Comprehensive profiling of lipid metabolic reprogramming expands precision medicine for HCC.

BACKGROUND AND AIMS: Liver HCC is the second leading cause of cancer-related deaths worldwide. The heterogeneity of this malignancy is driven by a wide range of genetic alterations, leading to a lack of effective therapeutic options. In this study, we conducted a systematic multi-omics characterization of HCC to uncover its metabolic reprogramming signature. APPROACH AND RESULTS: Through a comprehensive analysis incorporating transcriptomic, metabolomic, and lipidomic investigations, we identified significant changes in metabolic pathways related to glucose flux, lipid oxidation and degradation, and de novo lipogenesis in HCC. The lipidomic analysis revealed abnormal alterations in glycerol-lipids, phosphatidylcholine, and sphingolipid derivatives. Machine-learning techniques identified a panel of genes associated with lipid metabolism as common biomarkers for HCC across different etiologies. Our findings suggest that targeting phosphatidylcholine with saturated fatty acids and long-chain sphingolipid biosynthesis pathways, particularly by inhibiting lysophosphatidylcholine acyltransferase 1 ( LPCAT1 ) and ceramide synthase 5 ( CERS5 ) as potential therapeutic strategies for HCC in vivo and in vitro. Notably, our data revealed an oncogenic role of CERS5 in promoting tumor progression through lipophagy. CONCLUSIONS: In conclusion, our study elucidates the metabolic reprogramming nature of lipid metabolism in HCC, identifies prognostic markers and therapeutic targets, and highlights potential metabolism-related targets for therapeutic intervention in HCC.

Therapeutic effect and transcriptome-methylome characteristics of METTL3 inhibition in liver hepatocellular carcinoma.

Methyltransferase-like 3 (METTL3) is the key subunit of methyltransferase complex responsible for catalyzing N6-methyladenosine (m6A) modification on mRNA, which is the most prevalent post-transcriptional modification in eukaryotes. In this study, we utilized online databases to analyze the association between METTL3 expression and various aspects of tumorigenesis, including gene methylation, immunity, and prognosis. Our investigation revealed that METTL3 serves as a prognostic marker and therapeutic target for liver hepatocellular carcinoma (LIHC). Through experimental studies, we observed frequent upregulation of METTL3 in LIHC tumor tissue and cells. Subsequent inhibition of METTL3 using a novel small molecule inhibitor, STM2457, significantly impeded tumor growth in LIHC cell lines, spheroids, and xenograft tumor model. Further, transcriptome and m6A sequencing of xenograft bodies unveiled that inhibition of METTL3-m6A altered genes enriched in SMAD and MAPK signaling pathways that are critical for tumorigenesis. These findings suggest that targeting METTL3 represents a promising therapeutic strategy for LIHC.

Targeting FAM134B-mediated reticulophagy activates sorafenib-induced ferroptosis in hepatocellular carcinoma.

Ferroptosis is a kind of cell death closely related to selective autophagy, such as ferritinophagy, lipophagy, clockophagy and chaperone-mediated autophagy. However, the role of reticulophagy, which specifically degrades endoplasmic reticulum (ER) fragments (also known as ER-phagy), in ferroptosis regulation is still unclear. In this study, we found that sorafenib (ferroptosis inducer) can effectively activate the receptor protein FAM134B-mediated ER-phagy, and FAM134B knockdown not only blocked ER-phagy but also significantly strengthened cellular sensitivity to ferroptosis without affecting macroautophagy. In vivo experiments also yielded similar results. These evidences provided new clues for ferroptosis regulation. Subsequently, bioinformatic analysis combined with RNA binding protein immunoprecipitation and polyribosome fractionation preliminarily indicated that PABPC1 can interact with FAM134B mRNA and promote its translation. Taken together, this study revealed the role of the PABPC1-FAM134B-ER-phagy pathway on ferroptosis, providing important evidence for novel anti-cancer strategies.

WITHDRAWN: The anti-growth and anti-metastasis effects of Schisandrin B on hepatocarcinoma cells in vitro and in vivo.

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Comprehensive control of networked control systems with multistep delay.

In networked control systems with multi-step delay, long time-delay causes vacant sampling and controller design difficulty. In order to solve the above problems, comprehensive control methods are proposed in this paper. Time-delay compensation control and linear-quadratic-Guassian (LQG) optimal control are adopted and the systems switch different controllers between two different states. LQG optimal controller is used with probability 1--α in normal state, which is shown to render the systems mean square exponentially stable. Time-delay compensation controller is used with probability α in abnormal state to compensate vacant sampling and long time-delay. In addition, a buffer window is established at the actuator of the systems to store some history control inputs which are used to estimate the control state of present sampling period under the vacant sampling cases. The comprehensive control methods simplify control design which is easier to be implemented in engineering. The performance of the systems is also improved. Simulation results verify the validity of the proposed theory.

Bmi1 facilitates the progression of cholangiocarcinoma by inhibiting Foxn2 expression dependent on a histone H2A ubiquitination manner.

Cholangiocarcinoma (CCA), an exceptionally aggressive malignancy originating from the epithelium of the bile duct, poses a formidable challenge in cancer research and clinical management. Currently, attention is focused on exploring the oncogenic role and prognostic implications associated with Bmi1 in the context of CCA. In our study, we assessed the correlation of Bmi1 and Foxn2 expression across all types of CCA and evaluated their prognostic significance. Our results demonstrated that Bmi1 exhibits significantly upregulated expression in CCA tissues, while Foxn2 expression shows an inverse pattern. Simultaneously, the high expression of Bmi1, coupled with the low expression of Foxn2, indicates an unfavorable prognosis. Through in vitro and in vivo experiments, we confirmed the crucial role of Foxn2 in the proliferation, metastasis, and epithelial-mesenchymal transition (EMT) of CCA. Mechanistically, Bmi1 promotes the ubiquitination of histone H2A (H2AUb), leading to chromatin opening attenuation and a decrease in Foxn2 expression, ultimately driving CCA progression. Additionally, we described the potential value of Bmi1 and H2AUb inhibitors in treating CCA through in vitro experiments and orthotopic models. This study is of significant importance in deepening our understanding of the interaction between Bmi1 and Foxn2 in CCA and has the potential to advance the development of precision therapies for CCA.

Corrigendum to "Fault diagnosis for cooling dehumidifier based on fuzzy classifier optimized by adaptive genetic algorithm" [Heliyon 8(12), (December 2022) e12057].

[This corrects the article DOI: 10.1016/j.heliyon.2022.e12057.].

Risk factors, clinical correlates, and social functions of Chinese schizophrenia patients with drug-induced parkinsonism: A cross-sectional analysis of a multicenter, observational, real-world, prospective cohort study.

Background: Drug-induced parkinsonism (DIP) is the most prevalent neurological side effect of antipsychotics in the Chinese population. Early prevention, recognition, and treatment of DIP are important for the improvement of treatment outcomes and medication adherence of schizophrenia patients. However, the risk factors of DIP and the impact on the clinical syndromes of schizophrenia remain unknown. Aim: The goal of this study was to explore the risk factors, clinical correlates, and social functions of DIP in Chinese schizophrenia patients. Methods: A cross-sectional analysis of a multicenter, observational, real-world, prospective cohort study of the Chinese schizophrenia population with a baseline assessment was conducted from the year 2012 to 2018. Participants were recruited from four mental health centers in Shanghai and totaled 969 subjects. Sociodemographic data, drug treatment, and clinical variables were compared between the DIP group and the non-DIP group. Variables that correlated with the induction of DIP, and with p≤ 0.1, were included in the binary logistic model for analyzing the risk factors of DIP. First generation antipsychotics (FGA)/second generation antipsychotics (SGA) model and high and low/medium D2 receptor antipsychotics were analyzed respectively to control the bias of co-linearity. All risk factors derived from the a forementioned models and clinical variables with p≤ 0.1 were included in the multivariate analysis of clinical correlates and social function of DIP patients. The Positive and Negative Syndrome Scale (PANSS) model and the personal and social performance (PSP) model were analyzed separately to control for co-linearity bias. Results: Age (OR = 1.03, p< 0.001), high D2 receptor antagonist antipsychotic dose (OR = 1.08, p = 0.032), and valproate dose (OR = 1.01, p = 0.001) were the risk factors of DIP. FGA doses were not a significant contributor to the induction of DIP. Psychiatric symptoms, including more severe negative symptoms (OR = 1.09, p< 0.001), lower cognition status (OR = 1.08, p = 0.033), and lower excited symptoms (OR = 0.91, p = 0.002), were significantly correlated with DIP induction. Social dysfunction, including reduction in socially useful activities (OR = 1.27, p = 0.004), lower self-care capabilities (OR = 1.53, p< 0.001), and milder disturbing and aggressive behavior (OR = 0.65, p< 0.001), were significantly correlated with induction of DIP. Valproate dose was significantly correlated with social dysfunction (OR = 1.01, p = 0.001) and psychiatric symptoms (OR = 1.01, p = 0.004) of DIP patients. Age may be a profound factor that affects not only the induction of DIP but also the severity of psychiatric symptoms (OR = 1.02, p< 0.001) and social functions (OR = 1.02, p< 0.001) of schizophrenia patients with DIP. Conclusion: Age, high D2 receptor antagonist antipsychotic dose, and valproate dose are risk factors for DIP, and DIP is significantly correlated with psychiatric symptoms and social performance of Chinese schizophrenia patients. The rational application or discontinuation of valproate is necessary. Old age is related to psychotic symptoms and social adaption in Chinese schizophrenic patients, and early intervention and treatment of DIP can improve the prognosis and social performance of schizophrenia patients. Clinical Trial Registration: Identifier: NCT02640911.

Fault diagnosis for cooling dehumidifier based on fuzzy classifier optimized by adaptive genetic algorithm.

The running of cooling dehumidifier is characterized by strong coupling, large delay and nonlinearity, so it is not easy to establish a precise quantitative model for fault diagnosis. Aiming at this problem, a fuzzy classifier optimized by adaptive genetic algorithm (AGA) is proposed for the dehumidifier fault diagnosis. Firstly, the data acquisition and experiment system is built and the dehumidifier work statuses are simulated. Secondly, the fuzzy classifier for fault diagnosis is built. The classifier fuzzy rules and membership functions are step-wisely optimized by AGA to improve the model output precision, and a novel nearby mutation operator is proposed in order to extract the rules more accurately. Finally, the fuzzy classifier is validated and also compared with the conventional fuzzy classifier. The results demonstrate that this proposed model optimized by AGA is not only effective for the dehumidifier fault diagnosis, but also has advantages over the conventional model.

Combination of aloin and metformin enhances the antitumor effect by inhibiting the growth and invasion and inducing apoptosis and autophagy in hepatocellular carcinoma through PI3K/AKT/mTOR pathway.

Hepatocellular carcinoma (HCC) is a devastating and highly metastatic cancer worldwide. Metformin (MET) is the priority drug for treatment of type 2 diabetes; however, it possesses multiple biological effects like anticancer and hepatoprotective activity. Herein, we examined the effects of aloin (barbaloin) and MET as well as combination treatment in HCC cell line in vitro and in vivo. As a result, aloin and MET alone exhibited inhibitory effects on proliferation and invasion of HepG2 and Bel-7402 cells. Specially, combination treatment of aloin and MET showed enhanced inhibitory effects in vitro. Aloin and MET alone induced apoptosis and autophagy in vitro. Similarly, aloin and MET cooperated to promote apoptosis and autophagy in HepG2 and Bel-7402 cells. In the HepG2 xenograft models, aloin in combination with MET confine tumor growth and facilitate apoptosis and autophagy. Both the in vitro and in vivo results showed that aloin and MET alone as well as combination treatment activated the PI3K/AKT/mTOR pathway. Overall, our research demonstrated that the concomitant treatment with aloin and MET enhances the antitumor effect by inhibiting the growth and invasion as well as inducing apoptosis and autophagy in HCC through PI3K/AKT/mTOR pathway.

Network-based approach to identify molecular signatures in the brains of depressed suicides.

BACKGROUND: Suicide is a serious and global health problem that has a strong association with major depressive disorder (MDD). Weighted gene co-expression network analysis (WGCNA) was performed for the construction of a co-expression network to get important gene modules associated with depressed suicide. METHODS: Transcriptome sequencing data from dorsolateral prefrontal cortex was used, which included 29 non-psychiatric controls (CON), 21 MDD suicides (MDD-S) and 9 MDD non-suicides (MDD-NS) of medication-free sudden death individuals. RESULTS: The highest correlation in the module-traits relationship was discovered between the black module and suicide (r = -0.30, p = 0.024) as well as MDD (r = -0.34, p = 0.010).Furthermore, the expression levels of genes decreased progressively across the three groups (CON>MDD-NS>MDD-S). Therefore, the genes in the black module was selected for subsequent analyses. Protein-Protein Interaction Network found that the top 10 hub genes were somehow involved in depressed suicide including JUN, FOS, ATF3, MYC, EGR1, FOSB, DUSP1, NFKBIA, TLR2, NR4A1. Most of the GO terms were enriched in cell death and apoptosis and KEGG was mainly enriched in MAPK pathway. Cell Type-Specific Analysis found these genes were significantly enriched in endothelial and microglia (p<0.000) cell types. In addition, 92 genes in this module had at least one highly significant differentially methylated positions between MDD-S and controls. CONCLUSION: Cell death and apoptosis may participate in the interplay between depressed suicide and neuro-inflammation system.

Co-Expression Network Analysis Revealed That the ATP5G1 Gene Is Associated With Major Depressive Disorder.

Major depressive disorder (MDD) is a leading cause of disability worldwide, although its etiology and mechanism remain unknown. The aim of our study was to identify hub genes associated with MDD and to illustrate the underlying mechanisms. A weighted gene co-expression network analysis (WGCNA) was performed to identify significant gene modules and hub genes associated with MDD in peripheral blood mononuclear cells (PBMCs) (n = 45). In the blue module (R 2 = 0.95), five common hub genes in both co-expression network and protein-protein interaction (PPI) network were regarded as "real" hub genes. In another independent dataset, GSE52790, four genes were still significantly down-regulated in PBMCs from MDD patients compared with the controls. Furthermore, these four genes were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in PBMCs from 33 MDD patients and 41 healthy controls. The qRT-PCR analysis showed that ATP synthase membrane subunit c locus 1 (ATP5G1) was significantly down-regulated in samples from MDD patients than in control samples (t = -2.89, p-value = 0.005). Moreover, this gene was significantly differentially expressed between patients and controls in the prefrontal cortex (z = -2.83, p-value = 0.005). Highly significant differentially methylated positions were identified in the Brodmann area 25 (BA25), with probes in the ATP5G1 gene being significantly associated with MDD: cg25495775 (t = 2.82, p-value = 0.008), cg25856120 (t = -2.23, p-value = 0.033), and cg23708347 (t = -2.24, p-value = 0.032). These findings indicate that the ATP5G1 gene is associated with the pathogenesis of MDD and that it could serve as a peripheral biomarker for MDD.

Analysis of the association of MIR124-1 and its target gene RGS4 polymorphisms with major depressive disorder and antidepressant response.

BACKGROUND: Increasing evidence has indicated that dysfunction of miR-124 and target gene regulator of G protein signaling 4 (RGS4) may be involved in the etiology and treatment of major depressive disorder (MDD). However, the molecular mechanisms are not fully understood. This study aimed to investigate whether common genetic variations in these two genes are associated with MDD and therapeutic response to antidepressants in the Chinese population. METHODS: Three polymorphisms including rs531564 (a functional single-nucleotide polymorphism [SNP] in MIR124-1), rs10759 (a microRNA-binding site SNP in RGS4), and rs951436 (a promoter SNP in RGS4) were genotyped in 225 Chinese MDD patients and 436 controls. Among the MDD patients, 147 accepted antidepressant treatment for 8 weeks with therapeutic evaluation at baseline, week 2, week 4, week 6, and week 8 using the 17-item Hamilton Rating Scale for Depression. Multifactor dimensionality reduction (MDR) was used to identify gene-gene interactions. RESULTS: No significant association with MDD was discovered in single-SNP analyses. However, by MDR analysis, the three-locus model of gene-gene interaction was the best for predicting MDD risk. In pharmacogenetic study, a significant association was found in genotypic frequencies of rs951436 between the remitter and non-remitter groups (p=0.026, correction p=0.078). For further analysis, the rs951436 heterozygote carriers had threefold probabilities of achieving clinical complete remission (odds ratio =3.00, 95% confidence interval =1.33-6.76, p=0.007, correction p=0.021) as compared with rs951436 homozygotes (AA+CC) after 8 weeks of treatment. CONCLUSION: An interaction effect of MIR124-1 and RGS4 polymorphisms may play a more important role than individual factors for MDD development. Moreover, RGS4 gene polymorphisms may be associated with antidepressant response among the Han population.

Analysis of Family Functioning and Parent-Child Relationship between Adolescents with Depression and their Parents.

BACKGROUND: Drug therapy combined with family therapy is currently the best treatment for adolescent depression. Nevertheless, family therapy requires an exploration of unresolved problems in the family system, which in practice presents certain difficulties. Previous studies have found that the perceptual differences of family function between parents and children reflect the problems in the family system. AIMS: To explore the characteristics and role of family functioning and parent-child relationship between adolescents with depressive disorder and their parents. METHODS: The general information and clinical data of the 93 adolescents with depression were collected. The Family Functioning Assessment Scale and Parent-child Relationship Scale were used to assess adolescents with depressive disorder and their parents. RESULTS: a) The dimensions of family functioning in adolescents with depressive disorder were more negative in communication, emotional response, emotional involvement, roles, and overall functioning than their parents. The differences were statistically significant. Parent-child relationship dimensions: the closeness and parent-child total scores were more negative compared with the parents and the differences were statistically significant. b) All dimensions of parent-child relationship and family functioning in adolescents with depression except the time spent together were negatively correlated or significantly negatively correlated. c) The results of multivariate regression analysis showed: the characteristics of family functioning, emotional involvement, emotional response, family structure, and income of the adolescents with depressive disorder mainly affected the parent-child relationship. CONCLUSIONS: There were perceptual differences in partial family functioning and parent-child relationship between adolescents with depressive disorder and their parents. Unclear roles between family members, mutual entanglement, too much or too little emotional investment, negligence of inner feelings, parental divorce, and low average monthly family income were the main factors causing adverse parent-child relationship. These perceptual differences have a relatively good predictive effect on family problems, and can be used as an important guide for exploring the family relationship in family therapy.