PCSK9 dysregulates cholesterol homeostasis and triglyceride metabolism in olanzapine-induced hepatic steatosis via both receptor-dependent and receptor-independent pathways.

Schizophrenia, affecting approximately 1% of the global population, is often treated with olanzapine. Despite its efficacy, olanzapine's prolonged use has been associated with an increased risk of cardiovascular diseases and nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanism remains unclear. Proprotein convertase subtilisin kexin type 9 (PCSK9) plays a crucial role in lipid metabolism and is involved in NAFLD pathogenesis via an unknown mechanism. This study aims to investigate the role of PCSK9 in olanzapine-induced NAFLD. C57BL/6J mice and HepG2 and AML12 cell lines were treated with varying concentrations of olanzapine to examine the effects of olanzapine on PCSK9 and lipid metabolism. PCSK9 levels were manipulated using recombinant proteins, plasmids, and small interfering RNAs in vitro, and the effects on hepatic lipid accumulation and gene expression related to lipid metabolism were assessed. Olanzapine treatment significantly increased PCSK9 levels in both animal and cell line models, correlating with elevated lipid accumulation. PCSK9 manipulation demonstrated its central role in mediating hepatic steatosis through both receptor-dependent pathways (impacting NPC1L1) and receptor-independent pathways (affecting lipid synthesis, uptake, and cholesterol biosynthesis). Interestingly, upregulation of SREBP-1c, rather than SREBP-2, was identified as a key driver of PCSK9 increase in olanzapine-induced NAFLD. Our findings establish PCSK9 as a pivotal factor in olanzapine-induced NAFLD, influencing both receptor-related and metabolic pathways. This highlights PCSK9 inhibitors as potential therapeutic agents for managing NAFLD in schizophrenia patients treated with olanzapine.

Comparison of nitrification performance in SBR and SBBR with response to NaCl salinity shock: Microbial structure and functional genes.

Ammonia removal by nitrifiers at the extremely high salinity poses a great challenge for saline wastewater treatment. Sequencing batch reactor (SBR) was conducted with a stepwise increase of salinity from 10 to 40 g-NaCl·L-1, while sequencing batch biofilm reactor (SBBR) with one-step salinity enhancement, their nitrification performance, microbial structure and interaction were evaluated. Both SBR and SBBR can achieve high-efficiency nitrification (98% ammonia removal) at 40 g-NaCl·L-1. However, SBBR showed more stable nitrification performance than SBR at 40 g-NaCl·L-1 after a shorter adaptation period of 4-15 d compared to previous studies. High-throughput sequencing and metagenomic analysis demonstrated that the abundance and capability of conventional ammonia-oxidizing bacteria (Nitrosomonas) were suppressed in SBBR relative to SBR. Gelidibacter, Anaerolineales were the predominant genus in SBBR, which were not found in SBR. NorB and nosZ responsible for reducing NO to N2O and reducing N2O to N2 respectively had s strong synergistic effect in SBBR. This study will provide a valuable reference for the startup of nitrification process within a short period of time under the extremely high NaCl salinity.

Lactate from glycolysis regulates inflammatory macrophage polarization in breast cancer.

Globally, breast cancer is one of the leading causes of cancer death in women. Metabolic reprogramming and immune escape are two important mechanisms supporting the progression of breast cancer. Lactate in tumors mainly comes from glycolysis and glutaminolysis. Using multiomics data analysis, we found that lactate is mainly derived from glycolysis in breast cancer. Single-cell transcriptome analysis found that breast cancer cells with higher malignancy, especially those in the cell cycle, have higher expression levels of glycolytic metabolic enzymes. Combined with clinical data analysis, it was found that the expression of the lactate transporter SLC16A3 is correlated with breast cancer molecular subtypes and immune infiltration. Among 22 immune cells, macrophages are the most abundant immune cells in breast cancer tissues, and the proportion of M1 macrophages is lower in the high SLC16A3 expression group. Finally, in vitro experiments confirmed that lactate could inhibit the expression of M1 macrophage markers at both RNA and protein levels. In conclusion, we found that lactate produced by glycolysis regulates the polarization of inflammatory macrophages in breast cancer.

Circadian pattern subtyping unveiling distinct immune landscapes in breast cancer patients for better immunotherapy.

BACKGROUND: While epidemiological studies have established a firm link between circadian disruption and tumorigenesis, the role and mechanism are not fully understood, complicating the design of therapeutic targets related to circadian rhythms (CR). Here, we aimed to explore the intertumoral heterogeneity of CR and elucidate its impact on the tumor microenvironment (TME), drug sensitivity, and immunotherapy. METHODS: Based on unsupervised clustering of 28 CR genes, two distinct CR subtypes (cluster-A and cluster-B) were identified in the TCGA cohort. We further constructed a circadian rhythm signature (CRS) based on the CR genes primarily responsible for clustering to quantify CR activity and to distinguish CR subtypes of individual patients from external datasets. CR subtypes were evaluated by TME characteristics, functional annotation, clinical features, and therapeutic response. RESULTS: The cluster-B (low-CRS) group was characterized by highly enriched immune-related pathways, high immune cell infiltration, and high anti-tumor immunity, while the cluster-A (high-CRS) group was associated with immunosuppression, synaptic transmission pathways, EMT activation, poor prognosis, and drug resistance. Immunohistochemistry (IHC) results demonstrated that high CD8+ T cell infiltration was associated with low-CR-protein expression. Importantly, patients with low CRS were more likely to benefit from immune checkpoint blockade (ICB) treatment, possibly due to their higher tumor mutation burden (TMB), increased immune checkpoint expression, and higher proportion of "hot" immunophenotype. CONCLUSION: In a nutshell, the cross talk in CR could reflect the TME immunoreactivity in breast cancer. Besides providing the first comprehensive pathway-level analysis of CR in breast cancer, this work highlights the potential clinical utility of CR for immunotherapy.

Design, Synthesis, and Cellular Imaging Application of a Fluorescent Probe Based on Fluoride Ion-Induced Cyclization of Phenothiazine Derivatives.

Fluoride is both necessary and potentially harmful in excessive amounts, making its detection crucial. Fluorescent probes provide a sensitive and selective means for this purpose. In this study, we developed and synthesized a fluorescent probe for LDT using phenothiazine derivatives and aryl vinyl nitrile. Initially non-fluorescent, the probe undergoes a Si-O bond breakage in the presence of fluoride ions, resulting in the formation of a larger conjugated system and subsequent fluorescence emission. The probe exhibits superior selectivity and sensitivity towards fluoride ions, with a detection limit of 0.35 µM. Moreover, cellular imaging experiments demonstrated the probe's effectiveness in recognizing fluoride ions within HepG2 cells.

Olanzapine causes non-alcoholic fatty liver disease via inhibiting the secretion of apolipoprotein A5. / 奥氮平通过抑制载脂蛋白A5åˆ†æ³Œå¯¼è‡´éžé ’ç²¾æ€§è„‚è‚ªæ€§è‚ç— .

OBJECTIVES: Long-term treatment of olanzapine, the most widely-prescribed second-generation antipsychotic, remarkably increases the risk of non-alcoholic fatty liver disease (NAFLD), whereas the mechanism for olanzapine-induced NAFLD remains unknown. Excessive hepatic fat accumulation is the basis for the pathogenesis of NAFLD, which results from the disturbance of TG metabolism in the liver. Apolipoprotein A5 (ApoA5) is a key regulator for TG metabolism in vivo that promotes TG accumulation in hepatocytes, thereby resulting in the development of NAFLD. However, there are no data indicating the role of apoA5 in olanzapine-induced NAFLD. Therefore, this study aims to investigate the role of apoA5 in olanzapine-induced NAFLD. METHODS: This study was carried out via animal studies, cell experiment, and ApoA5 gene knockdown experiment. Six-week-old male C57BL/6J mice were randomized into a control group, a low-dose group, and a high-dose group, which were treated by 10% DMSO, 3 mg/(kg·d) olanzapine, and 6 mg/(kg·d) olanzapine, respectively for 8 weeks. The lipid levels in plasma, liver function indexes, and expression levels of ApoA5 were detected. HepG2 cells were treated with 0.1% DMSO (control group), 25 µmol/L olanzapine (low-dose group), 50 µmol/L olanzapine (medium-dose group), and 100 µmol/L olanzapine (high-dose group) for 24 h. HepG2 cells pretreated with 100 µmol/L olanzapine were transfected with siRNA and scrambled siRNA (negative control), respectively. We observed the changes in lipid droplets within liver tissues and cells using oil red O staining and fat deposition in liver tissues using HE staining. The mRNA and protein levels of ApoA5 were determined by real-time PCR and Western blotting, respectively. RESULTS: After intervention with 3 and 6 mg/(kg·d) olanzapine for 8 weeks, there was no significant difference in body weight among the 3 groups (P>0.05). Olanzapine dose-dependently increased the plasma TG, ALT and AST levels, and reduced plasma ApoA5 levels (all P<0.05), whereas there was no significant difference in plasma cholesterol (HDL-C, LDL-C, and TC) levels among the 3 groups (all P>0.05). Olanzapine dose-dependently up-regulated ApoA5 protein levels in liver tissues (all P<0.05), but there was no significant change in ApoA5 mRNA expression among groups (P>0.05). In the control group, the structure of liver tissues was intact, the morphology of liver cells was regular, and only a few scattered lipid droplets were found in the cells. In the olanzapine-treated group, there was a large amount of lipid deposition in hepatocytes, and cells were balloon-like and filled with lipid droplet vacuoles. The nucleus located at the edge of cell, and the number of lipid droplets was increased significantly, especially in the high-dose group. Likewise, when HepG2 cells were treated with olanzapine for 24 h, the number and size of lipid droplets were significantly elevated in a dose-dependent manner. Moreover, olanzapine dose-dependently up-regulated ApoA5 protein levels in HepG2 cells (all P<0.05), but there was no significant difference in ApoA5 mRNA expression among groups (P>0.05). Compared with the HepG2 cells transfected with scrambled siRNA, the number and size of lipid droplets in HepG2 cells transfected with ApoA5 siRNA were significantly reduced. CONCLUSIONS: The short-term intervention of olanzapine does not significantly increase body weight of mice, but it can directly induce hypertriglyceridemia and NAFLD in mice. Olanzapine inhibits hepatic apoA5 secretion but does not affect hepatic apoA5 synthesis, resulting in the pathogenesis of NAFLD. Inhibition of apoA5 secretion plays a key role in the development of olanzapine-related NAFLD, which may serve as an intervention target for this disease.

Manipulating fatty-acid profile at unit chain-length resolution in the model industrial oleaginous microalgae Nannochloropsis.

The chain length (CL) of fatty acids (FAs) is pivotal to oil property, yet to what extent it can be customized in industrial oleaginous microalgae is unknown. In Nannochloropsis oceanica, to modulate long-chain FAs (LCFAs), we first discovered a fungi/bacteria-originated polyketide synthase (PKS) system which involves a cytoplasmic acyl-ACP thioesterase (NoTE1). NoTE1 hydrolyzes C16:0-, C16:1- and C18:1-ACP in vitro and thus intercepts the specific acyl-ACPs elongated by PKS for polyunsaturated FA biosynthesis, resulting in elevation of C16/C18 monounsaturated FAs when overproduced and increase of C20 when knocked out. For medium-chain FAs (MCFAs; C8-C14), C8:0 and C10:0 FAs are boosted by introducing a Cuphea palustris acyl-ACP TE (CpTE), whereas C12:0 elevated by rationally engineering CpTE enzyme's substrate-binding pocket to shift its CL preference towards C12:0. A mechanistic model exploiting both native and engineered PKS and type II FAS pathways was thus proposed for manipulation of carbon distribution among FAs of various CL. The ability to tailor FA profile at the unit CL resolution from C8 to C20 in Nannochloropsis spp. lays the foundation for scalable production of designer lipids via industrial oleaginous microalgae.

Oroxylin A inhibits Kaposi's sarcoma-associated herpes virus (KSHV) vIL-6-mediated lymphatic reprogramming of vascular endothelial cells through modulating PPARγ/Prox1 axis.

BACKGROUND AND PURPOSE: Kaposi's sarcoma-associated herpes virus (KSHV) vIL-6 is sufficient to induce lymphatic reprogramming of vascular endothelial cells, which is a key event in Kaposi's sarcoma (KS) development. This study was aimed to investigate the effect of Chinese herb oroxylin A on lymphatic reprogramming and neovascularization by KSHV vIL-6 in vitro and in vivo. METHODS: The lymphatic-phenotype endothelial cell line was generated by lentiviral KSHV vIL-6 infection. Cell viability and apoptosis were determined by MTT assay or flow cytometry with annexin V/propidium iodide staining. Migration, invasion, and neovascularization of the vIL-6-expressing lymphatic-phenotype endothelial cells were determined by wound healing assay, transwell chamber assay, microtubule formation assay, and chick chorioallantoic membrane assay, respectively. Quantitative polymerase chain reaction and Western blot analysis were used to test the expression of Prox1, VEGFR3, podoplanin, LYVE-1, and PPARγ in cells. Co-localization of Prox1 and PPARγ was determined by immunofluorescence. Ubiquitination of Prox1 was detected by in vivo ubiquitination assay. RESULTS: The lymphatic-phenotype endothelial cell line expressing KSHV vIL-6 was successfully generated. Oroxylin A induced cellular invasion abrogation, apoptosis induction, and neovascularization inhibition of the vIL-6-expressing endothelial cells. Mechanically, oroxylin A elevated PPARγ expression, which in turn interacted with and facilitated Prox1 to undergo ubiquitinational degradation, and subsequently leads to VEGFR3, LYVE-1, and podoplanin reduction. CONCLUSION: Through modulating PPARγ/Prox1 axis, oroxylin A inhibits lymphatic reprogramming and neovascularization of KSHV vIL-6. Thus, oroxylin A may serve as a candidate for the treatment of KS as well as other aggressive angiomas.

SMYD3 activates the TCA cycle to promote M1-M2 conversion in macrophages.

BACKGROUND: SMYD3 refers to a histone lysine methyltransferase from the SMYD family, which acts as a gene transcriptional regulator chiefly through catalysis of the histone subunit 3 at lysine 4 trimethylation (H3K4me3). Great progress has been made that epigenetic modification plays a pivotal role in regulating macrophage polarization. However, the effects of the histone lysine methyltransferase SMYD3 on macrophage polarization and phenotypic switching are unclear. RESULTS: We found that LPS/IFN-γ-stimulated macrophages gradually transformed from M1 to M2 in the late stage, and SMYD3 played a key role in this process. As demonstrated by RNA-seq assessment, SMYD3 prominently activated a metabolic pathway known as TCA cycle inside macrophages during M1-M2 conversion. Besides, by modifying H3K4me3 histone, the target genes regulated by SMYD3 were identified via the ChIP-seq assessment, including citrate synthase (CS), succinate dehydrogenase complex subunit C (SDHC) and pyruvate carboxylase (PC). SMYD3 activated the transcriptional activities of the metabolic enzymes CS, SDHC and PC through H3K4me3 by causing the aggregation of citrate, an intramacrophage metabolite, and the depletion of succinate. And additionally, it facilitated the generation of ROS, as well as the expressions of genes associated with mitochondrial respiratory chain complexes. This increased ROS production ultimately induced mitophagy, triggering the M1 to M2 phenotype switch in the macrophages. CONCLUSIONS: Our study provides a detailed intrinsic mechanism in the macrophage phenotypic transition process, in short, SMYD3 promotes the M1-M2 conversion of macrophages by activating the TCA cycle through the simultaneous regulation of the transcriptional activities of the metabolic enzymes CS, SDHC and PC.

Tryptophan metabolism regulates inflammatory macrophage polarization as a predictive factor for breast cancer immunotherapy.

Metabolic reprogramming plays a pivotal role in regulating macrophage polarization and function. However, the impact of macrophage tryptophan metabolism on polarization within the breast cancer microenvironment remains elusive. In this study, we used single-cell transcriptome analysis and found that macrophages had the highest tryptophan metabolic activity in breast cancer, melanoma, and head and neck squamous cell carcinoma (HNSC). Further analysis revealed that the tryptophan metabolic activity of macrophages was positively correlated with the M1 macrophage scores in breast cancer. Pancancer analysis found positive correlations between tryptophan metabolism and the M1 macrophage score in almost all tumor types. Spatial transcriptome analysis revealed higher tryptophan metabolism in regions with higher M1 macrophage score in breast cancer tissues. Immune infiltration analysis revealed that the high tryptophan metabolism group exhibited a higher immune score, an increased proportion of CD8+ T cells, augmented cytolytic activity mediated by CD8+ T cells, and elevated expression of immune checkpoint molecules. Spatial immunophenotype cohort analysis exhibited that breast cancer patients expected to respond to immunotherapy had stronger tryptophan metabolism, with a 73.8 % area under the ROC curve. Single-cell transcriptome analysis of the immunotherapy cohort found that patients responding to immunotherapy had higher macrophage tryptophan metabolism prior to treatment initiation. Finally, in vitro experiments demonstrated elevated expression of tryptophan metabolic enzymes in M1 macrophages. Moreover, tryptophan facilitated the expression of M1 polarization markers, whereas inhibitors of tryptophan metabolic enzymes, such as NLG919, LM10, and Ro 61-8048, inhibited the expression of M1 polarization markers. In conclusion, this study identified a dual role for macrophage tryptophan metabolism in breast cancer; on the one hand, it promotes macrophage M1 polarization, while on the other hand, it serves as a promising predictor for the effectiveness of immunotherapy in breast cancer.

Efficacy and Safety of Radiotherapy Combined with Pyrotinib in the Treatment of HER2-Positive Breast Cancer with Brain Metastases.

Purpose: To explore the efficacy and safety of pyrotinib combined with different radiotherapy modes in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) patients with brain metastasis (BM). Patients and Methods: This study is a retrospective analysis of patients diagnosed with BM who underwent treatment with pyrotinib between November 2018 and April 2023. A total of 66 patients were administered radiotherapy in conjunction with pyrotinib (Group A), while 26 patients received pyrotinib as a standalone treatment (Group B). Within Group A, 18 patients underwent conventional fractionated radiotherapy (2Gy/F), while 48 patients received hyperfractionated radiotherapy (HFRT) (≥3Gy/F). The primary endpoints were intracranial progression-free survival (IC-PFS) and overall survival (OS). The secondary endpoints were objective response rate (ORR) and clinical benefit rate (CBR). Results: The ORR of Group A was 54.5% (36/66), while the ORR of Group B was 34.6% (9/26) (P= 0.047). The CBR of Group A was 89.4% (59/66) and that of Group B was 69.2% (18/26) (P= 0.041). The IC-PFS between Group A and Group B were 12 months and 8 months, respectively (P< 0.001), and the OS were 20 months and 16 months, respectively (P= 0.065). In Group A, the IC-PFS and OS between the conventional fractionation radiotherapy group and the HFRT group were 10 months and 12 months, respectively (P= 0.001) and 16 months and 24 months, respectively (P< 0.001). No serious adverse reactions were observed in Group A and Group B. Conclusion: For HER2-positive BC patients with BM, it is recommended to adopt the treatment mode of HFRT combined with pyrotinib, which can improve the local control and survival of patients.

Restricted-magnesium-vapor-reduction of amorphous SiO/C precursors to polycrystalline Si/SiOx/C hybrid anodes.

Considering the electrochemical activity/stability and preparation feasibility of silicon (Si) nanomaterials, we designed a restricted-magnesium-vapor-reduction to fabricate sustainable Si/SiOx/C porous anodes with nanopores and polycrystalline structures.

Expanding the applications of immune checkpoint inhibitors in advanced lung cancer beyond disease progression.

Background: Immunotherapy, particularly the utilization of immune checkpoint inhibitors (ICIs), assumes a pivotal role in the comprehensive management of advanced lung cancer. There has been substantial deliberation regarding the appropriateness of extending ICIs treatment beyond the point of disease progression. This study delves into the potential benefits of sustained utilization of ICIs subsequent to disease progression in patients. Methods: A retrospective analysis was conducted on a cohort of 248 patients diagnosed with advanced lung cancer who received treatment with ICIs. The study population comprised 99 patients in the treatment beyond progression (TBP) group and 42 patients in the non-treatment beyond progression (NTBP) group. Parameters including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) were assessed. The Cox proportional hazard regression model was employed to analyze prognostic factors related to immunotherapy. Results: Patients undergoing primary treatment with PD-1/PD-L1 inhibitors exhibited a median progression-free survival (mPFS) of 5.3 months. In the context of disease progression, a comparison between the TBP and NTBP groups was performed with respect to mPFS. The results demonstrated that the TBP group manifested an mPFS of 8.6 months, contrasting with the NTBP group's mPFS of 4.0 months (p=0.028). The mean overall survival (mOS) in the TBP group exhibited a statistically significant increase in comparison to the NTBP group (14.1 months vs. 6.0 months, p=0.028). Evaluation of the objective response rate (ORR) between the TBP and NTBP groups revealed a substantial distinction. The TBP group displayed an ORR of 12.1%, while the NTBP group exhibited a lower ORR of 2.4%. The statistical analysis yielded a p-value of 0.068, signifying a notable trend towards significance. The disease control rate (DCR) was also assessed and exhibited a noteworthy variance between the two groups, with a higher DCR of 92.9% in contrast to 71.4% in the control group (p = 0.001). Conclusion: Subsequent to ICIs treatment, a subset of patients may derive continued benefits from anticancer therapy, notwithstanding the progression of their advanced lung cancer.

Case Report: A Mysterious Giant Thrombus in the Right Atrium in a Patient With Dilated Cardiomyopathy.

An isolated right atrial thrombus is a life-threatening entity that is extremely rare in patients with dilated cardiomyopathy (DCM), which is characterized by a reduced left ventricular function and consequent left ventricular thrombosis. Here, we present the case of a mysterious isolated giant right atrial thrombus in a male patient with DCM. The presence of deep vein thrombosis prompted us to investigate for other underlying diseases for his right atrial thrombus. Interestingly, the elevation of two tumor markers indicated the likelihood of cancer-associated thrombosis. Further, the computed tomography demonstrated a spiculated mass in the lower right lung that was confirmed by an endobronchial biopsy as lung squamous cell carcinoma. Consequently, the giant thrombus in the right atrium should be attributed principally to lung squamous cell carcinoma on the background of DCM. After 3 weeks of enoxaparin, the echocardiogram indicated partial resolution of the thrombus. However, the patient suffered sudden death due to pulmonary embolism.

Advances of Synthesis Methods for Porous Silicon-Based Anode Materials.

Silicon (Si)-based anode materials have been the promising candidates to replace commercial graphite, however, there are challenges in the practical applications of Si-based anode materials, including large volume expansion during Li+ insertion/deinsertion and low intrinsic conductivity. To address these problems existed for applications, nanostructured silicon materials, especially Si-based materials with three-dimensional (3D) porous structures have received extensive attention due to their unique advantages in accommodating volume expansion, transportation of lithium-ions, and convenient processing. In this review, we mainly summarize different synthesis methods of porous Si-based materials, including template-etching methods and self-assembly methods. Analysis of the strengths and shortages of the different methods is also provided. The morphology evolution and electrochemical effects of the porous structures on Si-based anodes of different methods are highlighted.

Sodium-glucose cotransporter protein-2 inhibitors and glucagon-like peptide-1 receptor agonists versus thiazolidinediones for non-alcoholic fatty liver disease: A network meta-analysis.

AIMS: Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disorders worldwide. Some hypoglycemic drugs can improve NAFLD. However, it is unclear which of these types of hypoglycemic drugs are more effective for NAFLD. Therefore, we conducted a network meta-analysis to determine the effect of thiazolidinediones (TZDs), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists on NAFLD patients. METHODS: A literature search of PubMed, EMBASE, the Cochrane Library, and Medline was conducted, and the literature from database inception up to April 30, 2021 was obtained. Liver function tests, lipid profiles, body mass index (BMI) and glycemic parameters were obtained from randomized controlled trials. Weighted mean differences (WMDs), relative risks and 95% confidence intervals (CIs) were calculated for continuous outcomes, and the I2 statistic was used to evaluate the heterogeneity of the studies. RESULTS: In total, 22 trials, including 1361 patients, were selected. In direct meta-analysis, GLP-1 receptor agonists were superior to TZDs in decreasing alanine aminotransferase (WMD, -0.40, 95% CI: -0.60 to -0.20), γ-glutamyl transferase (WMD, -5.00, 95% CI: -6.47 to -3.53), BMI (WMD, -4.10, 95%CI: -6.55 to -1.65) and triglycerides (WMD, - 0.50, 95% CI: -0.68 to -0.32). Based on Bayesian network meta-analysis, the effect of SGLT-2 inhibitors on weight loss was superior to that of TZDs (WMD, -1.80, 95%CI: -3.30 to -0.41). CONCLUSIONS: GLP-1 receptor agonists and SGLT-2 inhibitors improved liver enzymes, BMI, blood lipid, blood glucose and insulin resistance in NAFLD patients.

Metformin Ameliorates Hepatic Steatosis induced by olanzapine through inhibiting LXRα/PCSK9 pathway.

Studies have confirmed that olanzapine, the mainstay treatment for schizophrenia, triggers metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). However, the etiology of olanzapine-induced NAFLD is poorly understood. Proprotein convertase subtilisin kexin type 9 (PCSK9) is involved in NAFLD pathogenesis, and metformin can significantly decrease circulating PCSK9. The purpose of this study was to investigate the role of PCSK9 and explore the therapeutic effect of metformin for olanzapine-associated NAFLD. Olanzapine significantly upregulated PCSK9 and promoted lipid accumulation in mouse livers and HepG2 and AML12 cells. Metformin ameliorated these pathological alterations. PCSK9 upstream regulator liver X receptor α (LXRα) was significantly upregulated in olanzapine-induced NAFLD. LXRα antagonist treatment and LXRα overexpression resulted in a decrease and increase of PCSK9, respectively. Hepatic lipogenesis-associated genes FAS and SCD1 were significantly upregulated in olanzapine-induced NAFLD mice and HepG2 cells overexpressing PCSK9, and genes related to lipid ß-oxidation (SCAD and PPARα) were downregulated, while metformin reversed these changes. In addition, we found that LXRα overexpression compromised the effect of metformin on PCSK9 levels and intracellular lipid droplet formation. Taken together, our findings suggest that olanzapine enhances hepatic PCSK9 expression by upregulating LXRα, thereby increasing FAS and SCD1 expression as well as decreasing SCAD and PPARα, and promoting lipid accumulation, and, subsequently, NAFLD, which is ameliorated by metformin.

The SMYD3-MTHFD1L-formate metabolic regulatory axis mediates mitophagy to inhibit M1 polarization in macrophages.

BACKGROUND: SMYD3 (protein 3 containing SET and MYND structural domains) belongs to the SMYD methylesterase family and is a histone lysine methyltransferase that promotes gene transcription mainly by catalysing the trimethylation of lysine at position 4 of histone subunit 3 (H3K4me3). Studies have shown that SMYD3 plays a key role in tumour cell proliferation and differentiation; however, its role in macrophage polarization is unclear. METHODS: We screened the M1- and M2-polarized macrophage differential histone modifying enzyme using bioinformatics analysis. The SMYD3 overexpression plasmid was transfected into M1 macrophages, and the SMYD3-regulated target gene was analysed by RNA-seq and ChIP-Seq. The effect of knocking down MTHFD1L on M1 polarization and the change of the intracellular metabolite formic acid content were investigated. M1 macrophages were stimulated with different concentrations of formic acid (2, 10 and 40 mM) to detect the expression of M1-related genes, ROS production, and changes in the expression of the mitophagy-related proteins LC3, PINK1 and p-Parkin. RESULTS: Here, we used bioinformatics to analyse SMYD3, a histone methyltransferase associated with M1 polarization; overexpression of SMYD3 significantly suppressed the LPS/IFN-γ-induced M1 phenotype in macrophages. RNA-seq analysis demonstrated that SMYD3 significantly activated the one-carbon folate metabolic pathway in M1 macrophages. In addition, we used ChIP-seq analysis to identify methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) as the target gene of the transcriptional activation by SMYD3 through H3K4me3 histone modification. Activation of MTHFD1L causes the accumulation of the intracellular metabolite formate. Exogenous stimulation with different concentrations of formate increased the expression of key genes involved in the mitochondrial respiratory chain complex, ROS production, and the expression of autophagy-related proteins LC3, PINK1, and p-Parkin and suppressed the expression of M1-related genes. CONCLUSIONS: Our study demonstrates that SMYD3 regulates the activity of the mitochondrial metabolic enzyme MTHFD1L through H3K4me3 histone methylation modification, promotes formate synthesis and induces mitophagy, which inhibits M1 polarization in macrophages.

Alterations in sorting and secretion of hepatic apoA5 induce hypertriglyceridemia due to short-term use of olanzapine.

Long-term use of olanzapine, an antipsychotic drug, induces hypertriglyceridemia, resulting in a higher risk of cardiovascular disease. However, the effects and underlying mechanisms of short-term use of olanzapine on circulating triglyceride levels remain poorly understood. Here, the role of apolipoprotein A5 (apoA5), a regulator of triglyceride metabolism, was investigated in olanzapine-induced hypertriglyceridemia. Our multi-center clinical study recruited 36 schizophrenia patients who received short-term (8 weeks) of olanzapine. Besides, female C57BL/6J mice were treated with olanzapine (3 mg/kg/day versus 6 mg/kg/day) for 6 weeks. We demonstrated that short-term use of olanzapine increased plasma triglyceride and decreased plasma apoA5 levels in the patients and mice, with a negative correlation between the two factors. However, no obesity was observed in the patients and mice. Interestingly, olanzapine increased hepatic apoA5 protein in the mice, without significant changes in hepatic Apoa5 mRNA. Consistently, in vitro studies indicated that olanzapine increased medium triglyceride levels and decreased medium apoA5 levels in a dose-dependent manner in human HepG2 cells and primary mouse hepatocytes. Whereas the olanzapine treatment increased hepatic apoA5 protein in vitro, without effects on hepatic APOA5 mRNA. Of note, olanzapine increased the co-localization between apoA5 protein and accumulated lipid droplets in hepatocytes, as opposed to at the hepatocellular plasma membrane, in mouse liver as demonstrated by fluorescence staining. Therefore, our study indicated that short-term use of olanzapine induced hypertriglyceridemia due to defects of sorting and secretion of hepatic apoA5.

Progress of Binder Structures in Silicon-Based Anodes for Advanced Lithium-Ion Batteries: A Mini Review.

Silicon (Si) has been counted as the most promising anode material for next-generation lithium-ion batteries, owing to its high theoretical specific capacity, safety, and high natural abundance. However, the commercial application of silicon anodes is hindered by its huge volume expansions, poor conductivity, and low coulombic efficiency. For the anode manufacture, binders play an important role of binding silicon materials, current collectors, and conductive agents, and the binder structure can significantly affect the mechanical durability, adhesion, ionic/electronic conductivities, and solid electrolyte interface (SEI) stability of the silicon anodes. Moreover, many cross-linked binders are effective in alleviating the volume expansions of silicon nanosized even microsized anodic materials along with maintaining the anode integrity and stable electrochemical performances. This mini review comprehensively summarizes various binders based on their structures, including the linear, branched, three-dimensional (3D) cross-linked, conductive polymer, and other hybrid binders. The mechanisms how various binder structures influence the performances of the silicon anodes, the limitations, and prospects of different hybrid binders are also discussed. This mini review can help in designing hybrid polymer binders and facilitating the practical application of silicon-based anodes with high electrochemical activity and long-term stability.