Network pharmacology-based investigation of the effects of Shenqi Fuzheng injection on glioma proliferation and migration via the SRC/PI3K/AKT signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: In the clinic, Shenqi Fuzheng Injection (SFI) is used as an adjuvant for cancer chemotherapy. However, the molecular mechanism is unclear. AIM OF THE STUDY: We screened potential targets of SFI action on gliomas by network pharmacology and performed experiments to validate possible molecular mechanisms against gliomas. MATERIALS AND METHODS: We consulted relevant reports on the SFI and glioma incidence from PubMed and Web of Science and focused on the mechanism through which the SFI inhibits glioma. According to the literature, two primary SFI components-Codonopsis pilosula (Franch.) Nannf. and Astragalus membranaceus (Fisch.) Bunge-have been found. All plant names have been sourced from "The Plant List" (www.theplantlist.org). The cell lines U87, T98G and GL261 were used in this study. The inhibitory effects of SFI on glioma cells U87 and T98G were detected by CCK-8 assay, EdU, plate cloning assay, scratch assay, Transwell assay, immunofluorescence, flow cytometry and Western blot. A subcutaneous tumor model of C57BL/6 mice was constructed using GL261 cells, and the SFI was evaluated by HE staining and immunohistochemistry. The targets of glioma and the SFI were screened using network pharmacology. RESULTS: A total of 110 targets were enriched, and a total of 26 major active components in the SFI were investigated. There were a total of 3,343 targets for gliomas, of which 79 targets were shared between the SFI and glioma tissues. SFI successfully prevented proliferation and caused cellular S-phase blockage in U87 and T98G cells, thus decreasing their growth. Furthermore, SFI suppressed cell migration by downregulating EMT marker expression. According to the results of the in vivo tests, the SFI dramatically decreased the development of tumors in a transplanted tumour model. Network pharmacological studies revealed that the SRC/PI3K/AKT signaling pathway may be the pathway through which SFI exerts its anti-glioma effects. CONCLUSIONS: The findings revealed that the SRC/PI3K/AKT signaling pathway may be involved in the mechanism through which SFI inhibits the proliferation and migration of glioma cells.

Molecular profile of metastasis, cell plasticity and EMT in pancreatic cancer: a pre-clinical connection to aggressiveness and drug resistance.

The metastasis is a multistep process in which a small proportion of cancer cells are detached from the colony to enter into blood cells for obtaining a new place for metastasis and proliferation. The metastasis and cell plasticity are considered major causes of cancer-related deaths since they improve the malignancy of cancer cells and provide poor prognosis for patients. Furthermore, enhancement in the aggressiveness of cancer cells has been related to the development of drug resistance. Metastasis of pancreatic cancer (PC) cells has been considered one of the major causes of death in patients and their undesirable prognosis. PC is among the most malignant tumors of the gastrointestinal tract and in addition to lifestyle, smoking, and other factors, genomic changes play a key role in its progression. The stimulation of EMT in PC cells occurs as a result of changes in molecular interaction, and in addition to increasing metastasis, EMT participates in the development of chemoresistance. The epithelial, mesenchymal, and acinar cell plasticity can occur and determines the progression of PC. The major molecular pathways including STAT3, PTEN, PI3K/Akt, and Wnt participate in regulating the metastasis of PC cells. The communication in tumor microenvironment can provide by exosomes in determining PC metastasis. The components of tumor microenvironment including macrophages, neutrophils, and cancer-associated fibroblasts can modulate PC progression and the response of cancer cells to chemotherapy.

Transcriptomics and molecular docking reveal the potential mechanism of lycorine against pancreatic cancer.

BACKGROUND: Pancreatic cancer is an extremely malignant digestive tumor, however, owing to its high drug resistance of pancreatic cancer, the search for more effective anti-pancreatic cancer drugs is urgently needed. Lycorine, an alkaloid of natural plant origin, exerts antitumor effects on a variety of tumors. PURPOSE: This study aimed to investigate the therapeutic effect of lycorine on pancreatic cancer and elucidate its potential molecular mechanism. METHODS: Two pancreatic cancer cell lines, PANC-1 and BxPC-3, were used to investigate the therapeutic effects of lycorine on pancreatic cancer in vitro using the CCK8 assay, colony formation assay, 5-Ethynyl-2'- deoxyuridine (EdU) incorporation assay, flow cytometry, and western blotting. Transcriptome sequencing and gene set enrichment analysis (GSEA) were used to analyze the differentially expressed genes and pathways after lycorine treatment. Molecular docking, quantitative real-time PCR (qRT-PCR), oil red O staining, small interfering RNA (siRNA) transfection, and other experiments were performed to further validate the differentially expressed genes and pathways. In vivo experiments were conducted to investigate lycorine's inhibitory effects and toxicity on pancreatic cancer using a tumor-bearing mouse model. RESULTS: Lycorine inhibited the proliferation of pancreatic cancer cells, caused G2/M phase cycle arrest and induced apoptosis. Transcriptome sequencing and GSEA showed that lycorine inhibition of pancreatic cancer was associated with fatty acid metabolism, and aldehyde dehydrogenase 3A1 (ALDH3A1) was a significantly enriched target in the fatty acid metabolism process. ALDH3A1 expression was significantly upregulated in pancreatic cancer and was closely associated with prognosis. Molecular docking showed that lycorine binds strongly to ALDH3A1. Further studies revealed that lycorine inhibited the fatty acid oxidation (FAO) process in pancreatic cancer cells and induced cell growth inhibition and apoptosis through ALDH3A1. Lycorine also showed significant suppressive effects in tumor-bearing mice. Importantly, it did not result in significant toxicity to liver and kidney of mice, demonstrating its therapeutic potential as a safe antitumor agent. CONCLUSION: Lycorine inhibited pancreatic cancer cell proliferation, blocked the cell cycle, and induced apoptosis by targeting ALDH3A1. FAO inhibition was identified for the first time as a possible mechanism for the anticancer effects of lycorine. These findings enrich the theory of targeted therapy for pancreatic cancer, expand our understanding of the pharmacological targets of lycorine, and provide a reference for exploring its natural components.

Expression and correlation of COX-2 and NUCB1 in colorectal adenocarcinoma.

Objective: To investigate the expression and correlation of COX-2 and NUCB1 in colorectal adenocarcinoma and adjacent tissues. Methods: The expression of COX-2 and NUCB1 and their effects on prognosis were predicted using bioinformatics. Immunohistochemistry was used to identify the expression of two molecules in 56 cases of colorectal adenocarcinoma and the surrounding tissues. The expression of two molecules and their association with clinicopathological variables were examined using the chi-square test. The association between COX-2 and NUCB1 was investigated using the Spearman correlation test. Results: The STRING database revealed that COX-2 and NUCB1 were strongly linked. According to the UALCAN and HPA database, COX-2 was upregulated while NUCB1 was downregulated in colorectal adenocarcinoma, both at the protein and gene levels. The OS times for COX-2 and NUCB1 high expression, however, exhibited the same patterns. The rate of positive COX-2 immunohistochemical staining in cancer tissues was 69.64% (39/56), which was significantly higher than the rate in healthy tissues 28.57% (16/56). NUCB1 was expressed positively in cancer tissues at a rate of 64.29% (36/56) compared to just 19.64% (11/56) in neighboring tissues. The positive expression levels of COX-2 and NUCB1 were both closely related to clinical stage, differentiation degree, and lymphatic metastases (P < 0.05). In colorectal cancer, COX-2 and NUCB1 expression were significantly correlated (rs = 0.6312, P < 0.001). Conclusion: Both COX-2 and NUCB1 are overexpressed and significantly associated in colorectal adenocarcinoma.

Anxiety and depression in lung cancer: effect of psychological interventions - network meta-analysis.

BACKGROUND: The prevalence of depression and anxiety is high in patients with lung cancer, while multiple psychological interventions have revealed a positive impact on patients' negative emotions. However, it remains scarce which psychological intervention is the best choice for patients.This study was conducted to compare and rank the efficacy of psychological interventions on anxiety and depression in patients with lung cancer using a network meta-analysis. METHODS: The Chinese academic database (CNKI, Wan Fang and Vip) and English academic database (The Cochrane Library, PubMed, PsycINFO and Web of Science) were searched from their inception to March 2022. Randomised controlled studies of psychological interventions on depression and anxiety in patients with lung cancer were included. Study selection and evaluation were conducted independently by two researchers. Included studies were performed a network meta-analysis to compare and rank the psychological interventions for negative emotions of patients with lung cancer. The clustered ranking of psychotherapies in the network was based on surface under the cumulative probability ranking curve values. RESULTS: 23 studies (2221 participants) with 13 psychological interventions were retrieved. The random-effects model showed a significantly large effect size of supportive therapy for anxiety (mean difference, MD 14.38, 95% CI 2.42 to 26.21) and depression (MD 14.29, 95% CI 2.74 to 25.70). The supportive therapy, sandplay therapy and music therapy were top three rankings of interventions for anxiety, while supportive therapy, dignity therapy and sandplay therapy were the top three interventions for depression. CONCLUSIONS: Supportive therapy would be a more appropriate option for alleviating negative emotions in patients with lung cancer. Other psychological intervention techniques may be used as alternatives, such as sandplay therapy and music therapy for anxiety, dignity therapy and sandplay therapy for depression. PROSPERO REGISTRATION NUMBER: CRD42022320188.

Lactate: The Mediator of Metabolism and Immunosuppression.

The Warburg effect, one of the hallmarks of tumors, produces large amounts of lactate and generates an acidic tumor microenvironment via using glucose for glycolysis. As a metabolite, lactate not only serves as a substrate to provide energy for supporting cell growth and development but also acts as an important signal molecule to affect the biochemical functions of intracellular proteins and regulate the biological functions of different kinds of cells. Notably, histone lysine lactylation (Kla) is identified as a novel post-modification and carcinogenic signal, which provides the promising and potential therapeutic targets for tumors. Therefore, the metabolism and functional mechanism of lactate are becoming one of the hot fields in tumor research. Here, we review the production of lactate and its regulation on immunosuppressive cells, as well as the important role of Kla in hepatocellular carcinoma. Lactate and Kla supplement the knowledge gap in oncology and pave the way for exploring the mechanism of oncogenesis and therapeutic targets. Research is still needed in this field.

Tripartite motif-containing protein 11 promotes hepatocellular carcinogenesis through ubiquitin-proteasome-mediated degradation of pleckstrin homology domain leucine-rich repeats protein phosphatase 1.

BACKGROUND AND AIMS: HCC is one of the main types of primary liver cancer, with high morbidity and mortality and poor treatment effect. Tripartite motif-containing protein 11 (TRIM11) has been shown to promote tumor formation in lung cancer, breast cancer, gastric cancer, and so on. However, the specific function and mechanism of TRIM11 in HCC remain open for study. APPROACH AND RESULTS: Through clinical analysis, we found that the expression of TRIM11 was up-regulated in HCC tissues and was associated with high tumor node metastasis (TNM) stages, advanced histological grade, and poor patient survival. Then, by gain- and loss-of-function investigations, we demonstrated that TRIM11 promoted cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Mechanistically, RNA sequencing and mass spectrometry analysis showed that TRIM11 interacted with pleckstrin homology domain leucine-rich repeats protein phosphatase 1 (PHLPP1) and promoted K48-linked ubiquitination degradation of PHLPP1 and thus promoted activation of the protein kinase B (AKT) signaling pathway. Moreover, overexpression of PHLPP1 blocked the promotional effect of TRIM11 on HCC function. CONCLUSIONS: Our study confirmed that TRIM11 plays an oncogenic role in HCC through the PHLPP1/AKT signaling pathway, suggesting that targeting TRIM11 may be a promising target for the treatment of HCC.

Decompressive hemicraniectomy versus medical treatment of malignant middle cerebral artery infarction: a systematic review and meta-analysis.

OBJECTIVES: To estimate evidence for decompressive hemicraniectomy (DHC) versus medical treatment effects on survival rate and favorable functional recovery among patients of malignant middle cerebral artery infarction (MMCAI) in randomized controlled trials (RCTs). DESIGN: The present study is a systematic review and meta-analysis of RCTs. SETTING: The MEDLINE/PubMed, EMBASE, Springer, Cochrane Collaboration database, China National Knowledge Infrastructure (CNKI) database, and Wanfang database were comprehensively searched for RCTs regarding the effects of DHC versus medical treatment among patients of MMCAI in these English and Chinese electronic databases from inception to 1 June 2019. Two reviewers independently retrieved RCTs and extracted relevant information. The methodological quality of the included trials was estimated using the Cochrane risk of bias tool. Review Manager5.3.5 software was used for statistical analyses. The statistical power of meta-analysis was estimated by Power and Precision, version 4 software. PARTICIPANTS: Nine RCTs with a total of 425 patients with MMCAI, containing 210 cases in the DHC group and 215 cases in the medical treatment group, met the inclusion criteria were included. Primary outcomes were measured by survival rate, defined as modified Rankin scale (mRS) score 0-5 and favorable functional recovery as mRS score 0-3. The follow-up time of all studies was at 6-12months. RESULTS: First, compared with the medical treatment group, DHC was associated with a statistically significant increase survival rate (RR: 1.96, 95%CI 1.61-2.38, P < 0.00001) and favorable functional recovery (RR: 1.62, 95%CI 1.11-2.37, P = 0.01). Second, subgroup analysis: (1) Compared with the medical treatment group among patients age ≤60 years, DHC was associated with a statistically significant increase survival rate (RR = 2.20, 95%CI 1.60-3.04, P < 0.00001); (2) Compared with the medical treatment group among patients of age >60 years, DHC was also associated with a statistically significant increase survival rate (RR: 1.93, 95%CI 1.45-2.59, P < 0.00001); (3) Compared with the medical treatment group, the time of DHC was preformed within 48 h from the onset of stroke that could statistically significant increase survival rate (RR: 2.16, 95%CI 1.69-2.75, P < 0.00001). Third, sensitivity analyses that measured the results were consistent, indicating that the results were stable. Fourth, the results of statistical power analysis were ≥80%. Finally, the funnel plot of the survival rate included nine RCTs showed no remarkable publication bias. CONCLUSIONS: Our study results indicated that DHC could increase survival rate and favorable functional recovery among patients age ≤60 or >60 years. The optimal time for DHC might be no more than 48 h from the onset of symptoms. However, due to the limitations of this research, it is necessary to design high quality, large-scale RCTs to further evaluate these findings.

Endoplasmic Reticulum Stress Causes Liver Cancer Cells to Release Exosomal miR-23a-3p and Up-regulate Programmed Death Ligand 1 Expression in Macrophages.

Endoplasmic reticulum (ER) stress promotes tumor cell escape from immunosurveillance. However, the underlying mechanisms remain unknown. We hypothesized that ER stress induces hepatocellular carcinoma (HCC) cells to release exosomes, which attenuate antitumor immunity by modulating the expression of programmed death ligand 1 (PD-L1) in macrophages. In this study, we demonstrated that expression of several ER stress markers (glucose-regulated protein 78, activating transcription factor 6, protein kinase R-like ER kinase, and inositol-requiring enzyme 1α) was up-regulated in HCC tissues and negatively correlated with the overall survival and clinicopathological scores in patients with HCC. Expression of ER stress-related proteins positively correlated with CD68+ macrophage recruitment and PD-L1 expression in HCC tissues. High-throughput sequencing analysis identified miR-23a-3p as one of the most abundant microRNAs in exosomes derived from tunicamycin (TM)-treated HCC cells (Exo-TMs). miR-23a-3p levels in HCC tissues negatively correlated with overall survival. Treatment with Exo-TMs up-regulated the expression of PD-L1 in macrophages in vitro and in vivo. Bioinformatics analysis suggests that miR-23a-3p regulates PD-L1 expression through the phosphatase and tensin homolog (PTEN)-phosphatidylinositol 3-kinase-protein kinase B (AKT) pathway. This notion was confirmed by in vitro transfection and coculture experiments, which revealed that miR-23a-3p inhibited PTEN expression and subsequently elevated phosphorylated AKT and PD-L1 expression in macrophages. Finally, coculture of T cells with Exo-TM-stimulated macrophages decreased CD8+ T-cell ratio and interleukin-2 production but increased T-cell apoptosis in vitro. Conclusion: ER-stressed HCC cells release exosomes to up-regulate PD-L1 expression in macrophages, which subsequently inhibits T-cell function through an exosome miR-23a-PTEN-AKT pathway. Our findings provide insight into the mechanism how tumor cells escape from antitumor immunity.

Long Noncoding RNA (lncRNA) Small Nucleolar RNA Host Gene 16 (SNHG16) Predicts Poor Prognosis and Sorafenib Resistance in Hepatocellular Carcinoma.

BACKGROUND Long noncoding RNAs (lncRNAs) play important roles in cancer development and therapeutic resistance. However, the role of small nucleolar RNA host gene 16 (SNHG16) in the development of hepatocellular carcinoma (HCC) remains largely unknown. MATERIAL AND METHODS In situ hybridization (ISH) staining was performed to detect the expression level of SNHG16 in HCC tissues and adjacent non-cancerous tissues. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the level of SNHG16 in HCC samples, adjacent non-cancerous tissues and HCC cell lines. Transwell assay was performed to investigate the migration and invasion ability of HCC cells. Cell viability assays were performed to determine the ability of proliferation and sorafenib resistance of HCC cells. RESULTS We found that SNHG16 was upregulated in HCC tissues and cell lines and that it was negatively correlated with survival time in HCC patients. Univariate and multivariate analyses revealed that SNHG16 was a significant and independent predictor for the overall survival of HCC patients. Furthermore, downregulation of SNHG16 inhibited proliferation, migration, invasion, and sorafenib resistance in hepatocellular carcinoma cell lines. CONCLUSIONS Our findings revealed that lncRNA SNHG16 could be used as an oncogene to predict the outcome of hepatocellular carcinoma.

Undifferentiated sinonasal malignant melanoma: A case report.

Undifferentiated sinonasal malignant melanoma (MM) is a rare type of tumor, which can be easily misdiagnosed. The present study reports a 41-year-old male patient who presented with a 4-day history of epistaxis. Clinical examination and radiological imaging lead to the detection of a mass in the right sinonasal region. Histopathological examination revealed that the mass was composed of malignant epithelioid cells arranged in nests and sheets. These cells displayed a hemangiopericytoma-like pattern with antler-like branching vessels. Immunohistochemical staining revealed that the tumor cells exhibited negative expression of melanocytic markers. This increased the difficulty of distinguishing undifferentiated MM from other malignant tumors located in the sinonasal area, particularly undifferentiated nasopharyngeal carcinoma. The diagnosis of undifferentiated MM was determined by ultrastructures, including the mature melanosomes and premelanosomes, in tumor cells by transmission electron microscopy. The present study suggests that the analysis of cancer stem cell marker and vasculogenic mimicry may be an important auxiliary tool for the diagnosis of MM.

MiR-200c inhibits autophagy and enhances radiosensitivity in breast cancer cells by targeting UBQLN1.

Radioresistance is a major challenge during the treatment of breast cancer. A further understanding of the mechanisms of radioresistance could provide strategies to address this challenge. In our study, we compared the expression of miR-200c in four distinct breast cancer cell lines: two representative basal cancer cells (MDA-MB-231 and BT549) vs. two representative luminal cancer cells (MCF-7 and BT474). The results revealed practically lower expression of miR-200c in the two basal cancer cell lines and higher expression of miR-200c in luminal cancer cells compared to the normal breast epithelial cell line MCF-10A. Ectopic expression of miR-200c in MDA-MB-231 cells inhibited irradiation-induced autophagy and sensitized the breast cancer cells to irradiation. We also identified UBQLN1 as a direct functional target of miR-200c involved in irradiation-induced autophagy and radioresistance. In 35 human breast cancer tissue samples, we detected an inverse correlation between the expression of miR-200c vs. UBQLN1 and LC3. These results indicate that the identified miR-200c/UBQLN1-mediated autophagy pathway may help to elucidate radioresistance in human breast cancer and might represent a therapeutic strategy.

Increased placental growth factor in cerebrospinal fluid of patients with epilepsy.

Recent studies suggest that angiogenesis and vascular endothelial growth factor (VEGF) are involved in the pathophysiology of epilepsy. However, relatively little data are available linking placenta growth factor (PIGF) with epilepsy. In this study, we assessed concentrations of PIGF in cerebrospinal fluid (CSF) of 60 epileptic patients and 24 non-seizure subjects using sandwich enzyme-linked immunosorbent assays. Epileptic patients in general had higher concentration of CSF-PIGF than controls (7.95 ± 0.88 ng/l vs. 5.87 ± 0.79 ng/l, P < 0.01). CSF-PIGF level in secondary epileptic patients (8.59 ± 1.26 ng/l) was higher than that in idiopathic epileptic patients (7.62 ± 0.20 ng/l) (P < 0.05). In idiopathic epilepsy, CSF-PIGF level in patients with high seizure frequency was higher than those in patients with low seizure frequency and seizure-free in recent 3 years (7.78 ± 0.23 ng/l vs. 7.49 ± 0.09 ng/l and 7.59 ± 0.10 ng/l, P < 0.05). Concentration of CSF-PIGF in patients with a disease duration of > 5 years was higher than those in patients with durations of 1-5 years and <1 year (7.72 ± 0.20 ng/l vs. 7.52 ± 0.09 ng/l and 7.41 ± 0.07 ng/l, P < 0.05). These results indicate that preexisting brain damage, seizure frequency and disease duration are important factors contributing to elevated PIGF.

[Expression and relationship of Ezh2, Runx3 and caspase-3 in endometrial adenocarcinoma].

OBJECTIVE: To investigate the role of the expression of Ezh2, Runx3 and caspase-3 proteins and their correlation in the pathogenesis of endometrial carcinoma. METHODS: Expression of Ezh2, Runx3 and caspase-3 proteins was examined by tissue microarray technique and immunohistochemistry (SP method) in 72 cases of endometrial adenocarcinomas, 60 endometrial hyperplasia and 30 normal endometrial tissues. RESULTS: The positive expression rates of Ezh2, Runx3 and caspase-3 proteins in endometrial adenocarcinomas were 83.3% (60/72), 26.4% (19/72) and 33.3% (24/72), respectively. The positive rate of Ezh2 protein in endometrial carcinomas was higher than that in normal endometrium and endometrial hyperplasia (16.7%, 33.3%, 63.3%;P < 0.05). However, the positive rate of Runx3 in endometrial carcinomas was lower than that in normal endometrium and endometrial hyperplasia (80.0%, 56.7%; P < 0.01). The positive rate of caspase-3 protein in endometrial carcinomas was lower than that in normal endometrium and endometrial hyperplasia (86.7%, 73.3%, 63.3%; P < 0.01). Positive expression of Ezh2 and Runx3 was related to the histological grade, FIGO stage, and depth of invasion of endometrial adenocarcinomas (P < 0.05), but it was not related to the lymph node metastasis (P > 0.05). Positive expression of caspase-3 protein was related to the histological grade (P < 0.05), but it was not related to the FIGO stage, depth of invasion and the lymph node metastasis of endometrial adenocarcinomas (P > 0.05). The expression of Ezh2 protein was negatively correlated to that of Runx3 (r(s) = -0.262, P < 0.05). CONCLUSIONS: Abnormal expression of Ezh2, Runx3 and caspase-3 proteins is associated with the development and progression of endometrioid adenocarcinoma. Combined analysis of Ezh2, Runx3 and caspase-3 may offer prognostic information for patients with endometrial cancer.