CLK2 mediates IκBα-independent early termination of NF-κB activation by inducing cytoplasmic redistribution and degradation.

Activation of the NF-κB pathway is strictly regulated to prevent excessive inflammatory and immune responses. In a well-known negative feedback model, IκBα-dependent NF-κB termination is a delayed response pattern in the later stage of activation, and the mechanisms mediating the rapid termination of active NF-κB remain unclear. Here, we showed IκBα-independent rapid termination of nuclear NF-κB mediated by CLK2, which negatively regulated active NF-κB by phosphorylating the RelA/p65 subunit of NF-κB at Ser180 in the nucleus to limit its transcriptional activation through degradation and nuclear export. Depletion of CLK2 increased the production of inflammatory cytokines, reduced viral replication and increased the survival of the mice. Mechanistically, CLK2 phosphorylated RelA/p65 at Ser180 in the nucleus, leading to ubiquitin‒proteasome-mediated degradation and cytoplasmic redistribution. Importantly, a CLK2 inhibitor promoted cytokine production, reduced viral replication, and accelerated murine psoriasis. This study revealed an IκBα-independent mechanism of early-stage termination of NF-κB in which phosphorylated Ser180 RelA/p65 turned off posttranslational modifications associated with transcriptional activation, ultimately resulting in the degradation and nuclear export of RelA/p65 to inhibit excessive inflammatory activation. Our findings showed that the phosphorylation of RelA/p65 at Ser180 in the nucleus inhibits early-stage NF-κB activation, thereby mediating the negative regulation of NF-κB.

Pradimicin U, a promising antimicrobial agent isolated from a newly found Nonomuraea composti sp. nov.

Pradimicin U is a new dihydrobenzo[a]naphthacenequinone compound found to be active on a screen designed to investigate compounds with antimicrobial activity, produced by the actinomycete designated strain FMUSA5-5T. The strain was isolated from a bio-fertilizer of Musa spp. collected from Suphanburi province, Thailand. The chemotaxonomic characteristics and 16S rRNA gene analysis revealed that strain FMUSA5-5T is a member of the genus Nonomuraea. Low genome-based taxonomic criteria, average nucleotide identity (ANI) (82.8-88.3%), average amino-acid identity (AAI) (79.4-87.3%), and digital DNA-DNA hybridization (dDDH) (29.5-38.5%) values and several phenotypic differences between strain FMUSA5-5T and its closest type strains of the genus Nonomuraea indicated that strain FMUSA5-5T represents a novel species of the genus Nonomuraea and the name Nonomuraea composti sp. nov. is proposed for the strain. The crude extract from the culture broth of strain FMUSA5-5T displayed promising antimicrobial activity against several pathogens and led to the isolation of a novel secondary metabolite, pradimicin U. Interestingly, this compound displayed a broad spectrum of biological activities such as antimalarial activity against Plasmodium falciparum K1 (IC50 value = 3.65 µg/mL), anti-Mycobacterium tuberculosis H37Ra (MIC value = 25.0 µg/mL), anti-Alternaria brassicicola BCC 42724 (MIC value = 25.0 µg/mL), anti-Bacillus cereus ATCC 11778 and anti-Staphylococcus aureus ATCC 29213 (MIC values = 6.25 and 1.56 µg/mL, respectively). Moreover, the compound possessed strong anti-human small cell lung cancer (NCI-H187) activity with IC50 value of 5.69 µg/mL, while cytotoxicity against human breast cancer (MCF-7) and Vero cells was very weak (IC50 values of 52.49 and 21.84 µg/mL, respectively).

circ_WASF2 regulates ferroptosis by miR-634/ GPX4 signaling in pancreatic cancer.

PURPOSE: Pancreatic cancer (PC) is one of the most lethal malignant gastrointestinal tumors (GI) characterized by a poor prognosis. Ferroptosis is an emerging programmed cell death that plays an essential role in the progression of various cancers. Ferroptosis is driven by iron-dependent phospholipid peroxidation and is regulated by mitochondrial activity, lipid peroxidation, and reactive oxygen species (ROS). The function and mechanism of ferroptosis in PC need more research. METHODS: The levels of circRNAs, miRNAs, and mRNAs were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was used for protein detection. CCK8 assays were used to detect cell proliferation. Cell death, lipid peroxidation, ROS, and Fe2+ were detected by indicted kits. Dual-luciferase reporter and RNA pull-down assays were conducted to confirm the interaction between circRNAs, miRNAs, and mRNAs. RESULTS: In this research, we found that circular RNA hsa_circ_0000003(circ_WASF2) was upregulated in pancreatic cancer cells. The silence of circ_WASF2 inhibited cancer proliferation and increased cell death by increasing ferroptosis accompanied by up-regulation of lipid peroxidation, ROS, and Fe2+. Further studies showed that circ_WASF2 could attenuate ferroptosis by targeting miR-634 and the downstream glutathione peroxidase 4 (GPX4). GPX4 has been well-reported as a central factor in ferroptosis. Our research revealed a new pathway for regulating ferroptosis in PC. CONCLUSION: In summary, we have determined that circ_WASF2/miR-634/GPX4 contributed to ferroptosis-induced cell death, and provided a possible therapeutic target in PC.

Commercializable Naphthalene Diimide Anolytes for Neutral Aqueous Organic Redox Flow Batteries.

Neutral aqueous organic redox flow batteries (AORFBs) hold the potential to facilitate the transition of renewable energy sources from auxiliary to primary energy, the commercial production of anolyte materials still suffers from insufficient performance of high-concentration and the high cost of the preparation problem. To overcome these challenges, this study provides a hydrothermal synthesis methodology and introduces the charged functional groups into hydrophobic naphthalene diimide cores, and prepares a series of high-performance naphthalene diimide anolytes. Under the synergistic effect of π-π stacking and H-bonding networks, the naphthalene diimide exhibits excellent structural stability and the highest water solubility (1.85 M for dex-NDI) reported to date. By employing the hydrothermal method, low-cost naphthalene diimides are successfully synthesized on a hundred-gram scale of $0.16 g-1 ($2.43 Ah-1), which is also the lowest price reported to date. The constructed full battery achieves a high electron concentration of 2.4 M, a high capacity of 54.4 Ah L-1, and a power density of 318 mW cm-2 with no significant capacity decay observed during long-duration cycling. These findings provide crucial support for the commercialization of AORFBs and pave the way for revolutionary developments in neutral AORFBs.

Increased miR-3074-5p expression promotes M1 polarization and pyroptosis of macrophages via ERα/NLRP3 pathway and induces adverse pregnancy outcomes in mice.

Decidual macrophages (dMϕs) play critical roles in regulation of immune-microhomeostasis at maternal-fetal interface during pregnancy, but the underlying molecular mechanisms are still unclear. In this study, it was found that litter size and fetal weight were significantly reduced, whereas the rate of embryo resorption was increased in miR-3074-5p knock-in (3074-KI) pregnant mice, compared to that of wild-type (WT) pregnant mice. Plasma levels of pro-inflammatory cytokines in 3074-KI pregnant mice were also significantly elevated compared to WT pregnant mice at GD7.5. The quantity of M1-Mϕs in uterine tissues of 3074-KI pregnant mice was significantly increased compared to WT pregnant mice at GD13.5. Estrogen receptor-α (ERα) was validated to be a target of miR-3074-5p. Either miR-3074-5p overexpression or ERα knockdown promoted transcriptional activity of NF-κB/p65, induced M1-polarization and pyroptosis of THP1-derived Mϕs, accompanied with increased intracellular levels of cleaved Caspase-1, cleaved IL-1ß, NLRP3, cleaved GSDMD and ASC aggregation. Furthermore, ERα could not only bind to NLRP3 or ASC directly, but also inhibit the interaction between NLRP3 and ASC. The endometrial miR-3074-5p expression level at the middle secretory stage of repeated implantation failure (RIF) patients was significantly decreased compared to that of control fertile women. These data indicated that miR-3074-5p could promote M1 polarization and pyroptosis of Mϕs via activation of NLRP3 inflammasome by targeting ERα, and the dysregulation of miR-3074-5p expression in dMϕs might damage the embryo implantation and placentation by interfering with inflammatory microenvironment at the maternal-fetal interface during early pregnancy.

Summary of evidence on comprehensive healthcare for chemotherapy-induced peripheral neuropathy in cancer patients.

OBJECTIVE: This paper aims to provide an evidence-based summary of the most effective strategies for comprehensive healthcare of chemotherapy-induced peripheral neuropathy (CIPN) in cancer patients. METHOD: Following the "6S" model, relevant evidence on CIPN management was collected from reputable evidence-based resource websites and databases nationally and internationally. The included articles were evaluated for methodological quality, and evidence was extracted using the Australian JBI Evidence-based Health Care Center's literature evaluation standard (2016 edition). RESULTS: A total of 60 articles were included in this study, comprising 2 guidelines, 5 expert consensus statements, and 53 systematic reviews. The findings of these articles were summarized across 7 dimensions, including risk factor screening, assessment, diagnosis, prevention, treatment, management, and health education, resulting in the identification of 42 relevant pieces of evidence. CONCLUSIONS: This study provides a comprehensive synthesis of evidence-based recommendations for managing CIPN in cancer patients, offering guidance for healthcare professionals engaged in clinical practice. However, when implementing these recommendations, it is crucial to consider the individual patient's clinical circumstances, preferences, and expert judgment, ensuring feasibility and applicability in real-world clinical settings.

FOXP3 promote the progression of glioblastoma via inhibiting ferroptosis mediated by linc00857/miR-1290/GPX4 axis.

The oncogenic properties of members belonging to the forkhead box (FOX) family have been extensively documented in different types of cancers. In this study, our objective was to investigate the impact of FOXP3 on glioblastoma multiforme (GBM) cells. By conducting a screen using a small hairpin RNA (shRNA) library, we discovered a significant association between FOXP3 and ferroptosis in GBM cells. Furthermore, we observed elevated levels of FOXP3 in both GBM tissues and cell lines, which correlated with a poorer prognosis. FOXP3 was found to promote the proliferation of GBM cells by inhibiting cell ferroptosis in vitro and in vivo. Mechanistically, FOXP3 not only directly upregulated the transcription of GPX4, but also attenuated the degradation of GPX4 mRNA through the linc00857/miR-1290 axis, thereby suppressing ferroptosis and promoting proliferation. Additionally, the FOXP3 inhibitor epirubicin exhibited the ability to impede proliferation and induce ferroptosis in GBM cells both in vitro and in vivo. In summary, our study provided evidences that FOXP3 facilitates the progression of glioblastoma by inhibiting ferroptosis via the linc00857/miR-1290/GPX4 axis, highlighting FOXP3 as a potential therapeutic target for GBM.

Selenosis in a Woman With Systemic Lupus Erythematosus.

This case report describes hypointensity in the cerebellum and midbrain in a 56-year-old woman with double vision and weakness and ptosis of eyelids.

Using new indices to predict metabolism dysfunction-associated fatty liver disease (MAFLD): analysis of the national health and nutrition examination survey database.

BACKGROUND: Metabolism dysfunction-associated fatty liver disease (MAFLD), is the most common chronic liver disease. Few MAFLD predictions are simple and accurate. We examined the predictive performance of the albumin-to-glutamyl transpeptidase ratio (AGTR), plasma atherogenicity index (AIP), and serum uric acid to high-density lipoprotein cholesterol ratio (UHR) for MAFLD to design practical, inexpensive, and reliable models. METHODS: The National Health and Nutrition Examination Survey (NHANES) 2007-2016 cycle dataset, which contained 12,654 participants, was filtered and randomly separated into internal validation and training sets. This study examined the relationships of the AGTR and AIP with MAFLD using binary multifactor logistic regression. We then created a MAFLD predictive model using the training dataset and validated the predictive model performance with the 2017-2018 NHANES and internal datasets. RESULTS: In the total population, the predictive ability (AUC) of the AIP, AGTR, UHR, and the combination of all three for MAFLD showed in the following order: 0.749, 0.773, 0.728 and 0.824. Further subgroup analysis showed that the AGTR (AUC1 = 0.796; AUC2 = 0.690) and the combination of the three measures (AUC1 = 0.863; AUC2 = 0.766) better predicted MAFLD in nondiabetic patients. Joint prediction outperformed the individual measures in predicting MAFLD in the subgroups. Additionally, the model better predicted female MAFLD. Adding waist circumference and or BMI to this model improves predictive performance. CONCLUSION: Our study showed that the AGTR, AIP, and UHR had strong MAFLD predictive value, and their combination can increase MAFLD predictive performance. They also performed better in females.

Identification of cuproptosis-related lncRNAs signature for predicting the prognosis in patients with kidney renal clear cell carcinoma.

BACKGROUND: Kidney renal clear cell carcinoma (KIRC), with low survival rate, is the most frequent subtype of renal cell carcinoma. Recently, more and more studies indicate that cuproptosis-related genes (CRGs) and long non-coding RNAs (lncRNAs) play a vital role in the occurrence and development of many types of cancers. However, the roles of cuproptosis-related lncRNAs (CRlncRNAs) in the KIRC was uncertain. RESULTS: In our study, CRlncRNAs were obtained by coexpression between differentially expressed and prognostic CRGs and differentially expressed and prognostic lncRNAs, and an 8-CRlncRNAs (AC007743.1, AC022915.1, AP005136.4, APCDD1L-DT, HAGLR, LINC02027, MANCR and SMARCA5-AS1) risk model was established according to least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression. This risk model could differentiate immune cell infiltration, immune function and gene mutation. CONCLUSIONS: This 8-CRlncRNAs risk model may be promising for the clinical prediction of prognoses, tumor immune, immunotherapy response and chemotherapeutic response in KIRC patients.

The impact of ammonia and microcystin-LR on neurobehavior and glutamate/gamma-aminobutyric acid balance in female zebrafish (Danio rerio): ROS and inflammation as key pathways.

Ammonia and microcystin-LR (MC-LR) are both toxins that can be in eutrophic waters during cyanobacterial blooms. While previous studies have focused on the effects of ammonia exposure on fish neurobehavioral toxicity, little attention has been given to the effects of MC-LR and combined exposures to both. This study exposed adult female zebrafish to ammonia (30 mg/L) and MC-LR (10 µg/L) alone and in combination for 30 days to investigate their neurotoxic effects and underlying mechanisms. Behavioral results showed that exposure to ammonia and MC-LR, both alone and in combination, led to decreased locomotor activity and increased anxiety in fish. Histomorphological analysis revealed the formation of thrombi and vacuolization in the brain across all exposure groups. Exposure to ammonia and MC-LR resulted in significant increases in MDA contents, decreases in Mn-SOD activities, and alterations in GSH contents compared to the control. Single and combined exposure to ammonia and MC-LR also induced the release of inflammatory factors (IL-1ß and TNF-α) by activating the NOD/NF-κB signaling pathway. Furthermore, both ammonia and MC-LR significantly changed the expression of genes related to the glutamatergic and GABAergic systems, elevated Glu and GABA contents, as well as increased the Glu/GABA ratio, indicating that a shift towards increased Glu levels. Overall, these findings suggested that exposure to MC-LR and ammonia, individually and in combination, could decrease locomotor activity and increase anxiety of female zebrafish. This was likely due to brain damage from over-activated ROS and the release of pro-inflammatory cytokines, which led to a disruption in the balance of glutamatergic and GABAergic systems. However, there was no significant interaction between MC-LR and ammonia in fish neurobehavioral toxicity.

Yin Yang 1 expression predicts a favourable survival in diffuse large B-cell lymphoma.

Aims: Yin Yang 1 (YY1) is a multifunctional transcription factor that plays an important role in tumour development and progression, while its clinical significance in diffuse large B-cell lymphoma (DLBCL) remains largely unexplored. This study aimed to investigate the expression and clinical implications of YY1 in DLBCL. Methods: YY1 expression in 198 cases of DLBCL was determined using immunohistochemistry. The correlation between YY1 expression and clinicopathological parameters as well as the overall survival (OS) and progression-free survival (PFS) of patients was analyzed. Results: YY1 protein expression was observed in 121 out of 198 (61.1 %) DLBCL cases. YY1 expression was significantly more frequent in cases of the GCB subgroup than in the non-GCB subgroup (P = 0.005). YY1 was positively correlated with the expression of MUM1, BCL6, pAKT and MYC/BCL2 but was negatively associated with the expression of CXCR4. No significant relationships were identified between YY1 and clinical characteristics, including age, sex, stage, localization, and B symptoms. Univariate analysis showed that the OS (P = 0.003) and PFS (P = 0.005) of patients in the YY1-negative group were significantly worse than those in the YY1-positive group. Multivariate analysis indicated that negative YY1 was a risk factor for inferior OS (P < 0.001) and PFS (P = 0.017) independent of the international prognostic index (IPI) score, treatment and Ann Arbor stage. Furthermore, YY1 is more powerful for stratifying DLBCL patients into different risk groups when combined with MYC/BCL2 double-expression (DE) status. Conclusions: YY1 was frequently expressed in DLBCL, especially in those of GCB phenotype and with MYC/BCL2-DE. As an independent prognostic factor, YY1 expression could predict a favourable outcome in DLBCL. In addition, a complex regulatory mechanism might be involved in the interactions between YY1 and MYC, pAKT as well as CXCR4 in DLBCL, which warrants further investigation.

Machine learning prediction models for in-hospital postoperative functional outcome after moderate-to-severe traumatic brain injury.

AIM: This study aims to utilize machine learning (ML) and logistic regression (LR) models to predict surgical outcomes among patients with traumatic brain injury (TBI) based on admission examination, assisting in making optimal surgical treatment decision for these patients. METHOD: We conducted a retrospective review of patients hospitalized in our department for moderate-to-severe TBI. Patients admitted between October 2011 and October 2022 were assigned to the training set, while patients admitted between November 2022 and May 2023 were designated as the external validation set. Five ML algorithms and LR model were employed to predict the postoperative Glasgow Outcome Scale (GOS) status at discharge using clinical and routine blood data collected upon admission. The Shapley (SHAP) plot was utilized for interpreting the models. RESULTS: A total of 416 patients were included in this study, and they were divided into the training set (n = 396) and the external validation set (n = 47). The ML models, using both clinical and routine blood data, were able to predict postoperative GOS outcomes with area under the curve (AUC) values ranging from 0.860 to 0.900 during the internal cross-validation and from 0.801 to 0.890 during the external validation. In contrast, the LR model had the lowest AUC values during the internal and external validation (0.844 and 0.567, respectively). When blood data was not available, the ML models achieved AUCs of 0.849 to 0.870 during the internal cross-validation and 0.714 to 0.861 during the external validation. Similarly, the LR model had the lowest AUC values (0.821 and 0.638, respectively). Through repeated cross-validation analysis, we found that routine blood data had a significant association with higher mean AUC values in all ML and LR models. The SHAP plot was used to visualize the contributions of all predictors and highlighted the significance of blood data in the lightGBM model. CONCLUSION: The study concluded that ML models could provide rapid and accurate predictions for postoperative GOS outcomes at discharge following moderate-to-severe TBI. The study also highlighted the crucial role of routine blood tests in improving such predictions, and may contribute to the optimization of surgical treatment decision-making for patients with TBI.

Epitope delimitation: A new method for defining epitopes of human IgG-reactive antigenic peptides based on rabbit-recognized epitope motifs.

The use of precise epitope peptides as antigens is essential for accurate serological diagnosis of viral-infected individuals, but now it remains an unsolvable problem for mapping precise B cell epitopes (BCEs) recognized by human serum. To address this challenge, we propose a novel epitope delimitation (ED) method to uncover BCEs in the delineated human IgG-reactive (HR) antigenic peptides (APs). Specifically, the method based on the rationale of similarities in humoral immune responses between mammalian species consists of a pair of elements: experimentally delineated HR-AP and rabbit-recognized (RR) BCE motif and corresponding pair of sequence alignment analysis. As a result of using the ED approach, after decoding four RR-epitomes of human papillomavirus types 16/18-E6 and E7 proteins utilizing rabbit serum against each recombinant protein and sequence alignment analysis of HR-APs and RR-BCEs, 19 fine BCEs in 17 of 22 known HR-APs were defined based on each corresponding RR-BCE motifs, including the type-specificity of each delimited BCE in homologous proteins. The test with 22 known 16/20mer HR-APs demonstrated that the ED method is effective and efficient, indicating that it can be used as an alternative method to the conventional identification of fine BCEs using overlapping 8mer peptides.

Construction and evaluation of a cloud follow-up platform for gynecological patients receiving chemotherapy.

BACKGROUND: Patient follow-up is an essential component of hospital management. In the current information era, the patient follow-up scheme is expected to be replaced by Internet technology. This study constructed a cloud follow-up platform for gynecological chemotherapy patients and assessed its cost-effectiveness and patients' feedback. METHODS: A total of 2,538 patients were followed up using a cloud follow-up system between January and October 2021. Prior to this, 690 patients were followed manually via telephone calls. Patients' characteristics, follow-up rate, satisfaction, and session duration were compared between the cloud follow-up and manual follow-up groups. In addition, the read rate of health education materials in the cloud follow-up group was analyzed. RESULTS: General information, including age, education attainment, cancer stage, and disease category, and follow-up rate (cloud: 6,957/7,614, 91.4%; manual: 1,869/2,070, 90.3%; P = 0.13) did not significantly differ between the two groups. The follow-up satisfaction of the cloud follow-up patients was significantly better than that of the manual follow-up group (cloud: 7,192/7,614, 94.5%; manual: 1,532/2,070, 74.0%; P<0.001). The time spent on the follow-up was approximately 1.2 h for 100 patients in the cloud follow-up group and 10.5 h in the manual follow-up group. Multivariate analysis indicated that the cloud follow-up group had significantly greater follow-up satisfaction (odds ratio: 2.239, 95% CI: 1.237 ~ 5.219). Additionally, the average follow-up duration of the cloud follow-up group decreased by 9.287 h (coefficient: -9.287, 95% CI: -1.439~-0.165). The read rate of health education materials was 72.9% in the cloud follow-up group. CONCLUSIONS: The follow-up effect of the cloud follow-up group was not inferior to that of the manual follow-up group. The cloud follow-up was more effective for prevention and control requirements in the post-epidemic era. Cloud follow-up can save medical resources, improve cost-effectiveness, provide sufficient health education resources for patients, and improve their satisfaction.

Machine learning models for predicting in-hospital outcomes after non-surgical treatment among patients with moderate-to-severe traumatic brain injury.

AIM: This study aims to develop prediction models for in-hospital outcomes after non-surgical treatment among patients with moderate-to-severe traumatic brain injury (TBI). METHOD: We conducted a retrospective review of patients hospitalized for moderate-to-severe TBI in our department from 2011 to 2020. Five machine learning (ML) algorithms and the conventional logistic regression (LR) model were employed to predict in-hospital mortality and the Glasgow Outcome Scale (GOS) functional outcomes. These models utilized clinical and routine blood data collected upon admission. RESULTS: This study included a total of 196 patients who received only non-surgical treatment after moderate-to-severe TBI. When predicting mortality, ML models achieved area under the curve (AUC) values of 0.921 to 0.994 using clinical and routine blood data, and 0.877 to 0.982 using only clinical data. In comparison, LR models yielded AUCs of 0.762 and 0.730 respectively. When predicting the GOS outcome, ML models achieved AUCs of 0.870 to 0.915 using clinical and routine blood data, and 0.858 to 0.927 using only clinical data. In comparison, the LR model yielded AUCs of 0.798 and 0.787 respectively. Repeated internal validation showed that the contributions of routine blood data for prediction models may depend on different prediction algorithms and different outcome measurements. CONCLUSION: The study reported ML-based prediction models that provided rapid and accurate predictions on short-term outcomes after non-surgical treatment among patients with moderate-to-severe TBI. The study also highlighted the superiority of ML models over conventional LR models and proposed the complex contributions of routine blood data in such predictions.

Histiocytic sarcoma of the spleen without thrombocytopenia.

One case of histiocytic sarcoma of the spleen is reported. The patient, a 54-year-old female, presented with a huge soft tissue mass with a clear border and pseudo capsule in the splenic parenchyma on CT. The density of the mass was uneven, multifocal cystic necrosis and irregular bleeding were observed inside, but no calcification could be seen. On contrast-enhancement scan, the solid component of tumor exhibited moderate progressive enhancement, and area of cystic necrosis exhibited no enhancement. In MRI, T1WI showed mixed low signal, and T2WI showed mixed slightly high signal. The pathological diagnosis was histiocytic sarcoma.

Aldehyde Dehydrogenase 2 Preserves Mitochondrial Function in the Ischemic Heart: A Redox-dependent Mechanism for AMPK Activation by Thioredoxin-1.

ABSTRACT: Aldehyde dehydrogenase 2 (ALDH2) protects the ischemic heart by activating adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling. However, the molecular mechanisms linking ALDH2 and AMPK signaling are not fully understood. This study aimed to explore the potential mechanisms linking ALDH2 and AMPK in myocardial ischemic injury. An ischemic model was established by ligating the left anterior descending coronary artery in rats. The overexpression or knockdown of ALDH2 in H9c2 cells treated with oxygen-glucose deprivation was obtained through lentivirus infection. Transferase-mediated dUTP nick-end labeling was used to evaluate apoptosis in an ischemic rat model and oxygen-glucose deprivation cells. ALDH2 activity, mitochondrial oxidative stress markers, adenosine triphosphate, respiratory control ratio, and cell viability in H9c2 cells were evaluated using a biological kit and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide. Protein expression of ALDH2 , 4-hydroxynonenal, thioredoxin-1 (Trx-1), and AMPK-proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling pathway was detected through Western blotting. ALDH2 activation reduced ischemic-induced myocardial infarct size and apoptosis. ALDH2 protected mitochondrial function by enhancing mitochondrial respiratory control ratio and adenosine triphosphate production, alleviated mitochondrial oxidative stress, and suppressed myocardial apoptosis. Moreover, ALDH2 attenuated ischemia-induced oxidative stress and maintained Trx-1 levels by reducing 4-hydroxynonenal, thereby promoting AMPK-PGC-1α signaling activation. Inhibiting Trx-1 or AMPK abolished the cardioprotective effect of ALDH2 on ischemia. ALDH2 alleviates myocardial injury through increased mitochondrial biogenesis and reduced oxidative stress, and these effects were achieved through Trx1-mediating AMPK-PGC1-α signaling activation.

Genome-wide DNA methylation analysis identifies potent CpG signature for temzolomide response in non-G-CIMP glioblastomas with unmethylated MGMT promoter: MGMT-dependent roles of GPR81.

PURPOSES: To identify potent DNA methylation candidates that could predict response to temozolomide (TMZ) in glioblastomas (GBMs) that do not have glioma-CpGs island methylator phenotype (G-CIMP) but have an unmethylated promoter of O-6-methylguanine-DNA methyltransferase (unMGMT). METHODS: The discovery-validation approach was planned incorporating a series of G-CIMP-/unMGMT GBM cohorts with DNA methylation microarray data and clinical information, to construct multi-CpG prediction models. Different bioinformatic and experimental analyses were performed for biological exploration. RESULTS: By analyzing discovery sets with radiotherapy (RT) plus TMZ versus RT alone, we identified a panel of 64 TMZ efficacy-related CpGs, from which a 10-CpG risk signature was further constructed. Both the 64-CpG panel and the 10-CpG risk signature were validated showing significant correlations with overall survival of G-CIMP-/unMGMT GBMs when treated with RT/TMZ, rather than RT alone. The 10-CpG risk signature was further observed for aiding TMZ choice by distinguishing differential outcomes to RT/TMZ versus RT within each risk subgroup. Functional studies on GPR81, the gene harboring one of the 10 CpGs, indicated its distinct impacts on TMZ resistance in GBM cells, which may be dependent on the status of MGMT expression. CONCLUSIONS: The 64 TMZ efficacy-related CpGs and in particular the 10-CpG risk signature may serve as promising predictive biomarker candidates for guiding optimal usage of TMZ in G-CIMP-/unMGMT GBMs.