Colorectal cancer (CRC) is one of the most common malignant carcinomas in the world, and metastasis is the main cause of CRC-related death. However, the molecular network involved in CRC metastasis ...remains poorly understood. Long noncoding RNA (lncRNA) plays a vital role in tumorigenesis and may act as a competing endogenous RNA (ceRNA) to affect the expression of mRNA by suppressing miRNA function. In this study, we identified 628 mRNAs, 144 lncRNAs, and 25 miRNAs that are differentially expressed (DE) in metastatic CRC patients compared with nonmetastatic CRC patients from the Cancer Genome Atlas (TCGA) database. Functional enrichment analyses confirmed that the identified DE mRNAs are extensively involved in CRC tumorigenesis and migration. By bioinformatics analysis, we constructed a metastasis-associated ceRNA network for CRC that includes 28 mRNAs, 12 lncRNAs, and 15 miRNAs. We then performed multivariate Cox regression analysis on the ceRNA-related DE lncRNAs and identified a 3-lncRNA signature (LINC00114, LINC00261, and HOTAIR) with the greatest prognostic value for CRC. Clinical feature analysis and functional enrichment analysis further proved that these three lncRNAs are involved in CRC tumorigenesis. Finally, we used Transwell, Cell Counting Kit (CCK)-8, and colony formation assays to clarify that the inhibition of LINC00114 promotes the migratory, invasive, and proliferative abilities of CRC cells. The results of the luciferase assay suggest that LINC00114 is the direct target of miR-135a, which also verified the ceRNA network. In summary, this study provides a metastasis-associated ceRNA network for CRC and suggests that the 3-lncRNA signature may be a useful candidate for the diagnosis and prognosis of CRC.
Mixed-lineage kinase domain-like protein (MLKL) is essential for TNF-α–induced necroptosis. How MLKL promotes cell death is still under debate. Here we report that MLKL forms SDS-resistant, disulfide ...bond-dependent polymers during necroptosis in both human and mouse cells. MLKL polymers are independent of receptor-interacting protein kinase 1 and 3 (RIPK1/RIPK3) fibers. Large MLKL polymers are more than 2 million Da and are resistant to proteinase K digestion. MLKL polymers are fibers 5 nm in diameter under electron microscopy. Furthermore, the recombinant N-terminal domain of MLKL forms amyloid-like fibers and binds Congo red dye. MLKL mutants that cannot form polymers also fail to induce necroptosis efficiently. Finally, the compound necrosulfonamide conjugates cysteine 86 of human MLKL and blocks MLKL polymer formation and subsequent cell death. These results demonstrate that disulfide bond-dependent, amyloid-like MLKL polymers are necessary and sufficient to induce necroptosis.
Tumor infiltrating lymphocytes may indicate an immune response to cancer development, but their significance remains controversial in breast cancer. We conducted this study to assess CD8+ (cytotoxic ...T) lymphocyte infiltration in a large cohort of invasive early stage breast cancers, and to evaluate its prognostic effect in different breast cancer intrinsic subtypes.
Immunohistochemistry for CD8 staining was performed on tissue microarrays from 3992 breast cancer patients. CD8+ tumor infiltrating lymphocytes were counted as intratumoral when in direct contact with tumor cells, and as stromal in adjacent locations. Kaplan-Meier functions and Cox proportional hazards regression models were applied to examine the associations between tumor infiltrating lymphocytes and breast cancer specific survival.
Among 3403 cases for which immunohistochemical results were obtained, CD8+ tumor infiltrating lymphocytes were identified in an intratumoral pattern in 32% and stromal pattern in 61% of the cases. In the whole cohort, the presence of intratumoral tumor-infiltrating lymphocytes was significantly correlated with young age, high grade, estrogen receptor negativity, human epidermal growth factor receptor-2 positivity and core basal intrinsic subtype, and was associated with superior breast cancer specific survival. Multivariate analysis indicated that the favorable prognostic effect of CD8+ tumor infiltrating lymphocytes was significant only in the core basal intrinsic subgroup (Hazard ratio, HR = 0.35, 95% CI = 0.23-0.54). No association with improved survival was present in those triple negative breast cancers that lack expression of basal markers (HR = 0.99, 95% CI = 0.48-2.04) nor in the other intrinsic subtypes.
CD8+ tumor infiltrating lymphocytes are an independent prognostic factor associated with better patient survival in basal-like breast cancer, but not in non-basal triple negative breast cancers nor in other intrinsic molecular subtypes.
Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcriptional factor widely expressed among immune, epithelial, endothelial and stromal cells in barrier tissues. It can be activated by small ...molecules provided by pollutants, microorganisms, food, and metabolism. It has been demonstrated that AHR plays an important role in modulating the response to many microbial pathogens, and the abnormal expression of AHR signaling pathways may disrupt endocrine, cause immunotoxicity, and even lead to the occurrence of cancer. Most humans are infected with at least one known human cancer virus. While the initial infection with these viruses does not cause major disease, the metabolic activity of infected cells changes, thus affecting the activation of oncogenic signaling pathways. In the past few years, lots of studies have shown that viral infections can affect disease progression by regulating the transmission of multiple signaling pathways. This review aims to discuss the potential effects of virus infections on AHR signaling pathways so that we may find a new strategy to minimize the adverse effects of the AHR pathway on diseases. Video Abstract.
Previous reports revealed that peel extracts of
(fig) have a wide range of pharmacological and biological activities. The current study aimed to determine the phytochemical components of the ethanol ...extracts of Peggy Red fig (PRF) and Green fig (GF) peels by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, along with its antioxidant properties and neuroprotective effect in
. LC-MS/MS analysis confirmed 50 compounds in the extract, which revealed the presence of phenols, flavonoids, and anthocyanins, and exhibited
antioxidant activity. PRF and GF peel had 163.25 (mg gallic acid equivalent mg GAE) g
, 125.32 (mg GAE) g
of total phenolic content, 62.52 (mg rutin equivalent mg RE) g
, and 43.36 (mg RE) g
flavonoids content, respectively. In all antioxidant assays, the extract of PRF peel showed higher antioxidant activity than the GF peel, and the extract of PRF peel could effectively reduce the aggregation of amyloid-beta (A
), decrease the paralysis of the body, and increase the antioxidant enzyme activities to reduce the toxicity of A
in Alzheimer's disease (AD) transgenic
CL4176. Therefore, PRF peel extract may have potential applications as a new source for drug development against AD.
Intracerebral hemorrhage (ICH) is a serious cerebrovascular disease with high rates of morbidity, mortality, and disability. Optimal treatment of ICH is a major clinical challenge, as the underlying ...mechanisms remain unclear. Ferroptosis, a newly identified form of non-apoptotic programmed cell death, is characterized by the iron-induced accumulation of lipid reactive oxygen species (ROS), leading to intracellular oxidative stress. Lipid ROS causes damage to nucleic acids, proteins, and cell membranes, eventually resulting in ferroptosis. In the past 10 years, ferroptosis has resulted in plenty of discoveries and breakthroughs in cancer, neurodegeneration, and other diseases. Some studies have also reported that ferroptosis does occur after ICH
and
and contribute to neuronal death. However, the studies on ferroptosis following ICH are still in the preliminary stage. In this review, we will summarize the current evidence on the mechanism underlying ferroptosis after ICH. And review the traditional modes of neuronal death to identify the crosstalk with ferroptosis in ICH, including apoptosis, necroptosis, and autophagy. Additionally, we also aim to explore the promising therapeutic application of ferroptosis in cell death-based ICH.
Receptor-interacting protein kinase 1 (RIPK1) is a key regulator of inflammation and cell death. Many sites on RIPK1, including serine 25, are phosphorylated to inhibit its kinase activity and cell ...death. How these inhibitory phosphorylation sites are dephosphorylated is poorly understood. Using a sensitized CRISPR whole-genome knockout screen, we discover that protein phosphatase 1 regulatory subunit 3G (PPP1R3G) is required for RIPK1-dependent apoptosis and type I necroptosis. Mechanistically, PPP1R3G recruits its catalytic subunit protein phosphatase 1 gamma (PP1γ) to complex I to remove inhibitory phosphorylations of RIPK1. A PPP1R3G mutant which does not bind PP1γ fails to rescue RIPK1 activation and cell death. Furthermore, chemical prevention of RIPK1 inhibitory phosphorylations or mutation of serine 25 of RIPK1 to alanine largely restores cell death in PPP1R3G-knockout cells. Finally, Ppp1r3g
mice are protected from tumor necrosis factor-induced systemic inflammatory response syndrome, confirming the important role of PPP1R3G in regulating apoptosis and necroptosis in vivo.
Metastasis is a well-known poor prognostic factor and primary cause of mortality in patients with colorectal cancer (CRC). Recently, with the progress of high through-put sequencing, aberrantly ...expressed non-coding RNAs (ncRNAs) were found to participate in the initiation and development of cancer. However, the mechanisms of ncRNA-mediated regulation of metastasis in CRC remain largely unknown. In this study, we systematically analyzed the expression network of microRNAs (miRNAs) and genes in CRC metastasis using bioinformatics, and discovered that the miR-581/SMAD7 axis could be a potential factor that drives CRC metastasis. A dual luciferase report assay and protein analysis confirmed the binding relationship between miR-581 and SMAD7. Further functional assays revealed that miR-581 inhibition could suppress cell proliferation and induce apoptosis in SW480 cells. Up-regulation or down-regulation of miR-581 could both affect cell invasion capacity and modulate epithelial to mesenchymal transition (EMT) via a SMAD7/TGFβ signaling pathway. In conclusion, our findings elucidated that miR-581/SMAD7 could be essential for CRC metastasis, and may serve as a potential therapeutic target for CRC patients.
The aim of the present Bayesian network meta-analysis (NMA) was to explore the comparative effectiveness and safeaty of different Chinese Medicine injections (CMIs) combined with the XELOX regimen
...XELOX alone for colorectal cancer (CRC).
A comprehensive search for randomized controlled trials (RCTs) was performed with regard to different CMIs for the treatment of CRC in several electronic databases up to April 2022. The quality assessment of the included RCTs was conducted according to the Cochrane risk of bias tool. Standard pair-wise and Bayesian NMA were designed to comparethe effectiveness and safety of different CMIs combined with the XELOX regimen by utilizing R 4.0.3 software and Stata 15.1 software simultaneously.
Initially, a total of 4296 citations were retrieved through comprehensive searching, and 32 eligible articles involving 2847 participants and 11 CMIs were ultimately included. CMIs combined with XELOX were superior to the XELOX regimen alone, and a total of ten Observation Indicators were included in the study, with the following results. Among all the injections, Shengmaiyin, Shenmai, and Kanglaite combined with the XELOX regimen were the three CMIs with the highest clinical efficiency. The top three in terms of improving CD3
values were Shengmaiyin, Shenqifuzheng, and Cinobufacini injections. Shenqifuzheng, Shengmaiyin, and BruceaJavanica oil injections combined with the XELOX regimen performed best at raising CD4
values. Kanglaite, Cinobufacini, and Matrine injections combined with the XELOX regimen performed best in improving CD4+/CD8+ rates. The top three in terms of improving performance status were Xiaoaiping, Shenmai, and Kanglaite injections. Cinobufacini and Brucea Javanica oil injections combined with the XELOX regimen performed best at raising CD8
values. Shenqifuzheng, Kangai, and Matrine injections combined with the XELOX regimen performed best in improving Gastrointestinal reactions.The top threein terms of improving Leukopenia were Shenqifuzheng, Compound Kushen and Kanglaite injections. The top three in terms of improving Platelet decline were Compound Kushen, Cinobufacini and Shenqifuzheng injections. Additionally, those that were best at improving nausea and vomitting were Cinobufacini, Compound Kushen and Aidi injections.
The results of the analysis demonstrated thatShengmaiyin, Kanglaite, and Cinobufacini injections and the XELOX regimen were associated with morepreferable and beneficial outcomes than other CMI groups. Nevertheless, additional results from multicenter trials and high-quality studies will bevital to support our findings.
https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=326097, CRD42022326097.
Based on the social identity theory, the relationship and influencing mechanism between high-performance human resource practices (HPHRPs) and employees' voice behavior were explored by constructing ...a moderated mediation model, and the relationship between the field of human resources and the field of organizational behavior was also established. Through 1,178 paired samples of supervisor-employee survey and multilevel linear model analysis technology, it was found that (1) HPHRPs had a positive impact on employees' voice behavior; (2) perceived insider status played a mediating role between HPHRPs and voice behavior; (3) voice efficacy played a moderating role between perceived insider status and voice behavior; and (4) voice efficacy played a mediating role in the relationship between "HPHRPs-perceived insider status-voice behavior."
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