Interceed combined with bone marrow mesenchymal stem cells improves endometrial receptivity of intrauterine adhesion.

Background: This study aimed to investigate the impact of intrauterine adhesions (IUA) therapy and endometrial receptivity by implanting autologous bone marrow mesenchymal stem cells (BMSCs) into the Interceed and subsequently placing them in the uterine cavity of rats. Methods: Fifty rats were divided into 5 groups according to the random number table method (10 rats in each group). Following the development of the IUA model through mechanical injury, the animals were categorized into different treatment groups: the IUA model (intrauterine perfusion of saline), Interceed therapy (intrauterine placement of Interceed), BMSCs therapy (intrauterine perfusion of BMSCs), BMSCs + Interceed therapy (intrauterine placement of BMSCs + Interceed), and a control group (intrauterine perfusion of saline). The Hematoxylin-eosin (HE) staining technique was employed to identify and assess the pathological alterations in the endometrium. Additionally, it facilitated the quantification of endometrial glands and the determination of endometrial thickness. Masson staining was used to detect fibrosis in rat uterus. The number of microvascular density (MVD) was detected by immunohistochemistry (IHC). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot were used to detect the levels of leukemia inhibitory factor (LIF), integrin ανß3, and vascular endothelial growth factor (VEGF) in uterine tissue. Male and female rats were combined in cages for reproductive and conception evaluation. Results: In comparison to the control, the number of endometrial glands in the IUA model was significantly reduced, and the degree of endometrial thinning and fibrosis was significantly increased (p < 0.05). Compared with the IUA model, the number of endometrial glands did not exhibit any significant alterations in endometrial thickness and MVD number. The expressions of LIF, integrin ανß3, and VEGF in the uterine tissue were not significantly improved with Interceed therapy, resulting in no significant improvement in the pregnancy rate (p > 0.05). The number of endometrial glands, endometrial thickness, and MVD in the BMSCs therapy group were significantly increased. Moreover, the expressions of LIF, integrin ανß3, and VEGF in uterine tissue exhibited a significant increase, leading to a comparatively higher pregnancy rate (p < 0.05). In the BMSCs + Interceed therapy group, the number of endometrial glands, endometrial thickness, and MVD were significantly increased, and the expressions of LIF, integrin ανß3, and VEGF in uterine tissue were significantly increased as well, along with a corresponding rise in the pregnancy rate (p < 0.05). Conclusion: The intrauterine placement of Interceed combined with BMSCs in IUA rats can thicken the damaged endometrium, increase the number of glands, promote endometrial angiogenesis, improve endometrial receptivity, and increase the rate of pregnancy in IUA rats.

Taurine attenuates activation of hepatic stellate cells by inhibiting autophagy and inducing ferroptosis.

BACKGROUND: Liver fibrosis is a compensatory response during the tissue repair process in chronic liver injury, and finally leads to liver cirrhosis or even hepatocellular carcinoma. The pathogenesis of hepatic fibrosis is associated with the progressive accumulation of activated hepatic stellate cells (HSCs), which can transdifferentiate into myofibroblasts to produce an excess of the extracellular matrix (ECM). Myofibroblasts are the main source of the excessive ECM responsible for hepatic fibrosis. Therefore, activated hepatic stellate cells (aHSCs), the principal ECM producing cells in the injured liver, are a promising therapeutic target for the treatment of hepatic fibrosis. AIM: To explore the effect of taurine on aHSC proliferation and the mechanisms involved. METHODS: Human HSCs (LX-2) were randomly divided into five groups: Normal control group, platelet-derived growth factor-BB (PDGF-BB) (20 ng/mL) treated group, and low, medium, and high dosage of taurine (10 mmol/L, 50 mmol/L, and 100 mmol/L, respectively) with PDGF-BB (20 ng/mL) treated group. Cell Counting Kit-8 method was performed to evaluate the effect of taurine on the viability of aHSCs. Enzyme-linked immunosorbent assay was used to estimate the effect of taurine on the levels of reactive oxygen species (ROS), malondialdehyde, glutathione, and iron concentration. Transmission electron microscopy was applied to observe the effect of taurine on the autophagosomes and ferroptosis features in aHSCs. Quantitative real-time polymerase chain reaction and Western blot analysis were performed to detect the effect of taurine on the expression of α-SMA, Collagen I, Fibronectin 1, LC3B, ATG5, Beclin 1, PTGS2, SLC7A11, and p62. RESULTS: Taurine promoted the death of aHSCs and reduced the deposition of the ECM. Treatment with taurine could alleviate autophagy in HSCs to inhibit their activation, by decreasing autophagosome formation, downregulating LC3B and Beclin 1 protein expression, and upregulating p62 protein expression. Meanwhile, treatment with taurine triggered ferroptosis and ferritinophagy to eliminate aHSCs characterized by iron overload, lipid ROS accumulation, glutathione depletion, and lipid peroxidation. Furthermore, bioinformatics analysis demonstrated that taurine had a direct targeting effect on nuclear receptor coactivator 4, exhibiting the best average binding affinity of -20.99 kcal/mol. CONCLUSION: Taurine exerts therapeutic effects on liver fibrosis via mechanisms that involve inhibition of autophagy and trigger of ferroptosis and ferritinophagy in HSCs to eliminate aHSCs.

Bioactive poly(salicylic acid)-poly(citric acid) scaffolds improve diabetic wound repair via regulating HIF-1α, Nrf2 and macrophage.

Diabetic wounds environment is over-oxidized, over-inflammatory, leading to difficulties in regenerating blood vessels, and retardation of healing in diabetic wounds. Therefore, diabetic wounds can be treated from the perspective of scavenging oxidative free radicals and reducing the level of inflammation. Herein, we report a bioactive poly(salicylic acid)-poly(citric acid) (FPSa-PCG) hydrogel for diabetic wound repair. The FPSa-PCG hydrogel shows abilities of antioxidation, anti-inflammation, and regulation of macrophage phenotype. The FPSa-PCG hydrogel showed good biocompatibility, and obtain the abilities of promotion of macrophages migration, reduction of ROS generation, suppression of the M1-type macrophage polarization. FPSa and PCG could synergistically enhance the angiogenesis through upregulating the mRNA expression of HIF1Α, VEGF, and CD31 in endothelial cells and reduce the ROS level of macrophages through upregulating the mRNA expression of Nrf2. The in vivo diabetic wound model confirmed the promoting effect of FPSa-PCG hydrogel on wound closure in diabetes. The further studies found that FPSa-PCG hydrogel could induce the CD31 protein expression in the subcutaneous tissue and inhibit the TNF-a protein expression. This work shows that the simple composition FPSa-PCG hydrogel has a promising therapeutic potential in the treatment of diabetic wounds.

Long-read sequencing unveils novel somatic variants and methylation patterns in the genetic information system of early lung cancer.

Lung cancer poses a global health challenge, necessitating advanced diagnostics for improved outcomes. Intensive efforts are ongoing to pinpoint early detection biomarkers, such as genomic variations and DNA methylation, to elevate diagnostic precision. We conducted long-read sequencing on cancerous and adjacent non-cancerous tissues from a patient with lung adenocarcinoma. We identified somatic structural variations (SVs) specific to lung cancer by integrating data from various SV calling methods and differentially methylated regions (DMRs) that were distinct between these two tissue samples, revealing a unique methylation pattern associated with lung cancer. This study discovered over 40,000 somatic SVs and over 180,000 DMRs linked to lung cancer. We identified approximately 700 genes of significant relevance through comprehensive analysis, including genes intricately associated with many lung cancers, such as NOTCH1, SMOC2, CSMD2, and others. Furthermore, we observed that somatic SVs and DMRs were substantially enriched in several pathways, such as axon guidance signaling pathways, which suggests a comprehensive multi-omics impact on lung cancer progression across various biological investigation levels. These datasets can potentially serve as biomarkers for early lung cancer detection and may hold significant value in clinical diagnosis and treatment applications.

NEAT1 repression by MED12 creates chemosensitivity in p53 wild-type breast cancer cells.

Breast cancer is often treated with chemotherapy. However, the development of chemoresistance results in treatment failure. Long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been shown to contribute to chemoresistance in breast cancer cells. In studying the transcriptional regulation of NEAT1 using multi-omics approaches, we showed that NEAT1 is up-regulated by 5-fluorouracil in breast cancer cells with wild-type cellular tumor antigen p53 but not in mutant-p53-expressing breast cancer cells. The regulation of NEAT1 involves mediator complex subunit 12 (MED12)-mediated repression of histone acetylation marks at the promoter region of NEAT1. Knockdown of MED12 but not coactivator-associated arginine methyltransferase 1 (CARM1) induced histone acetylation at the NEAT1 promoter, leading to elevated NEAT1 mRNAs, resulting in a chemoresistant phenotype. The MED12-dependent regulation of NEAT1 differs between wild-type and mutant p53-expressing cells. MED12 depletion led to increased expression of NEAT1 in a wild-type p53 cell line, but decreased expression in a mutant p53 cell line. Chemoresistance caused by MED12 depletion can be partially rescued by NEAT1 knockdown in p53 wild-type cells. Collectively, our study reveals a novel mechanism of chemoresistance dependent on MED12 transcriptional regulation of NEAT1 in p53 wild-type breast cancer cells.

Mammographically detected breast clustered microcalcifications localized by chest thin-section computed tomography.

BACKGROUND: To explore the capability and clinical significance of chest thin-section computed tomography (CT) for localization of mammographically detected clustered microcalcifications. METHODS: A total of 69 patients with 71 mammographically detected clustered microcalcifications received surgical biopsy under the guidance of mammography (MG), CT was used to localize calcifications combined with MG if calcifications can be seen on CT. Intraoperative mammography of the specimens were performed in all cases for identification of the resected microcalcifications. The clinical, imaging and pathological information of these patients were analyzed. RESULTS: A total of 42 (59.15%) cases of calcifications were localized by CT + MG, 29 (40.85%) cases were guided only by the mammography. All suspicious calcifications on the mammography were successfully removed. Pathological results showed 42 cases were cancer, 23 cases were benign, and 6 cases were atypical hyperplasia. The mean age in the CT + MG group was older than that of the MG group (54.12 vs. 49.27 years; P = 0.014). The maximum diameter of clusters of microcalcifications on mammography in the CT + MG group was larger than that of the MG group [(cranio-caudal view, 1.52 vs. 0.61 mm, P = 0.000; mediolateral oblique (MLO) view, 1.53 vs. 0.62 mm, P = 0.000)]. The gray value ratio (calcified area / paraglandular; MLO, P = 0.004) and the gray value difference (calcified area - paraglandular; MLO, P = 0.005) in the CT + MG group was higher than that of the MG group. Multivariate analysis showed that the max diameter of clusters of microcalcifications (MLO view) was a significant predictive factor of localization by CT in total patients (P = 0.001). CONCLUSIONS: About half of the mammographically detected clustered microcalcifications could be localized by thin-section CT. Maximum diameter of clusters of microcalcifications (MLO view) was a predictor of visibility of calcifications by CT. Chest thin-section CT may be useful for localization of calcifications in some patients, especially for calcifications that are only visible in one view on the mammography.

Effects of traditional Chinese exercises in fibromyalgia syndrome: A meta-analysis of randomized controlled trials.

OBJECTIVES: To explore the efficacy and safety of five traditional Chinese exercises (TCEs) in patients with fibromyalgia syndrome (FMS). METHODS: The PubMed, Embase, Scopus, ProQuest, Web of Science, Cochrane, CNKI, WanFang, and VIP databases were comprehensively searched for randomized controlled trials (RCTs) related to TCEs published from inception until February 2023. Standardized mean differences (SMD) and 95% confidence intervals (CI) were used to determine the combined effects of the intervention, and the Cochrane risk-of-bias assessment tool and Review 5.2 software were used to assess methodological quality. The data were extracted and analyzed by the Stata15.0 random effects model. RESULTS: Nineteen RCTs including 1315 participants were included in the analysis. The studies were found to be heterogeneous (I2 =86.2, P = 0.000), and thus a random effects model was used to combine the data. The results showed that traditional Chinese exercises had potentially beneficial effects on reducing pain (SMD =-0.66,95% CI [-1.08, -0.25], P = 0.002), improving sleep (SMD = -0.35,95% CI [-0.68,0. 01], P = 0.041) and relieving depression (SMD= -0.24,95% CI [-0.47, -0.02], P = 0.034) in FMS patients. However, no significant effects were found on improved quality of life (SMD =-0.20,95% CI [-0.48,0.09], P = 0.176). CONCLUSIONS: TCEs can improve pain, sleep quality and depression in patients with FMS and are safe. However, they do not improve the quality of life significantly. Further large-scale, high-quality, and multi-center RCTs are required to verify the efficacy of TCEs.

Adenoid cystic carcinoma of head and neck: Summary and review of imaging findings.

Purpose: Current reports of adenoid cystic carcinoma of the head and neck (ACC) are all case reports, and there is no basilar summary of its imaging findings. This study aims to summarise ACC's computed tomography (CT) and magnetic resonance imaging (MRI) findings to improve radiologists' knowledge of this disease. Methods: We collected clinical and imaging data of patients with ACC during the last decade, and two radiologists retrospectively analysed the imaging characteristics. Results: Of the 16 patients included, six were able to self-perceive bulkiness, and 11 had regional pain. Tumour morphology was regular in six cases, with clear borders in 11 cases, invasion of the surrounding bony mass in 12 cases, and invasion of peripheral nerves in 15 cases. CT mostly shows an irregular soft-tissue density mass with mild-to-moderate enhancement after contrast medium administration. On MRI, the ACC showed isointense or hypointense signals on T1-weighted images (T1WI) and hyperintense or slightly hyperintense signals on T2-weighted images (T2WI). All signals were markedly enhanced after gadolinium enhancement. Conclusions: ACC often has an irregular morphology, sometimes with a cystic component, enhancement on enhancement scans, easy destruction of adjacent bone, and invasion of peripheral nerves. The diagnosis should be considered when these features are encountered in clinical practice.

Development of Potent and Selective Coactivator-Associated Arginine Methyltransferase 1 (CARM1) Degraders.

CARM1 is amplified or overexpressed in many cancer types, and its overexpression correlates with poor prognosis. Potent small-molecule inhibitors for CARM1 have been developed, but the cellular efficacy of the CARM1 inhibitors is limited. We herein report the development of the proteolysis targeting chimera (PROTAC) for CARM1, which contains a CARM1 ligand TP-064, a linker, and a VHL E3 ligase ligand. Compound 3b elicited potent cellular degradation activity (DC50 = 8 nM and Dmax > 95%) in a few hours. Compound 3b degraded CARM1 in VHL- and proteasome-dependent manner and was highly selective for CARM1 over other protein arginine methyltransferases. CARM1 degradation by 3b resulted in potent downregulation of CARM1 substrate methylation and inhibition of cancer cell migration in cell-based assays. Thus, CARM1 PROTACs can be used to interrogate CARM1's cellular functions and potentially be developed as therapeutic agents for targeting CARM1-driven cancers.

Single nucleotide polymorphisms associated with female breast cancer susceptibility in Chinese population.

Breast cancer is a complex disease influenced by both external and internal factors, among which genetic factors play a critical role. Single-nucleotide polymorphisms (SNPs) are major contributors to the heritability of breast cancer, and their frequencies vary across ethnic groups. In this study, we aimed to investigate the association between 34 SNPs identified in previous genome-wide association studies (GWAS) and overall breast cancer risk, as well as breast cancer subtypes, in the Chinese female population. To accomplish this, we conducted an extensive association analysis using the high-throughput Sequenom MassARRAY® platform in a case-control study comprising 1848 breast cancer patients and 709 healthy controls. Our analysis, which utilized the SNPassoc package in R based on chi-squared (χ2) test and genetic model analysis, identified significant associations between breast cancer risk and SNP rs12493607 (TGFBR2, risk allele C, OR = 1.28 [1.11-1.47], P = 0.0005), as well as a less conservatively significant association with rs4784227 (CASC16, risk allele T, OR = 1.24 [1.08-1.42], P = 0.0017) and rs2046210 (ESR1, risk allele A, OR = 1.50 [1.16-1.95], P = 0.0016). Furthermore, our stratified analyses revealed that rs12493607 was significantly associated with invasive carcinoma, estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, HER2-negative, and young (aged younger than 45) breast cancer. SNP rs4784227 and rs3803662 (CASC16) were associated with invasive carcinoma and ER-positive breast cancer, while rs2046210 was linked to ductal carcinoma in situ, ER-negative, PR-negative, HER2-positive, and elder (aged more than 45) breast cancers. SNPs rs10484919 (ESR1) and rs1038304 (CCDC170) showed links to HER2-positive breast cancer, and rs616488 (PEX14) with premenopausal breast cancer. In summary, our study shed light on the relationship between SNPs and breast cancer susceptibility within a vast Chinese cohort, supporting the development of polygenetic risk scores for the Chinese population. These findings provide valuable insights into the genetic basis of breast cancer and have important implications for risk prediction, early detection, and personalized treatment of this disease.

The impact of humor therapy on people suffering from depression or anxiety: An integrative literature review.

OBJECTIVES: To identify and synthesize existing research on the effectiveness and feasibility of multiform humor therapy on people suffering from depression or anxiety, with the hope of benefiting future research. METHODS: An integrative literature review of quantitative, qualitative, and mixed studies was performed. The PubMed, Cochrane Library, Web of Science, Embase, and CINAHL databases were searched up to March 2022. Two independent reviewers conducted each stage of the review process, by assessing eligibility using preferred reporting items for systematic review and meta-analyses (PRISMA) and quality appraisal using the Mixed Methods Appraisal Tool, and data extraction. RESULTS: In this integrative review, 29 papers were included, containing 2964 participants across a diverse range of studies, including quantitative, qualitative, and mixed methods. The articles were from the United States, Australia, Italy, Turkey, South Korea, Iran, Israel, China, and Germany. The findings indicated that most of the subjects thought humor therapy was effective in improving depression and anxiety while a few participants considered the effect insignificant. However, more high-quality studies will be needed to confirm these conclusions. DISCUSSION: This review collated and summarized findings from studies examining the impact of humor therapy (medical clowns, laughter therapy/yoga) on people with depression or anxiety, including children undergoing surgery or anesthesia, older people in nursing homes, patients with Parkinson's disease, cancer, mental illness, and undergoing dialysis, retired women, and college students. The results from this review may help inform future research, policy, and practice in humor therapy to improve people's symptoms of depression and anxiety. IMPACT: This systematic review objectively evaluated the effect of humor therapy on depression and anxiety. As a simple and feasible complementary alternative therapy, humor therapy may provide a favorable alternative for clinicians, nurses, and patients in the future.

Point-of-Care Detection of Antioxidant in Agarose-Based Test Strip through Antietching of Au@Ag Nanostars.

Antioxidants are crucial for human health, and the detection of antioxidants can provide valuable information for disease diagnosis and health management. In this work, we report a plasmonic sensing approach for the determination of antioxidants based on their antietching capacity toward plasmonic nanoparticles. The Ag shell of core-shell Au@Ag nanostars can be etched by chloroauric acid (HAuCl4), whereas antioxidants can interact with HAuCl4, which prevents the surface etching of Au@Ag nanostars. We modulate the thickness of the Ag shell and morphology of the nanostructures, showing that the core-shell nanostars with the smallest thickness of Ag shell have the best etching sensitivity. Owing to the extraordinary surface plasmon resonance (SPR) property of Au@Ag nanostars, the antietching effect of antioxidants can induce a significant change in both the SPR spectrum and the color of solution, facilitating both the quantitative detection and naked-eye readout. This antietching strategy enables the determination of antioxidants such as cystine and gallic acid with a linear range of 0.1-10 µM. The core-shell Au@Ag nanostars are further immobilized in agarose gels to fabricate test strips, which can display different color changes in the presence of HAuCl4 from 0 to 1000 µM. The agarose-based test strip is also capable of detecting antioxidants in real samples, which allows naked-eye readout and quantitative detection by a smartphone.

Critical Role of the cGAS-STING Pathway in Doxorubicin-Induced Cardiotoxicity.

BACKGROUND: Doxorubicin is an effective chemotherapy drug for treating various types of cancer. However, lethal cardiotoxicity severely limits its clinical use. Recent evidence has indicated that aberrant activation of the cytosolic DNA-sensing cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-STING (stimulator of interferon genes) pathway plays a critical role in cardiovascular destruction. Here, we investigate the involvement of this mechanism in doxorubicin-induced cardiotoxicity (DIC). METHODS: Mice were treated with low-dose doxorubicin to induce chronic DIC. The role of the cGAS-STING pathway in DIC was evaluated in cGAS-deficiency (cGAS-/-), Sting-deficiency (Sting-/-), and interferon regulatory factor 3 (Irf3)-deficiency (Irf3-/-) mice. Endothelial cell (EC)-specific conditional Sting deficiency (Stingflox/flox/Cdh5-CreERT) mice were used to assess the importance of this pathway in ECs during DIC. We also examined the direct effects of the cGAS-STING pathway on nicotinamide adenine dinucleotide (NAD) homeostasis in vitro and in vivo. RESULTS: In the chronic DIC model, we observed significant activation of the cGAS-STING pathway in cardiac ECs. Global cGAS, Sting, and Irf3 deficiency all markedly ameliorated DIC. EC-specific Sting deficiency significantly prevented DIC and endothelial dysfunction. Mechanistically, doxorubicin activated the cardiac EC cGAS-STING pathway and its target, IRF3, which directly induced CD38 expression. In cardiac ECs, the cGAS-STING pathway caused a reduction in NAD levels and subsequent mitochondrial dysfunction via the intracellular NAD glycohydrolase (NADase) activity of CD38. Furthermore, the cardiac EC cGAS-STING pathway also regulates NAD homeostasis and mitochondrial bioenergetics in cardiomyocytes through the ecto-NADase activity of CD38. We also demonstrated that pharmacological inhibition of TANK-binding kinase 1 or CD38 effectively ameliorated DIC without compromising the anticancer effects of doxorubicin. CONCLUSIONS: Our findings indicate a critical role of the cardiac EC cGAS-STING pathway in DIC. The cGAS-STING pathway may represent a novel therapeutic target for preventing DIC.

Fibromyalgia in China: sleep quality is related to symptoms, quality of life and especially mental health.

OBJECTIVES: To investigate sleep quality in patients with fibromyalgia (FM) and to analyse the effect of sleep on FM symptoms and quality of life. METHODS: Patients with FM and healthy subjects were recruited to assess their sleep quality, and patients were further assessed for pain, fatigue, depression, psychological stress and quality of life. The patients were divided into a sleep disorder group as measured by the Pittsburgh Sleep Quality Index (PSQI score >7 points) and a group without sleep disorders (PSQI score ≤7 points). Linear regression analysis was used to explore the effect of sleep quality on FM pain controlling for sex and age, and the effect of sleep quality on FM fatigue, depression, psychological stress and quality of life controlling for sex, age and pain. RESULTS: A total of 450 patients and 50 healthy subjects participated in the study. The number of FM patients with sleep disorders was significantly higher than that of healthy subjects (90% vs. 14%, p≤0.001). In addition to the number of pain sites, the levels of pain, fatigue, depression, stress symptoms and quality of life were significantly impaired in FM patients with sleep disorders (p<0.05). In terms of the effects on quality of life assessed with the 36-item short-form health survey, the decrease in mental health was more substantial than the decrease in physical health (B=-12.10 vs. B=-5.40). CONCLUSIONS: Similar to FM patients in other countries and regions, a decrease in sleep quality is also the core symptom of FM patients in China and is significantly correlated with the severity of pain, fatigue, depression and stress symptoms and reduced quality of life, especially with regard to mental health, suggesting that the treatment of this disease should include sleep disorder interventions.

The protective effect of lncRNA NEAT1/miR-122-5p/Wnt1 axis on hippocampal damage in hepatic ischemic reperfusion young mice.

Hepatic ischemic reperfusion (HIR) is a common pathophysiological process in many surgical procedures such as liver transplantation (LT) and hepatectomy. And it is also an important factor leading to perioperative distant organ damage. Children undergoing major liver surgery are more susceptible to various pathophysiological processes, including HIR, since their brains are still developing and the physiological functions are still incomplete, which can lead to brain damage and postoperative cognitive impairment, thus seriously affecting the long-term prognosis of the children. However, the present treatments of mitigating HIR-induced hippocampal damage are not proven to be effective. The important role of microRNAs (miRNAs) in the pathophysiological processes of many diseases and in the normal development of the body has been confirmed in several studies. The current study explored the role of miR-122-5p in HIR-induced hippocampal damage progression. HIR-induced hippocampal damage mouse model was induced by clamping the left and middle lobe vessels of the liver of young mice for 1 h, removing the vessel clamps and re-perfusing them for 6 h. The changes in the level of miR-122-5p in the hippocampal tissues were measured, and its influences on the activity as well as apoptotic rate of neuronal cells were investigated. Short interfering RNA modified with 2'-O-methoxy substitution targeting long-stranded non-coding RNA (lncRNA) nuclear enriched transcript 1 (NEAT1) as well as miR-122-5p antagomir were used to further clarify the role played by the corresponding molecules in hippocampal injury in young mice with HIR. The result obtained in our study was that the expression of miR-122-5p in the hippocampal tissue of young mice receiving HIR is reduced. Upregulated expression of miR-122-5p reduces the viability of neuronal cells and promotes the development of apoptosis, thereby aggravating the damage of hippocampal tissue in HIR young mice. Additionally, in the hippocampal tissue of young mice receiving HIR, lncRNA NEAT1 exerts some anti-apoptotic effects by binding to miR-122-5p, promoting the expression of Wnt1 pathway. An essential observation of this study was the binding of lncRNA NEAT1 to miR-122-5p, which upregulates Wnt1 and inhibits HIR-induced hippocampal damage in young mice.

Glycolytic Genes Predict Immune Status and Prognosis Non-Small-Cell Lung Cancer Patients with Radiotherapy and Chemotherapy.

Background: Non-small-cell lung cancer (NSCLC) is a major health problem that endangers human health. The prognosis of radiotherapy or chemotherapy is still unsatisfactory. This study is aimed at investigating the predictive value of glycolysis-related genes (GRGs) on the prognosis of NSCLC patients with radiotherapy or chemotherapy. Methods: Download the clinical information and RNA data of NSCLC patients receiving radiotherapy or chemotherapy from TCGA and geo databases and obtain GRGs from MsigDB. The two clusters were identified by consistent cluster analysis, the potential mechanism was explored by KEGG and GO enrichment analyses, and the immune status was evaluated by estimate, TIMER, and quanTIseq algorithms. Lasso algorithm is used to build the corresponding prognostic risk model. Results: Two clusters with different GRG expression were identified. The high-expression subgroup had poor overall survival. The results of KEGG and GO enrichment analyses suggest that the differential genes of the two clusters are mainly reflected in metabolic and immune-related pathways. The risk model constructed with GRGs can effectively predict the prognosis. The nomogram combined with the model and clinical characteristics has good clinical application potential. Conclusion: In this study, we found that GRGs are associated with tumor immune status and can assess the prognosis of NSCLC patients receiving radiotherapy or chemotherapy.

Integrative epigenetic analysis reveals AP-1 promotes activation of tumor-infiltrating regulatory T cells in HCC.

Regulatory T (Treg) cells that infiltrate human tumors exhibit stronger immunosuppressive activity compared to peripheral blood Treg cells (PBTRs), thus hindering the induction of effective antitumor immunity. Previous transcriptome studies have identified a set of genes that are conserved in tumor-infiltrating Treg cells (TITRs). However, epigenetic profiles of TITRs have not yet been completely deciphered. Here, we employed ATAC-seq and CUT&Tag assays to integrate transcriptome profiles and identify functional regulatory elements in TITRs. We observed a global difference in chromatin accessibility and enhancer landscapes between TITRs and PBTRs. We identified two types of active enhancer formation in TITRs. The H3K4me1-predetermined enhancers are poised to be activated in response to tumor microenvironmental stimuli. We found that AP-1 family motifs are enriched at the enhancer regions of TITRs. Finally, we validated that c-Jun binds at regulatory regions to regulate signature genes of TITRs and AP-1 is required for Treg cells activation in vitro. High c-Jun expression is correlated with poor survival in human HCC. Overall, our results provide insights into the mechanism of AP-1-mediated activation of TITRs and can hopefully be used to develop new therapeutic strategies targeting TITRs in liver cancer treatment.

[Role of IRE1 in autophagy induced by vitamin E succinate in human gastric cancer cell].

OBJECTIVE: To investigate the role of inositol-requiring enzyme 1(IRE1) in autophagy of human gastric cancer cells induced by vitamin E succinate(VES). METHODS: Human gastric cancer SGC-7901 cells were cultured in vitro and divided into solvent control group(0.1% ethanol absolute), different doses(5, 10, 15 and 20 µg/mL) VES group, 4µ8C group, and VES + 4µ8C group. The endoplasmic reticulum stress-related molecules glucose regulated protein 78(GRP78) and C/EBP homologous protein(CHOP), autophagy marker microtubule associated Protein1 light chain 3(LC3), Beclin-1, unfolded protein response branching pathway Inositol-requiring enzyme 1(IRE1), X box-binding protein 1(XBP1), c-Jun n-terminal kinase(JNK) and p-JNK were detected by Western blot in the solvent control group and different doses of VES group. IRE1 was inhibited by 4µ8C. The expressions of IRE1, XBP1, JNK, p-JNK, GRP78 and CHOP were detected by Western blot, and the expressions of LC3 and Beclin-1 were detected. RESULTS: The expression of GRP78(1.16±0.06) and CHOP(1.36±0.11) in 20 µg/mL VES group were significantly higher than those in solvent control group GRP78(0.36±0.10) and CHOP(0.48±0.05)(P<0.001). The expression of Beclin-1(1.09±0.20) and LC3-Ⅱ/LC3-Ⅰ(1.29±0.03) in 20 µg/mL VES group were significantly higher than those in solvent control group(0.27±0.07) and LC3-Ⅱ/LC3-Ⅰ(0.43±0.06)(P<0.001). The expression levels of IRE1(1.07±0.20), XBP1(1.33±0.07) and p-JNK/JNK(1.19±0.31) in 20 µg/mL VES group were significantly higher than those in the solvent control group(P<0.01). After IRE1 is inhibited: The expression level of IRE1(0.63±0.27), XBP1(0.74±0.09), p-JNK/JNK(0.35±0.04), GRP78(0.66±0.02), CHOP(0.51±0.02), LC3-Ⅱ/LC3-Ⅰ(0.72±0.01), Beclin-1(0.70±0.15) was significantly lower than that of VES group(P<0.05). CONCLUSION: VES may participate in the regulation of autophagy in gastric cancer cells by upregulating IRE1 pathway.

Prognostic value of gut microbiota-derived metabolites in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Studies about the prognostic role of gut microbiota-derived metabolites including phenylacetyl glutamine (PAGln), indoxyl sulfate (IS), lithocholic acid (LCA), deoxycholic acid (DCA), trimethylamine (TMA), trimethylamine N-oxide (TMAO), and its precursor trimethyllysine (TML) are limited in patients with ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: To examine the relationship between plasma metabolite levels and major adverse cardiovascular events (MACEs), including nonfatal MI, nonfatal stroke, all-cause mortality, and heart failure in patients with STEMI. METHODS: We enrolled 1004 patients with STEMI undergoing percutaneous coronary intervention (PCI). Plasma levels of these metabolites were determined by targeted liquid chromatography/mass spectrometry. The associations of metabolite levels with MACEs were assessed with the Cox regression model and quantile g-computation. RESULTS: During a median follow-up of 360 d, 102 patients experienced MACEs. Higher plasma PAGln (hazard ratio [HR], 3.17 [95% CI: 2.05, 4.89]; P < 0.001), IS (2.67 [1.68, 4.24], P < 0.001), DCA (2.36 [1.40, 4.00], P = 0.001), TML (2.66 [1.77,3.99], P < 0.001), and TMAO (2.61 [1.70, 4.00], P < 0.001) levels were significantly associated with MACEs independent of traditional risk factors. According to quantile g-computation, the joint effect of all these metabolites was 1.86 (95% CI: 1.46, 2.27). PAGln, IS and TML had the greatest proportional positive contributions to the mixture effect. Additionally, plasma PAGln and TML combined with coronary angiography scores including the Synergy between PCI with Taxus and cardiac surgery (SYNTAX) score (area under the curve [AUC]: 0.792 vs. 0.673), Gensini score (0.794 vs. 0.647) and Balloon pump-assisted Coronary Intervention Study (BCIS-1) jeopardy score (0.774 vs. 0.573) showed better prediction performance for MACEs. CONCLUSIONS: Higher plasma PAGln, IS, DCA, TML, and TMAO levels are independently associated with MACEs suggesting that these metabolites may be useful markers for prognosis in patients with STEMI.