Programmed cell death factor 4-mediated hippocampal synaptic plasticity is involved in early life stress and susceptibility to depression.

Early life stress (ELS) increases the risk of depression later in life. Programmed cell death factor 4 (PDCD4), an apoptosis-related molecule, extensively participates in tumorigenesis and inflammatory diseases. However, its involvement in a person's susceptibility to ELS-related depression is unknown. To examine the effects and underlying mechanisms of PDCD4 on ELS vulnerability, we used a "two-hit" stress mouse model: an intraperitoneal injection of lipopolysaccharide (LPS) into neonatal mice was performed on postnatal days 7-9 (P7-P9) and inescapable foot shock (IFS) administration in adolescent was used as a later-life challenge. Our study shows that compared with mice that were only exposed to the LPS or IFS, the "two-hit" stress mice developed more severe depression/anxiety-like behaviors and social disability. We detected the levels of PDCD4 in the hippocampus of adolescent mice and found that they were significantly increased in "two-hit" stress mice. The results of immunohistochemical staining and Sholl analysis showed that the number of microglia in the hippocampus of "two-hit" stress mice significantly increased, with morphological changes, shortened branches, and decreased numbers. However, knocking down PDCD4 can prevent the number and morphological changes of microglia induced by ELS. In addition, we confirmed through the Golgi staining and immunohistochemical staining results that knocking down PDCD4 can ameliorate ELS-induced synaptic plasticity damage. Mechanically, the knockdown of PDCD4 exerts neuroprotective effects, possibly via the mediation of BDNF/AKT/CREB signaling. Combined, these results suggest that PDCD4 may play an important role in the ELS-induced susceptibility to depression and, thus, may become a therapeutic target for depressive disorders.

Programmable and Modularized Gas Sensor Integrated by 3D Printing.

The rapid advancement of intelligent manufacturing technology has enabled electronic equipment to achieve synergistic design and programmable optimization through computer-aided engineering. Three-dimensional (3D) printing, with the unique characteristics of near-net-shape forming and mold-free fabrication, serves as an effective medium for the materialization of digital designs into usable devices. This methodology is particularly applicable to gas sensors, where performance can be collaboratively optimized by the tailored design of each internal module including composition, microstructure, and architecture. Meanwhile, diverse 3D printing technologies can realize modularized fabrication according to the application requirements. The integration of artificial intelligence software systems further facilitates the output of precise and dependable signals. Simultaneously, the self-learning capabilities of the system also promote programmable optimization for the hardware, fostering continuous improvement of gas sensors for dynamic environments. This review investigates the latest studies on 3D-printed gas sensor devices and relevant components, elucidating the technical features and advantages of different 3D printing processes. A general testing framework for the performance evaluation of customized gas sensors is proposed. Additionally, it highlights the superiority and challenges of programmable and modularized gas sensors, providing a comprehensive reference for material adjustments, structure design, and process modifications for advanced gas sensor devices.

Assessing the interaction effects of mitochondrial DNA polymorphisms and lifestyle on heel bone mineral density.

BACKGROUND: Bone mineral density (BMD) is a major predictor of osteoporotic fractures, and previous studies have reported the effects of mitochondrial dysfunction and lifestyle on BMD, respectively. However, their interaction effects on BMD are still unclear. Therefore, we aimed to investigate the possible interaction of mitochondrial DNA (mtDNA) and common lifestyles contributing to osteoporosis. METHODS: Our analysis included 119,120 white participants (Nfemale=65,949 and Nmale=53,171) from the UK Biobank with heel BMD phenotype data. A generalized linear regression model of PLINK was performed to assess the interaction effects of mtDNA and five life environmental factors on heel BMD, including smoking, drinking, physical activity, dietary diversity score, and vitamin D. In addition, we also performed linear regression analysis for total body BMD. Finally, we assessed the potential causal relationships between mtDNA copy number (mtDNA-CN) and life environmental factors using Mendelian randomization (MR) analysis. RESULTS: Our study identified four mtDNA loci showing suggestive evidence of heel BMD, such as m.16356T>C (MT-DLOOP; P =1.50×10-3) in total samples. Multiple candidate mtDNA×lifetsyle interactions were also detected for heel BMD, such as MT-ND2×physical activity (P = 2.88×10-3) in total samples and MT-ND1×smoking (P = 8.54×10-4) in males. Notably, MT-CYB was a common candidate mtDNA loci for heel BMD to interact with five life environmental factors. Multivariable MR analysis indicated a causal effect of physical activity on heel BMD when mtDNA-CN was considered (P =1.13×10-3). CONCLUSIONS: Our study suggests the candidate interaction between mitochondria and lifestyles on heel BMD, providing novel clues for exploring the pathogenesis of osteoporosis.

The miR-9-5p/CXCL11 pathway is a key target of hydrogen sulfide-mediated inhibition of neuroinflammation in hypoxic ischemic brain injury.

We previously showed that hydrogen sulfide (H2S) has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice. However, the precise mechanism underlying the role of H2S in this situation remains unclear. In this study, we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine, a H2S precursor, attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionine ß synthase (a major H2S synthetase in the brain) in the prefrontal cortex. We also found that an miR-9-5p inhibitor blocked the expression of cystathionine ß synthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia. Furthermore, miR-9-5p overexpression increased cystathionine-ß-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury. L-cysteine decreased the expression of CXCL11, an miR-9-5p target gene, in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3, FSTL1, SOCS2 and SOCS5, while treatment with an miR-9-5p inhibitor reversed these changes. These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoring ß-synthase expression, thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.

MRD-directed and risk-adapted individualized stratified treatment of AML.

Measurable residual disease (MRD) has been widely recognized as a biomarker for deeply evaluating complete remission (CR), predicting relapse, guiding pre-emptive interventions, and serving as an endpoint surrogate for drug testing. However, despite the emergence of new technologies, there remains a lack of comprehensive understanding regarding the proper techniques, sample materials, and optimal time points for MRD assessment. In this review, we summarized the MRD methods, sample sources, and evaluation frequency according to the risk category of the European Leukemia Net (ELN) 2022. Additionally, we emphasize the importance of properly utilizing and combining these technologies. We have also refined the flowchart outlining each time point for pre-emptive interventions and intervention paths. The evaluation of MRD in acute myeloid leukemia (AML) is sophisticated, clinically applicable, and technology-dependent, and necessitates standardized approaches and further research.

A longitudinal genome-wide association study of bone mineral density mean and variability in the UK Biobank.

Bone mineral density (BMD) is an essential predictor of osteoporosis and fracture. We conducted a genome-wide trajectory analysis of BMD and analyzed the BMD change. PURPOSE: This study aimed to identify the genetic architecture and potential biomarkers of BMD. METHODS: Our analysis included 141,261 white participants from the UK Biobank with heel BMD phenotype data. We used a genome-wide trajectory analysis tool, TrajGWAS, to conduct a genome-wide association study (GWAS) of BMD. Then, we validated our findings in previously reported BMD genetic associations and performed replication analysis in the Asian participants. Finally, gene-set enrichment analysis (GSEA) of the identified candidate genes was conducted using the FUMA platform. RESULTS: A total of 52 genes associated with BMD trajectory mean were identified, of which the top three significant genes were WNT16 (P = 1.31 × 10-126), FAM3C (P = 4.18 × 10-108), and CPED1 (P = 8.48 × 10-106). In addition, 114 genes associated with BMD within-subject variability were also identified, such as AC092079.1 (P = 2.72 × 10-13) and RGS7 (P = 4.72 × 10-10). The associations for these candidate genes were confirmed in the previous GWASs and replicated successfully in the Asian participants. GSEA results of BMD change identified multiple GO terms related to skeletal development, such as SKELETAL SYSTEM DEVELOPMENT (Padjusted = 2.45 × 10-3) and REGULATION OF OSSIFICATION (Padjusted = 2.45 × 10-3). KEGG enrichment analysis showed that these genes were mainly enriched in WNT SIGNALING PATHWAY. CONCLUSIONS: Our findings indicated that the CPED1-WNT16-FAM3C locus plays a significant role in BMD mean trajectories and identified several novel candidate genes contributing to BMD within-subject variability, facilitating the understanding of the genetic architecture of BMD.

A systematical association analysis of 25 common virus infection and genetic susceptibility of COVID-19 infection.

OBJECTIVES: Previous studies identified a number of diseases were associated with 2019 coronavirus disease (COVID-19). However, the associations between these diseases related viral infections and COVID-19 remains unknown now. METHODS: In this study, we utilized single nucleotide polymorphisms (SNPs) related to COVID-19 from genome-wide association study (GWAS) and individual-level genotype data from the UK biobank to calculate polygenic risk scores (PRS) of 487,409 subjects for eight COVID-19 clinical phenotypes. Then, multiple logistic regression models were established to assess the correlation between serological measurements (positive/negative) of 25 viruses and the PRS of eight COVID-19 clinical phenotypes. And we performed stratified analyses by age and gender. RESULTS: In whole population, we identified 12 viruses associated with the PRS of COVID-19 clinical phenotypes, such as VZV seropositivity for Varicella Zoster Virus (Unscreened/Exposed_Negative: ß = 0.1361, P = 0.0142; Hospitalized/Unscreened: ß = 0.1167, P = 0.0385) and MCV seropositivity for Merkel Cell Polyomavirus (Unscreened/Exposed_Negative: ß = -0.0614, P = 0.0478). After age stratification, we identified seven viruses associated with the PRS of eight COVID-19 clinical phenotypes in the age < 65 years group. After gender stratification, we identified five viruses associated with the PRS of eight COVID-19 clinical phenotypes in the women group. CONCLUSION: Our study findings suggest that the genetic susceptibility to different COVID-19 clinical phenotypes is associated with the infection status of various common viruses.

Evaluating the interaction between 3'aQTL and alcohol consumption/smoking on anxiety and depression: 3'aQTL-by-environment interaction study in UK Biobank cohort.

BACKGROUND: Smoking and alcohol consumption were associated with the development of depression and anxiety. 3'UTR APA quantitative trait loci (3'aQTLs) have been associated with multiple health states and conditions. Our aim is to evaluate the interactive effects of 3'aQTLs-alcohol consumption/tobacco smoking on the risk of anxiety and depression. METHODS: The 3'aQTL data of 13 brain regions were extracted from the large-scale 3'aQTL atlas. The phenotype data (frequency of cigarette smoking and alcohol drinking, anxiety score, self-reported anxiety, depression score and self-reported depression) of 90,399-103,011 adults aged 40-69 years living in the UK and contributing to the UK Biobank during 2006-2010, were obtained from the UK Biobank cohort. The frequency of cigarette smoking and alcohol drinking of each subject were defined by the amount of smoking and alcohol drinking of self-reported, respectively. The continuous alcohol consumption/smoking terms were further categorized in tertiles. 3'aQTL-by-environmental interaction analysis was then performed to evaluate the associations of gene-smoking/alcohol consumption interactions with anxiety and depression using generalized linear model (GLM) of PLINK 2.0 with an additive mode of inheritance. Furthermore, GLM was also used to explore the relationship between alcohol consumption/smoking with hazard of anxiety/depression stratified by allele for the significant genotyped SNPs that modified the alcohol consumption/smoking-anxiety/depression association. RESULTS: The interaction analysis identified several candidate 3'aQTLs-alcohol consumption interactions, such as rs7602638 located in PPP3R1 (ß = 0.08, P = 6.50 × 10-6) for anxiety score; rs10925518 located in RYR2 (OR = 0.95, P = 3.06 × 10-5) for self-reported depression. Interestingly, we also observed that the interactions between TMOD1 (ß = 0.18, P = 3.30 × 10-8 for anxiety score; ß = 0.17, P = 1.42 × 10-6 for depression score), ZNF407 (ß = 0.17, P = 2.11 × 10-6 for anxiety score; ß = 0.15, P = 4.26 × 10-5 for depression score) and alcohol consumption was not only associated with anxiety, but related to depression. Besides, we found that relationship between alcohol consumption and hazard of anxiety/depression was significantly different for different SNPs genotypes, such as rs34505550 in TMOD1 (AA: OR = 1.03, P = 1.79 × 10-6; AG: OR = 1.00, P = 0.94; GG: OR = 1.00, P = 0.21) for self-reported anxiety. LIMITATIONS: The identified 3'aQTLs-alcohol consumption/smoking interactions were associated with depression and anxiety, and its potential biological mechanisms need to be further revealed. CONCLUSIONS: Our study identified important interactions between candidate 3'aQTL and alcohol consumption/smoking on depression and anxiety, and found that the 3'aQTL may modify the associations between consumption/smoking with depression and anxiety. These findings may help to further explore the pathogenesis of depression and anxiety.

Mechanistic Insights into the Role of OPN in Mediating Brain Damage via Triggering Lysosomal Damage in Microglia/Macrophage.

We previously found that osteopontin (OPN) played a role in hypoxia-ischemia (HI) brain damage. However, its underlying mechanism is still unknown. Bioinformatics analysis revealed that the OPN protein was linked to the lysosomal cathepsin B (CTSB) and galectin-3 (GAL-3) proteins after HI exposure. In the present study, we tested the hypothesis that OPN was able to play a critical role in the lysosomal damage of microglia/macrophages following HI insult in neonatal mice. The results showed that OPN expression was enhanced, especially in microglia/macrophages, and colocalized with lysosomal-associated membrane protein 1 (LAMP1) and GAL-3; this was accompanied by increased LAMP1 and GAL-3 expression, CTSB leakage, as well as impairment of autophagic flux in the early stage of the HI process. In addition, the knockdown of OPN expression markedly restored lysosomal function with significant improvements in the autophagic flux after HI insult. Interestingly, cleavage of OPN was observed in the ipsilateral cortex following HI. The wild-type OPN and C-terminal OPN (Leu152-Asn294), rather than N-terminal OPN (Met1-Gly151), interacted with GAL-3 to induce lysosomal damage. Furthermore, the secreted OPN stimulated lysosomal damage by binding to CD44 in microglia in vitro. Collectively, this study demonstrated that upregulated OPN in microglia/macrophages and its cleavage product was able to interact with GAL-3, and secreted OPN combined with CD44, leading to lysosomal damage and exacerbating autophagosome accumulation after HI exposure.

Assessing the interaction effects of brain structure longitudinal changes and life environmental factors on depression and anxiety.

Disrupted brain structures and several life environmental factors have been shown to influence depression and anxiety, but their interactions with anxiety and depression remain elusive. Genome-wide association study datasets of 15 brain structure longitudinal changes (N = 15,640) were obtained from the published study. Genotype and phenotype-related data of depression, anxiety, and life environmental factors (including smoking, alcohol drinking, coffee intake, maternal smoking, physical activity, vitamin D, insomnia, sleep duration, and family satisfaction) were collected from UK Biobank. We calculated the polygenic risk scores (PRS) of 15 brain structure changes and then conducted linear regression analyses to explore the interactions of brain structure changes and life environmental factors on depression and anxiety using 15 brain structure change-related PRS, life environmental factors and interactions of them as instrumental variables, and depression score or anxiety score as outcomes. Sex stratification in all analyses was performed to reveal sex-specific differences in the interactions. We found 14 shared interactions related to both depression and anxiety in total sample, such as alcohol drinking × cerebellum white matter 3 (WM; beta = -.003, p = .018 for depression; beta = -003, p = .008 for anxiety) and maternal smoking × nucleus accumbens 2 (beta = .088, p = .002 for depression; beta = .070, p = .008 for anxiety). We also observed sex-specific differences in the interactions, for instance, alcohol drinking × cerebellum WM 3 was negatively associated with depression and anxiety in males (beta = -.004, p = .020 for depression; beta = -.005, p = .002 for anxiety). Our study results reveal the important interactions between brain structure changes and several life environmental factors on depression and anxiety, which may help to explore the pathogenesis of depression and anxiety.

Comprehensive analysis of ECHDC3 as a potential biomarker and therapeutic target for acute myeloid leukemia: Bioinformatic analysis and experimental verification.

Background: Enoyl-CoA hydratase domain containing 3 (ECHDC3) increased in CD34+ progenitor cells of acute myeloid leukemia (AML) cells after chemotherapy. However, the prognostic significance and function of ECHDC3 in AML remain to be clarified. Methods: In the training cohort, 24 AML (non-acute promyelocytic leukemia, APL) patients were enrolled in Peking University People's Hospital and tested for ECHDC3 in enriched CD34+ cells at diagnosis. In the validation set, 351 bone marrow RNA-seq data of non-APL AML were obtained by two independent online datasets (TCGA-LAML and BEAT-AML). LASSO regression model was conducted to a new prediction model of ECHDC3-related genes. In addition, the ECHDC3 signature was further explored by GO, KEGG, GSEA, and immuno-infiltration analysis. By RNA interference, the function of ECHDC3 in mitochondrial DNA (mt-DNA) transcriptome and chemoresistance was further explored, and the GSE52919 database re-verified the ECHDC3 chemoresistance feature. Results: By Kaplan-Meier analysis, patients with ECHDC3high demonstrated inferior overall survival (OS) compared to those with ECHDC3low both in the training (2-year OS, 55.6% vs. 100%, p = 0.011) and validation cohorts (5-year OS, 9.6% vs. 24.3%, p = 0.002). In addition, ECHDC3high predicted inferior OS in the subgroup of patients with ELN 2017 intermediated (int) risk (5-year OS, 9.5% vs. 26.3%, p = 0.039) or FLT3+NPM1- adverse (adv) risk (4-year OS, 6.4% vs. 31.8%, p = 0.003). In multivariate analysis, ECHDC3 was an independent risk factor of inferior OS (HR 1.159, 95% CI 1.013-1.326, p = 0.032). In the prediction model combining ECHDC3 and nine selected genes (RPS6KL1, RELL2, FAM64A, SPATS2L, MEIS3P1, CDCP1, CD276, IL1R2, and OLFML2A) by Lasso regression, patients with high risk showed inferior 5-year OS (9.3% vs. 23.5%, p < 0.001). Bioinformatic analysis suggested that ECHDC3 alters the bone marrow microenvironment by inducing NK, resting mast cell, and monocyte differentiation. Knocking down ECHDC3 in AML cells by RNAi promoted the death of leukemia cells with cytarabine and doxorubicin. Conclusion: These bioinformatic analyses and experimental verification indicated that high ECHDC3 expression might be a poor prognostic biomarker for non-APL AML, which might be a potential target for reverting chemoresistance.

Clinical Study of Progesterone Combined with Vitamin B6 in the Treatment of Amenorrhea Endocrine Disorders Caused by Antipsychotics.

Background: Endocrine disorders such as amenorrhea, lactation, and irregular menstruation caused by antipsychotics are common in female patients. How to reduce or eliminate these adverse reactions is a matter of concern. Objective: To evaluate the therapeutic effect of progesterone in combination with vitamin B6 in the treatment of antipsychotic-induced amenorrhea. Methods: In our hospital, from May 2019 to May 2021, 120 patients with amenorrhea caused by antipsychotics who underwent surgery were selected for this prospective study. The random residue grouping method divided them into a progesterone group (60 cases) and a vitamin B6 group (60 cases). Among them, the progesterone group was treated only with progesterone, while the vitamin B6 group was given progesterone in combination with vitamin B6. The differences in endocrine index, prolactin, uterine size, and endometrial thickness, effectiveness, and safety analysis of the progesterone and vitamin B6 groups of patients were observed and compared. Results: Before treatment, there was no change in the comparison of endocrine indexes between the progesterone and vitamin B6 groups (P > 0.05). After 1 month of treatment, there were significant differences in estradiol, prolactin, and follicle-stimulating hormone between the progesterone and vitamin B6 groups of patients (P < 0.05). After 1 month of treatment, there were significant differences in prolactin, uterine size, and endometrial thickness, and the vitamin B6 group was significantly lower than the progesterone group (P < 0.05). The clinical efficiency of 95.00% in the vitamin B6 group was significantly higher than 83.33% in the progesterone group (P < 0.05). There were no adverse reactions in the progesterone and vitamin B6 groups. Conclusion: The effectiveness of progesterone combined with vitamin B6 in treating amenorrhea caused by antipsychotics is significantly better than simple progesterone, which can effectively improve the endocrine condition of patients and provide a reference for the clinical treatment of amenorrhea caused by antipsychotics.

Identification of Human Brain Proteins for Bitter-Sweet Taste Perception: A Joint Proteome-Wide and Transcriptome-Wide Association Study.

Objective: Bitter or sweet beverage perception is associated with alterations in brain structure and function. Our aim is to analyze the genetic association between bitter or sweet beverage perception and human brain proteins. Materials and methods: In our study, 8356 and 11,518 proteins were first collected from two reference datasets of human brain proteomes, the ROS/MAP and Banner. The bitter or sweet beverage perception-related proteome-wide association studies (PWAS) were then conducted by integrating recent genome-wide association study (GWAS) data (n = 422,300) of taste perception with human brain proteomes. The human brain gene expression profiles were collected from two reference datasets, including the brain RNA-seq (CBR) and brain RNA-seq splicing (CBRS). The taste perception-related transcriptome-wide association studies (TWAS) were finally performed by integrating the same GWAS data with human brain gene expression profiles to validate the PWAS findings. Results: In PWAS, four statistically significant proteins were identified using the ROS/MAP and then replicated using the Banner reference dataset (all permutated p < 0.05), including ABCG2 for total bitter beverages and tea, CPNE1 for total bitter beverage, ACTR1B for artificially sweetened beverages, FLOT2 for alcoholic bitter beverages and total sweet beverages. In TWAS analysis, six statistically significant genes were detected by CBR and confirmed by the CBRS reference dataset (all permutated p < 0.05), including PIGG for total bitter beverages and non-alcoholic bitter beverages, C3orf18 for total bitter beverages, ZSWIM7 for non-alcoholic bitter beverages, PEX7 for coffee, PKP4 for tea and RPLP2 for grape juice. Further comparison of the PWAS and TWAS found three common statistically significant proteins/genes identified from the Banner and CBR reference datasets, including THBS4 for total bitter beverages, CA4 for non-alcoholic bitter beverages, LIAS for non-grape juices. Conclusions: Our results support the potential effect of bitter or sweet beverage perception on brain function and identify several candidate brain proteins for bitter or sweet beverage perception.

L-Cysteine attenuates osteopontin-mediated neuroinflammation following hypoxia-ischemia insult in neonatal mice by inducing S-sulfhydration of Stat3.

We previously show that L-Cysteine administration significantly suppresses hypoxia-ischemia (HI)-induced neuroinflammation in neonatal mice through releasing H2S. In this study we conducted proteomics analysis to explore the potential biomarkers or molecular therapeutic targets associated with anti-inflammatory effect of L-Cysteine in neonatal mice following HI insult. HI brain injury was induced in postnatal day 7 (P7) neonatal mice. The pups were administered L-Cysteine (5 mg/kg) at 24, 48, and 72 h post-HI. By conducting TMT-based proteomics analysis, we confirmed that osteopontin (OPN) was the most upregulated protein in ipsilateral cortex 72 h following HI insult. Moreover, OPN was expressed in CD11b+/CD45low cells and infiltrating CD11b+/CD45high cells after HI exposure. Intracerebroventricular injection of OPN antibody blocked OPN expression, significantly attenuated brain damage, reduced pro-inflammatory cytokine levels and suppressed cerebral recruitment of CD11b+/CD45high immune cells following HI insult. L-Cysteine administration reduced OPN expression in CD11b+/CD45high immune cells, concomitant with improving the behavior in Y-maze test and suppressing cerebral recruitment of CD11b+/CD45high immune cells post-HI insult. Moreover, L-Cysteine administration suppressed the Stat3 activation by inducing S-sulfhydration of Stat3. Intracerebroventricular injection of Stat3 siRNA not only decreased OPN expression, but also reversed HI brain damage. Our data demonstrate that L-Cysteine administration effectively attenuates the OPN-mediated neuroinflammation by inducing S-sulfhydration of Stat3, which contributes to its anti-inflammatory effect following HI insult in neonatal mice. Blocking OPN expression may serve as a new target for therapeutic intervention for perinatal HI brain injury.

L-Cysteine Provides Neuroprotection of Hypoxia-Ischemia Injury in Neonatal Mice via a PI3K/Akt-Dependent Mechanism.

BACKGROUND: Previous work within our laboratory has revealed that hydrogen sulfide (H2S) can serve as neuroprotectant against brain damage caused by hypoxia-ischemia (HI) exposure in neonatal mice. After HI insult, activation of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway has been shown to be implicated in neuro-restoration processes. The goal of the current study was to determine whether the neuroprotective effects of H2S were mediated by the PI3K/Akt signaling pathway. METHODS: The mouse HI model was built at postnatal day 7 (P7), and the effects of L-Cysteine treatment on acute brain damage (72 h post-HI) and long-term neurological responses (28 days post-HI) were evaluated. Nissl staining and Transmission electron microscopy were used to evaluate the neuronal loss and apoptosis. Immunofluorescence imaging and dihydroethidium staining were utilized to determine glial cell activation and ROS content, respectively. RESULTS: Quantitative results revealed that L-Cysteine treatment significantly prevented the acute effects of HI on apoptosis, glial cell activation and oxidative injury as well as the long-term effects upon memory impairment in neonatal mice. This protective effect of L-Cysteine was found to be associated with the phosphorylation of Akt and phosphatase and a tensin homolog deletion on chromosome 10 (PTEN). Following treatment with the PI3K inhibitor, LY294002, the neuroprotective effects of L-Cysteine were attenuated. CONCLUSION: PTEN/PI3K/Akt signaling was involved in mediating the neuroprotective effects of exogenous H2S against HI exposure in neonatal mice.

Nuclear-Encoded lncRNA MALAT1 Epigenetically Controls Metabolic Reprogramming in HCC Cells through the Mitophagy Pathway.

Mitochondrial dysfunction is a metabolic hallmark of cancer cells. In search of molecular factors involved in this dysregulation in hepatocellular carcinoma (HCC), we found that the nuclear-encoded long noncoding RNA (lncRNA) MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) was aberrantly enriched in the mitochondria of hepatoma cells. Using RNA reverse transcription-associated trap sequencing (RAT-seq), we showed that MALAT1 interacted with multiple loci on mitochondrial DNA (mtDNA), including D-loop, COX2, ND3, and CYTB genes. MALAT1 knockdown induced alterations in the CpG methylation of mtDNA and in mitochondrial transcriptomes. This was associated with multiple abnormalities in mitochondrial function, including altered mitochondrial structure, low oxidative phosphorylation (OXPHOS), decreased ATP production, reduced mitophagy, decreased mtDNA copy number, and activation of mitochondrial apoptosis. These alterations in mitochondrial metabolism were associated with changes in tumor phenotype and in pathways involved in cell mitophagy, mitochondrial apoptosis, and epigenetic regulation. We further showed that the RNA-shuttling protein HuR and the mitochondria transmembrane protein MTCH2 mediated the transport of MALAT1 in this nuclear-mitochondrial crosstalk. This study provides the first evidence that the nuclear genome-encoded lncRNA MALAT1 functions as a critical epigenetic player in the regulation of mitochondrial metabolism of hepatoma cells, laying the foundation for further clarifying the roles of lncRNAs in tumor metabolic reprogramming.

Isoorientin Inhibits Inflammation in Macrophages and Endotoxemia Mice by Regulating Glycogen Synthase Kinase 3ß.

Isoorientin has anti-inflammatory effects; however, the mechanism remains unclear. We previously found isoorientin is an inhibitor of glycogen synthase kinase 3ß (GSK3ß) in vitro. Overactivation of GSK3ß is associated with inflammatory responses. GSK3ß is inactivated by phosphorylation at Ser9 (i.e., p-GSK3ß). Lithium chloride (LiCl) inhibits GSK3ß and also increases p-GSK3ß (Ser9). The present study investigated the anti-inflammatory effect and mechanism of isoorientin via GSK3ß regulation in lipopolysaccharide- (LPS-) induced RAW264.7 murine macrophage-like cells and endotoxemia mice. LiCl was used as a control. While AKT phosphorylates GSK3ß, MK-2206, a selective AKT inhibitor, was used to activate GSK3ß via AKT inhibition (i.e., not phosphorylate GSK3ß at Ser9). The proinflammatory cytokines TNF-α, IL-6, and IL-1ß were detected by ELISA or quantitative real-time PCR, while COX-2 by Western blotting. The p-GSK3ß and GSK3ß downstream signal molecules, including NF-κB, ERK, Nrf2, and HO-1, as well as the tight junction proteins ZO-1 and occludin were measured by Western blotting. The results showed that isoorientin decreased the production of TNF-α, IL-6, and IL-1ß and increased the expression of p-GSK3ß in vitro and in vivo, similar to LiCl. Coadministration of isoorientin and LiCl showed antagonistic effects. Isoorientin decreased the expression of COX-2, inhibited the activation of ERK and NF-κB, and increased the activation of Nrf2/HO-1 in LPS-induced RAW264.7 cells. Isoorientin increased the expressions of occludin and ZO-1 in the brain of endotoxemia mice. In summary, isoorientin can inhibit GSK3ß by increasing p-GSK3ß and regulate the downstream signal molecules to inhibit inflammation and protect the integrity of the blood-brain barrier and the homeostasis in the brain.

Machine learning-based radiomics analysis in predicting the meningioma grade using multiparametric MRI.

PURPOSE: To investigate the prediction performance of radiomic models based on multiparametric MRI in predicting the meningioma grade. METHOD: In all, 229 low-grade [Grade I] and 87 high-grade [Grade II/III] patients with pathologically diagnosed meningiomas were enrolled. Radiomic features from conventional MRI (cMRI), ADC maps and SWI were extracted based on the volume of entire tumor. Classification performance of different radiomic models (cMRI, ADC, SWI, cMRI + ADC, cMRI + SWI, ADC + SWI, and cMRI + ADC + SWI models) was evaluated by a nested LOOCV approach, combining the LASSO feature selection and RF classifier that was trained (1) without subsampling, and (2) with the synthetic minority over-sampling technique (SMOTE). The prediction performance of radiomic models was assessed using ROC curve and AUC of them was compared using Delong's test. RESULTS: The cMRI + ADC + SWI model demonstrated the best performance without or with subsampling, which AUCs were 0.84 and 0.81, respectively. Following the cMRI + ADC + SWI model, the AUC range of the other models was 0.75-0.80 without subsampling, and was 0.71-0.79 with subsampling. Although the cMRI + ADC model and cMRI + SWI model showed higher AUCs than the cMRI model without subsampling (0.77 vs 0.80, P = 0.037 and 0.77 vs 0.80, P = 0.009, respectively), there was no significant difference among these models with subsampling (0.78 vs 0.77, P = 0.552 and 0.78 vs 0.79, P = 0.246, respectively). CONCLUSIONS: Multiparametric radiomic model based on cMRI, ADC map and SWI yielded the best prediction performance in predicting the meningioma grade, which might offer potential guidance in clinical decision-making.

Machine-learning-based computed tomography radiomic analysis for histologic subtype classification of thymic epithelial tumours.

PURPOSE: To evaluate the performance of machine-learning-based computed tomography (CT) radiomic analysis to differentiate high-risk thymic epithelial tumours (TETs) from low-risk TETs according to the WHO classification. METHOD: This retrospective study included 155 patients with a histologic diagnosis of high-risk TET (n = 72) and low-risk TET (n = 83) who underwent unenhanced CT (UECT) and contrast-enhanced CT (CECT). The radiomic features were extracted from the UECT and CECT of each patient at the largest cross-section of the lesion. The classification performance was evaluated with a nested leave-one-out cross-validation approach combining the least absolute shrinkage and selection operator feature selection and four classifiers: generalised linear model (GLM), k-nearest neighbor (KNN), support vector machine (SVM) and random forest (RF). The receiver-operating characteristic curve (ROC) and the area under the curve (AUC) were used to evaluate the performance of the classifiers. RESULTS: The combination of UECT and CECT radiomic features demonstrated the best performance to differentiate high-risk TETs from low-risk TETs for all four classifiers. Among these classifiers, the RF had the highest AUC of 0.87, followed by GLM (AUC = 0.86), KNN (AUC = 0.86) and SVM (AUC = 0.84). CONCLUSIONS: Machine learning-based CT radiomic analysis allows for the differentiation of high-risk TETs and low-risk TETs with excellent performance, representing a promising tool to assist clinical decision making in patients with TETs.