched in mitochondrial oxidative phosphorylation, transcriptional translation, amino acid metabolism, and other related pathways. PER2 expression levels significantly correlated with immune cell infiltration and immune checkpoint genes and positively correlated with TP53 expression in HCC tissues. The DNA methylation status in eight CpG islands of the PER2 gene was associated with HCC outcomes. Conclusion: PER2 is a potential diagnostic and prognostic biomarker and a promising therapeutic target in HCC.

Exploring the anticancer potential of Actinidia chinensis Planch root extracts (acRoots) on hepatocellular carcinoma: A molecular mechanism study.

Hepatocellular carcinoma (HCC), ranking as the seventh most prevalent cancer worldwide, poses a significant health challenge. Actinidia chinensis Planch Root extracts (acRoots), a traditional Chinese medicine, has exhibited promising inhibitory effects on the proliferation, invasion, and migration of various cancer cell types. Nevertheless, its specific impact and underlying mechanisms concerning HCC remain unclear. This research aimed to elucidate the anticancer properties and potential molecular mechanisms of acRoots in the HepG2 and LM3 cell lines. Our findings demonstrate that acRoots effectively hampers the in vitro proliferation, migration, and invasion of HCC cells. Furthermore, acRoots induces apoptosis and autophagy by impeding the AKT/mTOR signaling pathway, with its inhibitory effects on cells being restored under AKT activator induction. This study, for the first time, elucidates that acRoots can suppress HepG2 and LM3 cell proliferation by blocking the Akt/mTOR pathway, thereby activating apoptosis and autophagy. These results underscore the potential of acRoots as a promising antitumor agent for HCC.

Lower Dorsal Lateral Prefrontal Cortex Functional Connectivity in Late-Life Depression With Suicidal Ideation.

OBJECTIVE: The dorsal lateral prefrontal cortex (DLPFC) has been identified as a neuromodulation target for alleviating suicidal ideation. Dysfunctional DLPFC has been implicated in suicidality in depression. This study aimed to investigate the functional connectivity (FC) of the DLPFC in late-life depression (LLD) with suicidal ideation. METHODS: Resting-state functional magnetic resonance imaging (fMRI) data from 32 LLD patients with suicidal ideation (LLD-S), 41 LLD patients without suicidal ideation (LLD-NS), and 54 healthy older adults (HOA) were analyzed using DLPFC seed-based FC analyses. Group differences in FC were examined, and machine learning was applied to explore the potential of DLPFC-FC for classifying LLD-S from LLD-NS. RESULTS: Abnormal DLPFC-FC patterns were observed in LLD-S, characterized by lower connectivity with the angular gyrus, precuneus, and superior frontal gyrus compared to LLD-NS and healthy controls. A classification model based on the identified DLPFC-FC achieved an accuracy of 75%. CONCLUSION: The lower FC of DLPFC networks may contribute to the neurobiological mechanism of suicidal ideation in late-life depression. These findings may facilitate suicide prevention for LLD by providing potential neuroimaging markers and network-based neuromodulation targets. However, further confirmation with larger sample sizes and experimental designs is warranted.

DAPT suppresses proliferation and migration of hepatocellular carcinoma by regulating the extracellular matrix and inhibiting the Hes1/PTEN/AKT/mTOR signaling pathway.

BACKGROUND: The aim of the present study was to investigate the antitumor properties of N-(N-[3,5-difluorophenacetyl]-1-alanyl)-S-phenylglycine t-butyl ester (DAPT) against hepatocellular carcinoma (HCC), as well as the underlying mechanism. METHODS: Immunohistochemistry and quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay were used to determine the expression of Notch1 in HCC tissues. The expression of Notch1 in 3 HCC cell lines was evaluated by qRT-PCR and Western blot. The proliferation ability of cells was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays. Flow cytometry and Transwell assay were used to check the apoptosis and migration of HepG2 cells, respectively. Western blot was used to determine the expression level of Notch1, Hes1, Phosphatase and tensin homolog (PTEN), protein kinase B1 (AKT1), phosphorylated AKT1, mammalian target of rapamycin (mTOR), phosphorylated mTOR, intracellular adhesion molecule-1, vascular cell adhesion protein 1, matrix metalloproteinase (MMP)-2, MMP-9, and focal adhesion kinase in cells and tumor tissues. A HepG2 xenograft experiment was conducted to evaluate the in vivo antitumor properties of DAPT. RESULTS: Notch1 was found to be significantly upregulated in both HCC tissues and cell lines. DAPT significantly inhibited the proliferation and migration of HepG2 cells in a dose-dependent manner, accompanied by the suppression of Notch1/Hes1 signaling, inactivation of AKT/mTOR signaling, downregulation of MMPs, and decreased expression of adhesion molecules. The activation of Notch1/Hes1 or AKT/mTOR signaling removed the inhibitory effect of DAPT on the proliferation and migration of HepG2 cells, as well as the inhibitory properties of DAPT on the expression of MMPs and adhesion molecules. The antitumor properties and regulatory effect of DAPT against the extracellular matrix (ECM) and Hes1/PTEN/AKT/mTOR signaling were verified by the HepG2 xenograft experiments. CONCLUSIONS: DAPT could suppress the proliferation and migration of HCC by regulating the ECM and inhibiting the Hes1/PTEN/AKT/mTOR signaling pathway.

miR-3677-5p promotes the proliferation, migration and invasion of hepatocellular carcinoma cells and is associated with prognosis.

MicroRNA (miRNA/miR)-3677 has been indicated to be negatively associated with the survival of patients with hepatocellular carcinoma (HCC) based on The Cancer Genome Atlas database. However, as a novel miRNA, the role of miR-3677-5p in HCC has remained to be elucidated. In the present study, the expression of miR-3677-5p was assessed in HCC tissues and cell lines using reverse transcription-quantitative PCR. Survival analysis was performed using Kaplan-Meier curves. Furthermore, the prognostic significance of miR-3677-5p was evaluated using Cox regression analysis. The effects of miR-3677-5p on cell proliferation, as well as migration and invasion capacities, were analyzed using Cell Counting Kit-8, crystal violet and Transwell assays. The results demonstrated that the level of miR-3677-5p expression was upregulated in human HCC tissues and cell lines and that miR-3677-5p expression was closely associated with tumor size, TNM stage and vascular invasion. Furthermore, high miR-3677-5p expression was significantly associated with unfavorable clinical prognosis for patients with HCC. Overexpression of miR-3677-5p was indicated to significantly promote the proliferation, migration and invasion of HCC cells, whereas knockdown of miR-3677-5p was observed to have an inhibitory effect. In conclusion, the present study demonstrated that miR-3677-5p acts as an oncogene that has a critical role in the regulation of HCC proliferation and progression. Hence, miR-3677-5p may serve as a valuable prognostic biomarker and may be developed as a promising therapeutic target for HCC.

The effect of breathing exercises on patients with GERD: a meta-analysis.

BACKGROUND: Breathing exercises can improve the symptoms of patients with gastroesophageal reflux disease (GERD), but their specific effect and function are disputed. To evaluate and conduct a meta-analysis on the effect of breathing exercises on patients with GERD. METHODS: A literature search for randomized controlled trials (RCTs) and prospective studies on the effects of employing breathing exercises on patients with GERD was conducted of all major online English databases (PubMed, Embase, the Cochrane library, CENTRAL, Web of Science, AMED, and CINAHL). After the systematic review of all the studies according to inclusion and exclusion criteria, we analyzed the extracted data through meta-analysis by using RevMan 5.3 software. RESULTS: This thesis analyzes 7 studies (including three RCTs), which together involved 194 patients and 16 healthy volunteers. The primary outcomes of these studies included GERD symptoms, esophageal manometry, esophageal pH monitoring, laryngoscopic findings, and acid suppression usage. The results of meta-analysis indicate that breathing exercises can improve pressure generated by the lower oesophageal sphincter (LES), and a statistically significant difference was observed. The possible mechanism behind this is the enhancement of the anti-regurgitation barrier [especially crural diaphragm (CD) tension]. CONCLUSIONS: To some extent, breathing exercises can relieve the symptoms of patients with GERD.

Downregulation of Notch1 inhibits the invasion of human hepatocellular carcinoma HepG2 and MHCC97H cells through the regulation of PTEN and FAK.

Tumor invasion and metastasis are the main causes of mortality in patients with hepatocellular carcinoma (HCC). Thus, the effective inhibition of these tumorigenic processes is critical in order for HCC therapy to be effective. Previous studies have demonstrated that Notch1 is associated with metastasis in several human malignancies. However, the exact molecular mechanisms underlying the Notch1-mediated induction of the invasion of HCC cells remain poorly understood. In the present study, we demonstrate that, compared to the normal liver cell line, L02, Notch1 is highly expressed in the human HCC cell lines, HepG2 and MHCC97H. Using small interfering RNA (siRNA), we knocked down the expression of Notch1 in the cell lines. Notch1 expression in the HCC cell lines was also measured following transfection with siRNA using RT-PCR and western blot analysis. In addition, a migration and invasion assay was performed to determine the effects of Notch1 knockdown on cell migration and invasion. Our results demonstrated that the downregulation of Notch1 by small interfering RNA (siRNA) significantly inhibited the migration and invasion of both HCC cell lines. Additionally, we demonstrated that the knockdown of Notch1 in both HCC cell lines increased both the total expression of phosphatase and tensin homolog (PTEN) and its phosphorylated form. By contrast, focal adhesion kinase (FAK) and phospho-FAK expression was decreased following Notch1 depletion. Taken together, our data suggest that targeting Notch1 may be a useful therapeutic approach to inhibiting the metastasis of HCC cells.