Targeting epigenetic and post-translational modifications regulating pyroptosis for the treatment of inflammatory diseases.

Inflammatory diseases, including infectious diseases, diabetes-related diseases, arthritis-related diseases, neurological diseases, digestive diseases, and tumor, continue to threaten human health and impose a significant financial burden despite advancements in clinical treatment. Pyroptosis, a pro-inflammatory programmed cell death pathway, plays an important role in the regulation of inflammation. Moderate pyroptosis contributes to the activation of native immunity, whereas excessive pyroptosis is associated with the occurrence and progression of inflammation. Pyroptosis is complicated and tightly controlled by various factors. Accumulating evidence has confirmed that epigenetic modifications and post-translational modifications (PTMs) play vital roles in the regulation of pyroptosis. Epigenetic modifications, which include DNA methylation and histone modifications (such as methylation and acetylation), and post-translational modifications (such as ubiquitination, phosphorylation, and acetylation) precisely manipulate gene expression and protein functions at the transcriptional and post-translational levels, respectively. In this review, we summarize the major pathways of pyroptosis and focus on the regulatory roles and mechanisms of epigenetic and post-translational modifications of pyroptotic components. We also illustrate these within pyroptosis-associated inflammatory diseases. In addition, we discuss the effects of novel therapeutic strategies targeting epigenetic and post-translational modifications on pyroptosis, and provide prospective insight into the regulation of pyroptosis for the treatment of inflammatory diseases.

Transplantation of human neural stem cell prevents symptomatic motor behavior disability in a rat model of Parkinson's disease.

Parkinson's disease (PD) is a ubiquitous brain cell degeneration disease and presents a significant therapeutic challenge. By injecting 6-hydroxydopamine (6-OHDA) into the left medial forebrain bundle, rats were made to exhibit PD-like symptoms and treated by intranasal administration of a low-dose (2 × 105) or high-dose (1 × 106) human neural stem cells (hNSCs). Apomorphine-induced rotation test, stepping test, and open field test were implemented to evaluate the motor behavior and high-performance liquid chromatography was carried out to detect dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin, and 5-hydroxyindole-3-acetic acid in the striatum of rats. Animals injected with 6-OHDA showed significant motor function deficits and damaged dopaminergic system compared to the control group, which can be restored by hNSCs treatment. Treatment with hNSCs significantly increased the tyrosine hydroxylase-immunoreactive cell count in the substantia nigra of PD animals. Moreover, the levels of neurotransmitters exhibited a significant decline in the striatum tissue of animals injected with 6-OHDA when compared to that of the control group. However, transplantation of hNSCs significantly elevated the concentration of DA and DOPAC in the injured side of the striatum. Our study offered experimental evidence to support prospects of hNSCs for clinical application as a cell-based therapy for PD.

The association between plasma GPNMB and Parkinson's disease and multiple system atrophy.

AIMS: Parkinson's disease (PD), as the second most common neurodegenerative disorder, often presents diagnostic challenges in differentiation from other forms of Parkinsonism. Recent studies have reported an association between plasma glycoprotein nonmetastatic melanoma protein B (pGPNMB) and PD. METHODS: A retrospective study was conducted, comprising 401 PD patients, 111 multiple system atrophy (MSA) patients, 13 progressive supranuclear palsy (PSP) patients and 461 healthy controls from the Chinese Han population, with an assessment of pGPNMB levels. RESULTS: The study revealed that pGPNMB concentrations were significantly lower in PD and MSA patients compared to controls (area under the receiver operating characteristics curve (AUC) 0.62 and 0.74, respectively, P < 0.0001 for both), but no difference was found in PSP patients compared to controls (P > 0.05). Interestingly, the level of pGPNMB was significantly higher in PD patients than in MSA patients (AUC = 0.63, P < 0.0001). Furthermore, the study explored the association between pGPNMB levels and disease severity in PD and MSA patients, revealing a positive correlation in PD patients but not in MSA patients with both disease severity and cognitive impairment. CONCLUSION: This study successfully replicated prior findings, demonstrating an association between pGPNMB levels and disease severity, and also identified a correlation with cognitive impairment in PD patients of the Chinese Han population. Additionally, this study is the first to identify a significant difference in pGPNMB levels between MSA, PD, and normal controls. The data provide new evidence supporting the potential role of pGPNMB in the diagnosis and differential diagnosis of Parkinsonism.

Association between CTLA4 + 49A/G polymorphism and risk of hepatocellular carcinoma: a systematic review and meta-analysis.

The aim of this systematic review and meta-analysis was to compile the data examining the association between the CTLA4 + 49 A/G polymorphism and the risk for HCC. Multiple databases were systematically searched for eligible studies and the pooled odds ratios (ORs) were generated using five genetic models. Pooled data from 11 studies with 3,055 HCC patients and 3,450 controls found no statistically significant association between the polymorphism and HCC risk, both overall and in subgroup analyses. In conclusion, the current meta-analysis shows that the CTLA4 + 49 A/G polymorphism is not significantly associated with the risk of developing HCC.

Role of Lipocalin-2 in N1/N2 Neutrophil Polarization After Stroke.

BACKGROUND: Neutrophils and Lipocalin-2 (LCN2) play pivotal roles in cerebral ischemiareperfusion (I/R) injury. However, their contribution is not fully clarified. OBJECTIVE: This study aimed to explore the role of LCN2 and its association with neutrophil polarization in I/R injury. METHODS: A mouse model of middle cerebral artery occlusion (MCAO) was used to induce cerebral ischemia. LCN2mAb was administered 1 h and Anti-Ly6G was administered for 3d before MCAO. The role of LCN2 in the polarity transition of neutrophils was explored using an in vitro HL-60 cell model. RESULTS: LCN2mAb pretreatment had neuroprotective effects in mice. The expression of Ly6G was not significantly different, but the expression of N2 neutrophils was increased. In the in vitro study, LCN2mAb-treated N1-HL-60 cells induced N2-HL-60 polarization. CONCLUSION: LCN2 may affect the prognosis of ischemic stroke by mediating neutrophil polarization.

Screening of potent RIPK3 inhibitors to attenuate necroptosis and inflammation in mouse traumatic brain injury models.

Necroptosis is a type of cell death that occurs when cells are exposed to external stressors such as inflammation, infections, or injury. In necroptosis, cells use a different set of proteins including: receptor-interacting kinase 1 (RIPK1 or RIP1), receptor-interacting kinase 3 (RIPK3 or RIP3) and the phosphorylation of its substrate mixed lineage kinase domain-like protein (MLKL) and pathways to trigger their own death. Mutations in the gene encoding RIPK3 have been associated with many diseases, including neurodegenerative diseases, neuroinflammatory diseases, inflammatory diseases，tumors, and it is being studied as a potential target for inflammatory injury therapy. RIPK3 has also been implicated in the pathology of neuroinflammation following Traumatic brain injury and is currently being explored as a potential therapy. We screened through necroptosis blocking compounds, a library of FDA-approved compounds. We found four compounds:1D6-Foretinib GSK1363089; 15F6-Poziotinib (HM781-36B); 15F9-Dasatinib monohydrate; 15A10-Pexmetinib (ARRY-614); acts as potent inhibitors of necroptosis (Necroptosis Blocking Compounds, NBCs) by blocking the RIPK3 kinase activity. These four compounds effectively block necroptosis induced by death receptor ligands Toll-like receptors as well as viral infections in human, rat and mouse cells. The cellular activation of RIPK3 and MLKL stimulated by necroptosis was strongly inhibited by NBCs. The compounds are promising for targeting RIPK3 kinase activity, thereby preventing necroptosis and inflammatory responses. In our study, we explored the role of NBCs in neuroprotection after traumatic brain injury. It's effectiveness in traumatic brain injury animal models and favorable safety profiles make it a potential candidate for the advances of new therapies for necroptosis-associated neuroinflammatory disorders.

Children with severe neurological symptoms associated with SARS-CoV-2 infection during Omicron pandemic in China.

BACKGROUND: To analyze the clinical characteristics and outcomes of children with severe neurological symptoms associated with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection during the Omicron pandemic in China. METHODS: This study used a questionnaire to obtain data from pediatric intensive care unit (PICU) centers in seven tertiary hospitals in Northeast China from December 1, 2022, to January 31, 2023. RESULTS: A total of 255 patients were confirmed to have SARS-CoV-2 infection, and 45 patients (17.65 %) were included in this study. Of these, seven (15.6%) patients died, and the median time from admission to death was 35 h (IQR, 14-120 h). Twenty (52.6%) survivors experienced neurological sequelae. Patients with platelet counts lower than 100 × 109/L had a higher incidence of complications such as multiple organ dysfunction, mechanical ventilation rate, and mortality. Cranial magnetic resonance imaging (MRI) always reveals cerebral tissue edema, with some severe lesions forming a softening site. CONCLUSION: Children infected with SARS-CoV-2 often exhibit severe neurological symptoms, and in some cases, they may rapidly develop malignant cerebral edema or herniation, leading to a fatal outcome. An early decrease in platelet count may associated with an unfavorable prognosis. IMPACT: Since early December 2022, China has gradually adjusted its prevention and control policy of SARS-CoV-2; Omicron outbreaks have occurred in some areas for a relatively short period. Due to the differences in ethnicity, endemic strains and vaccination status, there was a little difference from what has been reported about children with SARS-CoV-2 infection with severe neurological symptoms in abroad. This is the first multicenter clinical study in children with nervous system involvement after acute SARS-CoV-2 infection in China, and helpful for pediatricians to have a more comprehensive understanding of the clinical symptoms and prognosis of such disease.

Salicylate induces AMPK and inhibits c-MYC to activate a NRF2/ARE/miR-34a/b/c cascade resulting in suppression of colorectal cancer metastasis.

Aspirin and its active metabolite salicylate have emerged as promising agents for the chemoprevention of colorectal cancer (CRC). Moreover, aspirin suppresses the progression of established CRCs. However, the underlying molecular mechanisms are not completely understood. Here we found that salicylate induces the expression of the miR-34a and miR-34b/c genes, which encode tumor suppressive microRNAs, in a p53-independent manner. Salicylate activated AMPK, thereby activating NRF2, which directly induced miR-34a/b/c expression via ARE motifs. In addition, salicylate suppressed c-MYC, a known repressor of NRF2-mediated transactivation, via activating AMPK. The suppression of c-MYC by salicylate was necessary for NRF2-mediated activation of miR-34a/b/c. Inactivation of miR-34a/b/c largely abrogated the inhibitory effects of salicylate on migration, invasion and metastasis formation by CRC cells. In the future, aspirin and its derivates may be used therapeutically to activate miR-34a and miR-34b/c in tumors that have lost p53.

c-MYC/METTL3/LINC01006 positive feedback loop promotes migration, invasion and proliferation of non-small cell lung cancer.

BACKGROUND: This study aims to clarify the N6-methyladenosine (m6A) modification of LINC01006, which is involved in migration, invasion and proliferation of non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: LINC01006 and METTL3 expressions were analyzed in TCGA-LUAD cohort. Colony formation assay, wound-healing assay and transwell assay were performed to evaluate the ability of colony formation, migration and invasion. Q-PCR and western blot analysis determined gene expressions. M6A-RNA immunoprecipitation and m6A quantification assay were used to evaluate m6A modification. qChIP assay was used to validate transcriptional target. Luciferase assay validated the miRNA targets and transcriptional targets. In-situ xenograft model were included to evaluate tumor proliferation in vivo. RESULTS: LINC01006 and METTL3 expressions were elevated in NSCLC cells and tissues. LINC01006 promoted the migration and invasion of NSCLC via epithelial - mesenchymal transition (EMT). The expression of LINC01006 was positively correlated to the expression of METTL3. METTL3 promoted tumor formation and proliferation in the in-situ xenograft model of NSCLC. The expression of LINC01006 was increased by METTL3 via m6A modification. c-MYC directly induced METTL3. Both c-MYC and LINC01006 were commonly targeted by miR-34a/b/c and miR-2682, and thereby c-MYC/METTL3/LINC01006 formed a positive feedback loop through miRNA targets in NSCLC. CONCLUSIONS: LINC01006 is an oncogenic lncRNA, which induces migration, invasion and proliferation of NSCLC. METTL3 increases LINC01006 expression through stabilizing LINC01006 mRNA. c-MYC, as a transcription factor, activates METTL3, which results in an elevated level of LINC01006. c-MYC, METTL3 and LINC01006 form a positive feedback loop through multiple miRNA targets in NSCLC.

[Manipulation of isocitrate dehydrogenase genes affects the anti-autolytic ability of lager yeast].

Yeast autolysis affects the flavor and quality of beer. The regulation of yeast autolysis is a need for industrial beer production. Previous studies on brewer's yeast autolysis showed that the citric acid cycle-related genes had a great influence on yeast autolysis. To explore the contribution of isocitrate dehydrogenase genes in autolysis, the IDP1 and IDP2 genes were destroyed or overexpressed in typical lager yeast Pilsner. The destruction of IDP1 gene improved the anti-autolytic ability of yeast, and the anti-autolytic index after 96 h autolysis was 8.40, 1.5 times higher than that of the original strain. The destruction of IDP1 gene increased the supply of nicotinamide adenine dinucleotide phosphate (NADPH) and the NADPH/NADP+ ratio was 1.94. After fermentation, intracellular ATP level was 1.8 times higher than that of the original strain, while reactive oxygen species (ROS) was reduced by 10%. The destruction of IDP2 gene resulted in rapid autolysis and a decrease in the supply of NADPH. Anti-autolytic index after 96 h autolysis was 4.03 and the NADPH/NADP+ ratio was 0.89. After fermentation, intracellular ATP level was reduced by 8% compared with original strain, ROS was 1.3 times higher than that of the original strain. The results may help understand the regulation mechanism of citric acid cycle-related genes on yeast autolysis and provide a basis for the selection of excellent yeast with controllable anti-autolytic performance.

Expanding the toolset of fluorescent covalent staining of biological samples by labeling carboxylate and phosphate groups.

Recently, fluorescent covalent staining methods have been developed for visualization of anatomical structures in cells and tissues. Coupled with expansion microscopy, these stains revealed various ultrastructural details. However, the covalently stainable chemical groups have been limited to amines, carbohydrates, and thiols. Here, we developed procedures for covalently labeling tissues for carboxylate and phosphate groups, utilizing carbodiimide crosslinker chemistry. In porcine kidney tissues, the carboxylate and phosphate stain provides 1.8-4.8-fold higher signal intensity than those from the three existing stains. In cancer cells, such stain allows 2-8-fold more accurate identification of nucleoli than the amine stain. In expansion microscopy samples, such stain reveals a variety of sub-cellular structures in tissues when combined with the amine stain. Such stain also allows imaging of lipid-based structures in cultured cells. With these advantages, this new covalent staining method further expands the toolset for fluorescent visualization of histology.

Overlapping Epstein-Barr virus encephalitis and autoimmune glial fibrillary acidic protein astrocytopathy.

We describe three cases of overlapping Epstein-Barr virus (EBV) Encephalitis and Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy (GFAP-A). The three cases all presented with initial symptoms of fever, headache, coma, and posture tremor of the upper limbs, then followed by limb weakness and dysuria. All of the three cases were on ventilators. Case 1 and 2 improved dramatically after intravenous methylprednisoloneand immunoglobulin treatment. However, case 3 presented dyspneic, and died from gastrointestinal hemorrhage. The GFAP-A triggered by EBV intracranial infection could initially masquerade as EBV encephalitis only, and the detection of GFAP antibody is essential for differentiation.

PACAP/PAC1-R activation contributes to hyperalgesia in 6-OHDA-induced Parkinson's disease model rats via promoting excitatory synaptic transmission of spinal dorsal horn neurons.

Pain is a common annoying non-motor symptom in Parkinson's disease (PD) that causes distress to patients. Treatment for PD pain remains a big challenge, as its underlying mechanisms are elusive. Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1-R play important roles in regulating a variety of pathophysiological processes. In this study, we investigated whether PACAP/PAC1-R signaling was involved in the mechanisms of PD pain. 6-hydroxydopamine (6-OHDA)-induced PD model was established in rats. Behavioral tests, electrophysiological and Western blotting analysis were conducted 3 weeks later. We found that 6-OHDA rats had significantly lower mechanical paw withdrawal 50% threshold in von Frey filament test and shorter tail flick latency, while mRNA levels of Pacap and Adcyap1r1 (gene encoding PAC1-R) in the spinal dorsal horn were significantly upregulated. Whole-cell recordings from coronal spinal cord slices at L4-L6 revealed that the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in dorsal horn neurons was significantly increased, which was reversed by application of a PAC1-R antagonist PACAP 6-38 (250 nM). Furthermore, we demonstrated that intrathecal microinjection of PACAP 6-38 (0.125, 0.5, 2 µg) dose-dependently ameliorated the mechanical and thermal hyperalgesia in 6-OHDA rats. Inhibition of PACAP/PAC1-R signaling significantly suppressed the activation of Ca2+/calmodulin-dependent protein kinase II and extracellular signal-regulated kinase (ERK) in spinal dorsal horn of 6-OHDA rats. Microinjection of pAAV-Adcyap1r1 into L4-L6 spinal dorsal horn alleviated hyperalgesia in 6-OHDA rats. Intrathecal microinjection of ERK antagonist PD98059 (10 µg) significantly alleviated hyperalgesia in 6-OHDA rats associated with the inhibition of sEPSCs in dorsal horn neurons. In addition, we found that serum PACAP-38 concentration was significantly increased in PD patients with pain, and positively correlated with numerical rating scale score. In conclusion, activation of PACAP/PAC1-R induces the development of PD pain and targeting PACAP/PAC1-R is an alternative strategy for treating PD pain.

Cystathionine ß-Synthase Suppresses NLRP3 Inflammasome Activation via Redox Regulation in Microglia.

Aims: Cystathionine ß-synthase (CBS) is essential for homocysteine (Hcy) transsulfuration, yielding cysteine as a common precursor of hydrogen sulfide (H2S), glutathione (GSH), and other sulfur molecules, which produce neuroprotective effects in neurological conditions. We previously reported a disruption of microglial CBS/H2S signaling in a Parkinson's disease (PD) mouse model. Yet, it remains unclear whether CBS affects nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome activity and other pathologies in PD. Results: Microglial CBS expression decreased after lipopolysaccharide (LPS) stimulation. Elevated GSSG (the oxidized GSH) content and decreased H2S generation were found in the brains of microglial cbs conditional-knockout (cbscKO) mice, whereas serum and brain Hcy levels remained unaltered. Moreover, microglial cbscKO mice were susceptible to NLRP3 inflammasome activation and dopaminergic neuron losses caused by LPS injection into the substantia nigra, whereas cbs overexpression or activation produced opposite effects. In vitro studies showed that cbs overexpression or activation suppressed microglial NLRP3 inflammasome activation and interleukin (IL)-1ß secretion by reducing mitochondrial reactive oxygen species (mitoROS) level. Conversely, ablation of cbs enhanced NLRP3 expression and mitoROS generation and augmented microglial NLRP3 inflammasome activity in response to adenosine triphosphate challenge, which was blocked by the mitoROS scavenger. Innovation and Conclusion: The study demonstrated an elevated GSSG level and reduced H2S generation, which correlated with a susceptible status of microglia in the brain of cbscKO mice. Our findings reveal a critical role of CBS in restraining the microglial NLRP3 inflammasome by controlling redox homeostasis and highlight that activation or upregulation of CBS may become a potential strategy for PD treatment.

Roles of protein post-translational modifications in glucose and lipid metabolism: mechanisms and perspectives.

The metabolism of glucose and lipids is essential for energy production in the body, and dysregulation of the metabolic pathways of these molecules is implicated in various acute and chronic diseases, such as type 2 diabetes, Alzheimer's disease, atherosclerosis (AS), obesity, tumor, and sepsis. Post-translational modifications (PTMs) of proteins, which involve the addition or removal of covalent functional groups, play a crucial role in regulating protein structure, localization function, and activity. Common PTMs include phosphorylation, acetylation, ubiquitination, methylation, and glycosylation. Emerging evidence indicates that PTMs are significant in modulating glucose and lipid metabolism by modifying key enzymes or proteins. In this review, we summarize the current understanding of the role and regulatory mechanisms of PTMs in glucose and lipid metabolism, with a focus on their involvement in disease progression associated with aberrant metabolism. Furthermore, we discuss the future prospects of PTMs, highlighting their potential for gaining deeper insights into glucose and lipid metabolism and related diseases.

Curcumin activates a ROS/KEAP1/NRF2/miR-34a/b/c cascade to suppress colorectal cancer metastasis.

Curcumin, a natural phytochemical isolated from tumeric roots, represents a candidate for prevention and therapy of colorectal cancer/CRC. However, the exact mechanism of action and the downstream mediators of curcumin's tumor suppressive effects have remained largely unknown. Here we used a genetic approach to determine the role of the p53/miR-34 pathway as mediator of the effects of curcumin. Three isogenic CRC cell lines rendered deficient for the p53, miR-34a and/or miR-34b/c genes were exposed to curcumin and subjected to cell biological analyses. siRNA-mediated inhibition and ectopic expression of NRF2, as well as Western blot, qPCR and qChIP analyses of its target genes were performed. CRC cells were i.v. injected into NOD/SCID mice and lung-metastases formation was determined by longitudinal, non-invasive imaging. In CRC cells curcumin induced apoptosis and senescence, and suppressed migration and invasion in a p53-independent manner. Curcumin activated the KEAP1/NRF2/ARE pathway by inducing ROS. Notably, curcumin induced miR-34a and miR-34b/c expression in a ROS/NRF2-dependent and p53-independent manner. NRF2 directly induced miR-34a and miR-34b/c via occupying multiple ARE motifs in their promoter regions. Curcumin reverted repression of miR-34a and miR-34b/c induced by IL6 and hypoxia. Deletion of miR-34a and miR-34b/c significantly reduced curcumin-induced apoptosis and senescence, and prevented the inhibition of migration and invasion by curcumin or ectopic NRF2. In CRC cells curcumin induced MET and prevented the formation of lung-metastases in mice in a miR-34a-dependent manner. In addition, we found that curcumin may enhance the therapeutic effects of 5-FU on CRC cells deficient for p53 and miR-34a/b/c. Activation of the KEAP1/NRF2/miR-34a/b/c axis mediates the tumor suppressive activity of curcumin and suggests a new approach for activating miR-34 genes in tumors for therapeutic purposes.

Identification of an individualized therapy prognostic signature for head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) are the most common cancers in the head and neck. Therapeutic response-related genes (TRRGs) are closely associated with carcinogenesis and prognosis in HNSCC. However, the clinical value and prognostic significance of TRRGs are still unclear. We aimed to construct a prognostic risk model to predict therapy response and prognosis in TRRGs-defined subgroups of HNSCC. METHODS: The multiomics data and clinical information of HNSCC patients were downloaded from The Cancer Genome Atlas (TCGA). The profile data GSE65858 and GSE67614 chip was downloaded from public functional genomics data Gene Expression Omnibus (GEO). Based on TCGA-HNSC database, patients were divided into a remission group and a non-remission group according to therapy response, and differentially expressed TRRGs between those two groups were screened. Using Cox regression analysis and Least absolute shrinkage and selection operator (LASSO) analysis, candidate TRRGs that can predict the prognosis of HNSCC were identified and used to construct a TRRGs-based signature and a prognostic nomogram. RESULT: A total of 1896 differentially expressed TRRGs were screened, including 1530 upregulated genes and 366 downregulated genes. Then, 206 differently expressed TRRGs that was significantly associated with the survival were chosen using univariate Cox regression analysis. Finally, a total of 20 candidate TRRGs genes were identified by LASSO analysis to establish a signature for risk prediction, and the risk score of each patient was calculated. Patients were divided into a high-risk group (Risk-H) and a low-risk group (Risk-L) based on the risk score. Results showed that the Risk-L patients had better overall survival (OS) than Risk-H patients. Receiver operating characteristic (ROC) curve analysis revealed great predictive performance for 1-, 3-, and 5-year OS in TCGA-HNSC and GEO databases. Moreover, for patients treated with post-operative radiotherapy, Risk-L patients had longer OS and lower recurrence than Risk-H patients. The nomogram involves risk score and other clinical factors had good performance in predicting survival probability. CONCLUSIONS: The proposed risk prognostic signature and Nomogram based on TRRGs are novel promising tools for predicting therapy response and overall survival in HNSCC patients.

Dual-Regulated Mechanism of EZH2 and KDM6A on SALL4 Modulates Tumor Progression via Wnt/ß-Catenin Pathway in Gastric Cancer.

BACKGROUND: SALL4 has been demonstrated in many cancers and participated in tumorigenesis and tumor progression, however, its expression and function still remain ambiguous in GC, especially its upstream mechanistic modulators. PURPOSE: We explored whether the dual mediation of EZH2 and KDM6A could be involved in upstream regulation of SALL4, which promotes GC cell progression via the Wnt/ß-catenin pathway. METHOD: Analysis of discrepant gene expression in GC and normal gastric tissues from The Cancer Genome Atlas (TCGA) dataset. GC cell lines were transfected by siEZH2 and siKDM6A, the transduction molecules of KDM6A/EZH2-SALL4-ß-catenin signaling were quantified in the GC cells. RESULTS: Here, we showed that only SALL4 levels of SALL family members were upregulated in nonpaired and paired GC tissues than those in corresponding normal tissues and were associated with its histological types, pathological stages, TNM stages including T stage (local invasion), N stage (lymph node metastasis), M stage (distant metastasis), and overall survival from the TCGA dataset. SALL4 level was elevated in GC cells compared to normal gastric epithelial cell line (GES-1) and was correlated to cancer cell progression and invasion through the Wnt/ß-catenin pathway in GC, which levels would be separately upregulated or downregulated by KDM6A or EZH2. CONCLUSION: We first proposed and demonstrated that SALL4 promoted GC cell progression via the Wnt/ß-catenin pathway, which was mediated by the dual regulation of EZH2 and KDM6A on SALL4. This mechanistic pathway in gastric cancer represents a novel targetable pathway.

miR-199a-3p promotes gastric cancer progression by promoting its stemness potential via DDR2 mediation.

BACKGROUND: Peritoneal metastasis (PM) is an independent prognostic factor in gastric cancer (GC), however, the underlying mechanisms of PM occurrence remain unclear. METHOD: The roles of DDR2 were investigated in GC and its potential relationship to PM, and orthotopic implants into nude mice were performed to assess the biological effects of DDR2 on PM. RESULTS: Herein, DDR2 level is more significantly observed to elevate in PM lesion than the primary lesion. GC with DDR2-high expression evokes a worse overall survival (OS) in TCGA, similar results of the gloomy OS with high DDR2 levels are clarified via the stratifying stage of TNM. The conspicuously increased expression of DDR2 was found in GC cell lines, luciferase reporter assays verified that miR-199a-3p directly targeted DDR2 gene, which was correlated to tumor progression. We ulteriorly observed DDR2 participated in GC stemness maintenance via mediating pluripotency factor SOX2 expression and implicated in autophagy and DNA damage of cancer stem cells (CSCs). In particular, DDR2 dominated EMT programming through recruiting NFATc1-SOX2 complex to Snai1 in governing cell progression, controlling by DDR2-mTOR-SOX2 axis in SGC-7901 CSCs. Furthermore, DDR2 promoted the tumor peritoneal dissemination in gastric xenograft mouse model. CONCLUSION: Phenotype screens and disseminated verifications incriminating in GC exposit the miR-199a-3p-DDR2-mTOR-SOX2 axis as a clinically actionable target for tumor PM progression. The herein-reported DDR2-based underlying axis in GC represents novel and potent tools for studying the mechanisms of PM.

Plasma sDPP4 (Soluble Dipeptidyl Peptidase-4) and Cognitive Impairment After Noncardioembolic Acute Ischemic Stroke.

BACKGROUND: DPP4 (dipeptidyl peptidase-4) inhibitors have been proven to promote neuronal regeneration, reverse the development of cognitive deficits. However, the association of circulating soluble form (sDPP4 [soluble DPP4]) with poststroke cognitive impairment (PSCI) is unclear. We aimed to investigate the association between plasma sDPP4 levels and PSCI in patients with ischemic stroke. METHODS: A total of 600 noncardioembolic stroke patients were included based on a preplanned ancillary study from the CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). We used the Montreal Cognitive Assessment to evaluate cognitive function at 3 months follow-up after ischemic stroke. Binary logistic regression analyses were performed to investigate the association of plasma sDPP4 levels with subsequent PSCI. We further calculated integrated discrimination improvement and category-free net reclassification improvement to investigate the incremental prognostic effect of plasma sDPP4 beyond the basic model with conventional risk factors. RESULTS: Plasma sDPP4 was inversely associated with PSCI after ischemic stroke, and the adjusted odds ratio (95% CI) for the highest versus lowest quartile of sDPP4 was 0.49 (0.29-0.81; P for trend=0.011). Each 1-SD increase of logarithm-transformed plasma sDPP4 concentration was associated with 17% (odds ratio, 0.83 [95% CI, 0.70-0.99]) lower risk of PSCI. Adding plasma sDPP4 to the basic model notably improved risk reclassification for PSCI, as shown by a category-free net reclassification improvement of 19.10% (95% CI, 2.52%-35.68%; P=0.03) and integrated discrimination improvement of 0.79% (95% CI, 0.13%-1.46%; P=0.02). CONCLUSIONS: Higher plasma sDPP4 levels were associated with decreased risk of cognitive impairment after noncardioembolic ischemic stroke.