Comprehensive profiling of lipid metabolic reprogramming expands precision medicine for hepatocellular carcinoma.

BACKGROUND AND AIMS: Liver hepatocellular carcinoma (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 (PC), and sphingolipid (SL) 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 (SFA-PC) 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. CONCLUSION: In conclusion, our study elucidates the metabolic reprogramming gnature 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.

A comparative study on effects of dietary three strains of lactic acid bacteria on the growth performance, immune responses, disease resistance and intestinal microbiota of Pacific white shrimp, Penaeus vannamei.

The present study evaluated the growth performance, immune responses, disease resistance and intestinal microbiota in Penaeus vannamei fed diets supplemented with three strains of lactic acid bacteria (LAB). The basal diet (control, CO) supplemented with Lactobacillus plantarum W2 (LA), Pediococcus acidilactici Nj (PE), Enterococcus faecium LYB (EN) and florfenicol (FL), respectively, formed three LAB diets (1 × 1010 cfu kg-1) and a florfenicol diet (15 mg kg-1, positive control), were fed to shrimp for 42 days. Results indicated that specific growth rate, feed efficiency rate, and disease resistance of shrimp against Vibrio parahaemolyticus in the treatment groups were significantly improved versus the control (P < 0.05). Compared with the control, acid phosphatase, alkaline phosphatase, phenonoloxidase, total nitric oxide synthase, peroxidase, superoxide dismutase activities, total antioxidant capacity, and lysozyme content in the serum and the relative expression levels of SOD, LZM, proPO, LGBP, HSP70, Imd, Toll, Relish, TOR, 4E-BP, eIF4E1α and eIF4E2 genes in the hepatopancreas of LAB groups were enhanced to various extents. Intestinal microbiota analysis showed that the LA and EN groups significantly improved microbial diversity and richness, and LAB groups significantly altered intestinal microbial structure of shrimp. At the phylum level, the Verrucomicrobiota in the LA and PE groups, the Firmicutes in the EN group, and the Actinobacteriota in the PE and EN groups were enriched. Moreover, the CO group increased the proportion of potential pathogens (Vibrionaceae and Flavobacteriaceae). The potential pathogen (Vibrio) was reduced, and potential beneficial bacteria (Tenacibaculum, Ruegeria and Bdellovibrio) were enriched in response to dietary three strains of LAB. When the intestinal microbiota homeostasis of shrimp is considered, L. plantarum and E. faecium showed better effects than P. acidilactici. However, due to the concerns on the possible potential risks of E. faecium strains to human health, L. plantarum W2 is more suitable for application in aquaculture than E. faecium LYB. Considering collectively the above, Lactobacillus plantarum W2 could be applied as better probiotic to improve the growth performance, non-specific immunity, disease resistance and promote intestinal health of P. vannamei.

A Pyrolysis-Free Method Toward Large-Scale Synthesis of Ultra-Highly Efficient Bifunctional Oxygen Electrocatalyst for Zinc-Air Flow Batteries.

The transition-metal nitrogen-carbon (M-N-C) catalysts, as one of the optimal bifunctional oxygen catalysts, are vital for cathodic oxygen electrode of Zn-based air flow batteries (ZAFBs). However, chemical complexity of M-N-C catalysts prepared via the traditional pyrolytic process increases the difficulties of precise control toward configuration and repeatability, especially in large-scale synthesis. Herein, a bifunctional oxygen catalyst via a pyrolysis-free approach based on closed π-conjugated covalent organic polymers (COPs, microwave synthesis) is developed, which inherits the advantage of the well-defined configuration in an atomic manner. Profited from distinct catalytic centers and strong electronic coupling at the interface between COP and layered double hydroxides, the as-synthesized catalyst not only more easily permits large quantity production (>1 kg per batch), but also maintains an ultrahigh bifunctional activity and a long cycle stability even after scale synthesis (ΔE [Ej10 - E1/2 ] = 591 mV; energy efficiency drops by only 2.02% after 1200 cycles), which overwhelmingly exceeds the benchmark Pt/C+IrO2 and the state-of-the-art pyrolytic bifunctional M-N-C oxygen catalysts.

Passive smoking induces pediatric asthma by affecting the balance of Treg/Th17 cells.

BACKGROUND: We aimed to explore the effects of passive smoking on the severity of pediatric asthma and associated molecular mechanisms. METHODS: A total of 378 children with asthma were assigned into four groups according to asthma severity (from grades I to IV). Univariate and multivariate regression analyses were used to analyze possible factors associated with asthma severity in children. Environmental tobacco smoke (ETS) exposure was measured via cotinine concentration in urine. Serum levels of immunoglobulin E (IgE) and cytokines were measured using allergen diagnostic and ELISA (enzyme-linked immunosorbent assay) kits. The percentage of T-regulatory (Treg) and T-helper type 17 (Th17) cells in peripheral blood mononuclear cells (PMBCs) were measured by flow cytometry. Treg- and Th17-associated transcription factors from PMBCs were measured by using ELISA kits. RESULTS: The levels of ETS and serum IgE, and the duration and amounts of passive smoking were closely associated with asthma severity. Passive smoking significantly reduced the levels of FoxP3 (Forkhead/winged helix transcription factor) and tumor growth factor-ß, which were associated with Treg cells, and increased the levels of interleukin-17A and interleukin-23, which were associated with Th17 cells. Meanwhile, passive smoking significantly reduced the ratio of Treg/Th17 cells (P < 0.05). CONCLUSIONS: Passive smoking was closely associated with the severity of childhood asthma by affecting the balance of Treg/Th17 cells.

Indoor air pollution aggravates asthma in Chinese children and induces the changes in serum level of miR-155.

Indoor air pollution is associated with childhood asthma but the molecular mechanism remains unclear. We aimed to explore the relationship between indoor air pollution and pediatric asthma, and the potential molecular mechanism. The serum level of miR-155 was measured by real-time qPCR in 180 Chinese children with asthma caused by air pollution (an asthma group). Meanwhile, 180 healthy subjects were selected as a control group. HCHO, NO2, and particles (PM10, PM2.5, and PM1) were measured. Univariate and multivariate logistic regression were analyzed to assess the relationship between air pollutants and asthma risk. A rank correlation test was used to explore the relationship between serum level of miR-155 and the level of PM2.5 or HCHO. Serum level of miR-155 was higher in the asthma group than the control group (p < 0.001). The history of childhood allergy, breastfeeding, environmental tobacco smoke, PM2.5, and HCHO were significantly different between two groups (p < 0.05). Serum level of miR-155 was closely associated with the levels of indoor PM2.5 and HCHO in the asthma group (p < 0.05) but not in the control group (p > 0.05). Indoor air pollution aggravates the asthma in Chinese children and induces the changes in the serum level of miR-155. Abbreviation: DEP: Diesel exhaust particles; PAHs: Polycyclic aromatic hydrocarbons; THBS1: thrombospondin 1; ISAAC: International Study of Asthma and Allergies in Childhood; PFTs: Pulmonary Function Tests; FEV1: The first second of forced expiration; EDTA, ethylenediaminetetraacetic acid; RT-qPCR, Reverse transcription quantitative real-time PCR; ETS: environmental tobacco smoke; PAEs: phthalate esters.

Bifidobacterium lactis Ameliorates the Risk of Food Allergy in Chinese Children by Affecting Relative Percentage of Treg and Th17 Cells.

We aimed to explore the therapeutic effect of Bifidobacterium lactis on food allergy by investigating the percentage of Treg and Th17 cells in Chinese children and related molecular mechanisms. A total of 256 children with food allergy were evenly assigned into two groups: BG, the children received 10 ml B. lactis (1 × 106/ml) daily, and CG, the children received the solution without B. lactis daily for three months. Allergic symptoms, serum IgE, and food antigen-specific IgE were measured. A mouse allergy model was established by using shrimp tropomyosin and treated with B. lactis. Relative mRNA levels of Treg- and Th17-associated cytokines were measured by using quantitative PCR. The percentage of Treg and Th17 cells in spleen were measured by using flow cytometry. After 3-month therapy, the allergic symptoms of the BG were remarkably reduced when compared with the CG (P < 0.05). Serum levels of IgE and food antigen-specific IgE were decreased too (P < 0.05). Similar results were also found in a mouse allergy model. After B. lactis treatment, the relative mRNA level of FoxP3 was significantly enhanced in the B. lactis therapy group when compared to positive controls. In addition, relative mRNA levels of FoxP3 and TGF-ß associated with Treg cells were increased, whereas relative mRNA levels of IL-17A and IL-23 associated with Th17 were reduced. B. lactis treatment significantly increased the ratio of Treg and Th17 cells in a mouse allergy model (P < 0.05). B. lactis effectively alleviates allergic symptoms by increasing the ratio of Treg and Th17 cells.

Functional interaction of CCAAT/enhancer-binding-protein-α basic region mutants with E2F transcription factors and DNA.

The transcription factor CCAAT/enhancer-binding protein α (C/EBPα) regulates cell cycle arrest and terminal differentiation of neutrophils and adipocytes. Mutations in the basic leucine zipper domain (bZip) of C/EBPα are associated with acute myeloid leukemia. A widely used murine transforming C/EBPα basic region mutant (BRM2) entails two bZip point mutations (I294A/R297A). BRM2 has been discordantly described as defective for DNA binding or defective for interaction with E2F. We have separated the two BRM2 mutations to shed light on the intertwined reciprocity between C/EBPα-E2F-DNA interactions. Both, C/EBPα I294A and R297A retain transactivation capacity and interaction with E2F-DP. The C/EBPα R297A mutation destabilized DNA binding, whereas the C/EBPα I294A mutation enhanced binding to DNA. The C/EBPα R297A mutant, like BRM2, displayed enhanced interaction with E2F-DP but failed to repress E2F-dependent transactivation although both mutants were readily suppressed by E2F1 for transcription through C/EBP cis-regulatory sites. In contrast, the DNA binding enhanced C/EBPα I294A mutant displayed increased repression of E2F-DP mediated transactivation and resisted E2F-DP mediated repression. Thus, the efficient repression of E2F dependent S-phase genes and the activation of differentiation genes reside in the balanced DNA binding capacity of C/EBPα.

Comprehensive transcriptome analysis of mesenchymal stem cells in elderly patients with osteoporosis.

OBJECTIVE: To explore the role of aging in the pathogenesis of osteoporosis, several differentially expressed genes (DEGs) and altered biological pathways were identified in mesenchymal stem cells (MSCs) in elderly patients with osteoporosis. METHODS: Raw data were downloaded from Gene Expression Omnibus database. A total of 14 human MSC samples were available, including five samples from elderly patients suffering from osteoporosis, five controls from young non-osteoporotic donors and five controls from old non-osteoporotic donors. The DEGs were identified using LIMMA package among the three groups. Gene ontology and KEGG pathway analysis were carried out using DAVID. A protein-protein interaction (PPI) network of DEGs was constructed with STRING and then visualized with Cytoscape. RESULTS: A total of 3179 DEGs were screened, including 1071 up- and 2108 down-regulated genes. Compared with young and old controls, 271 and 781 genes were up-regulated in osteoporosis, respectively, and 17 genes were shared. Function and pathway enrichment showed that the up-regulated genes in osteoporosis were involved in extracellular matrix (ECM)-receptor interaction, focal adhesion and mammalian target of rapamycin signaling pathway. Moreover, a range of genes linked to cell adhesion, ECM-receptor interaction and cell cycle were revealed in the PPI network, such as transforming growth factor beta 1, insulin-like growth factor 2 and integrin beta 2. CONCLUSION: A number of DEGs and altered pathways were screened in osteoporosis. Our study provided insights into the role of aging in the pathogenesis of osteoporosis and some DEGs might be potential biomarkers for osteoporosis.

Modified Biejia Jianwan decoction restrains PD-L1-mediated immune evasion through the HIF-1α/STAT3/NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Modified Biejia Jianwan (M-BJJW), a Traditional Chinese Medicine (TCM) decoction, has exhibited great potential in treating hepatocellular carcinoma (HCC). However, its underlying functional mechanism still remains unknown. AIM OF THE STUDY: The study aimed to explore the anti-hepatocarcinogenic effects of M-BJJW, specifically its influence on PD-L1-mediated immune evasion in hypoxic conditions, and elucidate the related molecular mechanisms in HCC. MATERIALS AND METHODS: To investigate the therapeutic efficacy and mechanisms underlying M-BJJW's effects on HCC, we employed a diethylnitrosamine (DEN)-induced rat model maintained for 120 days. Following model establishment, flow cytometry was utilized to assess the distribution of immune cell populations in peripheral blood, spleens, and tumor tissues after M-BJJW administration. Simultaneously, enzyme-linked immunosorbent assays (ELISA) were conducted to analyze cytokine profiles in serum samples. Immunohistochemistry was employed to determine the expression levels of crucial proteins within tumor tissues. Furthermore, HCC cells exposed to CoCl2 underwent Western blot analysis to validate the expression levels of HIF-1α, PD-L1, STAT3, and nuclear factor kappa B (NF-κB) p65. The modulatory effects of STAT3 and NF-κB p65 were investigated using specific inhibitors and activators in wild-type cell lines. High-performance liquid chromatography coupled with mass spectrometry (HPLC/MS) was utilized to identify the chemical constituents present in M-BJJW-medicated serum. The immunomodulatory properties and the anti-tumor activities of M-BJJW were evaluated by co-culturing with peripheral blood mononuclear cells (PBMC) and the CCK-8 assay. Additionally, we assessed M-BJJW's impact on hypoxia-induced alterations in HCC cell lines using immunofluorescence and Western blot assessments. RESULTS: M-BJJW exhibited substantial therapeutic advantages by effectively alleviating pathological deterioration within the HCC microenvironment. In the DEN-induced rat model, M-BJJW administration notably reduced tumor growth. Flow cytometry analyses revealed an increased proportion of Cytotoxic T lymphocytes (CTLs) accompanied by a simultaneous decrease in regulatory T cells (Tregs). ELISA data supported a marked decrease in pro-inflammatory cytokines, including interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor α (TNF-α). Immunohistochemistry confirmed the suppressive effect of M-BJJW on the expression of HIF-1α and PD-L1. Notably, western blotting unveiled the role of HIF-1α in regulating PD-L1 expression via the STAT3 and NF-κB signaling pathways in HCC cell lines, which was validated using activators and inhibitors of STAT3 and NF-κB. The CCK-8 assay and co-culture techniques demonstrated the anti-tumor activity of M-BJJW. Immunofluorescence and western blotting further confirmed that M-BJJW-containing serum dose-dependently inhibited HIF-1α, PD-L1, p-STAT3, and p-p65 in hypoxic HCC cell lines. CONCLUSIONS: M-BJJW demonstrates significant therapeutic potential against HCC by influencing the hypoxic microenvironment, thereby regulating the immunosuppressive milieu. Specifically, M-BJJW modulates the HIF-1α/STAT3/NF-κB signaling pathway, leading to reduced PD-L1 expression and an elevated ratio of cytotoxic T lymphocytes (CTLs), while concurrently decreasing T regulatory cells (Tregs) and immunosuppressive factors. These synergistic effects aid in countering PD-L1-mediated immune evasion, presenting compelling pharmacological evidence supporting the clinical application of M-BJJW as a therapeutic approach for HCC.

Low-Temperature Thermal Transport Characteristics in Epitaxial Bilayer Graphene Microbridges.

In this paper, we present a study of the thermal transport of epitaxial bilayer graphene microbridges. The thermal conductance of three graphene microbridges with different lengths was measured at different temperatures using Johnson noise thermometry. We find that with the decrease of the temperature, the thermal transport in the graphene microbridges switches from electron-phonon coupling to electron diffusion, and the switching temperature is dependent on the length of the microbridge, which is in good agreement with the simulation based on a distributed hot-spot model. Moreover, the electron-phonon thermal conductance has a temperature power law of T3 as predicted for pristine graphene and the electron-phonon coupling coefficient σep is found to be approximately 0.18 W/(m2 K4), corresponding to a deformation potential D of 55 eV. In addition, the electron diffusion in the graphene microbridges adheres to the Wiedemann-Franz law, requiring no corrections to the Lorentz number.

Neuron-restrictive silencer factor (NRSF) represses cocaine- and amphetamine-regulated transcript (CART) transcription and antagonizes cAMP-response element-binding protein signaling through a dual NRSE mechanism.

Cocaine- and amphetamine-regulated transcript (CART) peptide plays a pivotal role in neuroprotection against stroke-related brain injury. However, the regulatory mechanism on CART transcription, especially the repression mechanism, is not fully understood. Here, we show that the transcriptional repressor neuron-restrictive silencer elements (NRSF, also known as REST) represses CART expression through direct binding to two NRSF-binding elements (NRSEs) in the CART promoter and intron 1 (named pNRSE and iNRSE, respectively). EMSA show that NRSF binds to pNRSE and iNRSE directly in vitro. ChIP assays show that NRSF recruits differential co-repressor complexes including CoREST and HDAC1 to these NRSEs. The presence of both NRSEs is required for efficient repression of CART transcription as indicated by reporter gene assays. NRSF overexpression antagonizes forskolin-mediated up-regulation of CART mRNA and protein. Ischemia insult triggered by oxygen-glucose deprivation (OGD) enhances NRSF mRNA levels and then NRSF antagonizes the CREB signaling on CART activation, leading to augmented cell death. Depletion of NRSF in combination with forskolin treatment increases neuronal survival after ischemic insult. These findings reveal a novel dual NRSE mechanism by which NRSF represses CART expression and suggest that NRSF may serve as a therapeutic target for stroke treatment.

Effects of sodium metabisulfite on pyroptosis, mitophagy and degranulation in mast cells.

Sodium metabisulphite (SMB) is the most used foods and drugs antioxidant among sulfites. So far, there were few studies about its harm, especially in mast cells. Our study was to investigate the effects of SMB on mitophagy and pyroptosis in mast cells. The results revealed that SMB dose-dependently promoted the expressions of NLRP3, GSDMD-N and other marker proteins of pyroptosis. Knockdown of GSDMD, NLRP3 inhibitor, mitophagy activator and mtROS inhibitor all reversed the changes in pyroptosis indicators caused by SMB. Considering the degranulation characteristics of mast cells and the sensitization of sulfite, we examined the effects of the above inhibitors on the degranulation of mast cells caused by SMB. The results showed that SMB-mediated mast cell degranulation was significantly inhibited by the above inhibitors. Meanwhile, we used immunofluorescence co-localization experiments and found that GSDMD pore-forming protein and histamine co-localized near the cell membrane. Overall, evidence suggested that SMB caused pyroptosis by inhibiting mitophagy, leading to mast cell degranulation. These findings are of great significance to the sensitization mechanism of SMB and provide a new insight into SMB toxicology and mast cell degranulation.

Insights into the role of nucleotide methylation in metabolic-associated fatty liver disease.

Metabolic-associated fatty liver disease (MAFLD) is a chronic liver disease characterized by fatty infiltration of the liver. In recent years, the MAFLD incidence rate has risen and emerged as a serious public health concern. MAFLD typically progresses from the initial hepatocyte steatosis to steatohepatitis and then gradually advances to liver fibrosis, which may ultimately lead to cirrhosis and carcinogenesis. However, the potential evolutionary mechanisms still need to be clarified. Recent studies have shown that nucleotide methylation, which was directly associated with MAFLD's inflammatory grading, lipid synthesis, and oxidative stress, plays a crucial role in the occurrence and progression of MAFLD. In this review, we highlight the regulatory function and associated mechanisms of nucleotide methylation modification in the progress of MAFLD, with a particular emphasis on its regulatory role in the inflammation of MAFLD, including the regulation of inflammation-related immune and metabolic microenvironment. Additionally, we summarize the potential value of nucleotide methylation in the diagnosis and treatment of MAFLD, intending to provide references for the future investigation of MAFLD.

A New Auto-RPA-Fluorescence Detection Platform for SARS-CoV-2.

OBJECTIVE: The outbreak of COVID-19 caused by SARS-CoV-2 has led to a serious worldwide pandemic. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR)-based methods were recommended for routine detection of SARS-CoV-2 RNA. Because the reaction time and analytical sensitivity of qRT-PCR limits the diagnosis of SARS-CoV-2, development of a quick process of SARS-CoV-2 detection technology with high analytical sensitivity remains urgent. METHODS: We combined isothermal amplification and fluorescence detection technology to develop a new auto-recombinase polymerase amplification (RPA)-fluorescence platform that could be used in the diagnosis of SARS-CoV-2. RESULTS: By optimization of primers and probes, the RPA platform could detect SARS-CoV-2 nucleotides within 15 min. The limits of detection and specificity of the auto-RPA-fluorescence platform were 5 copies/µL and 100%, respectively. The accuracy of detection of the auto-RPA-fluorescence platform in the 16 positive samples was 100%. CONCLUSION: The RPA platform is a potential technology for the diagnosis of SARS-CoV-2 infection.

Robust and efficient transfer hydrogenation of carbonyl compounds catalyzed by NN-Mn(I) complexes.

A series of manganese(I) carbonyl complexes bearing structurally related NN- and NNN-chelating ligands have been synthesized and assessed as catalysts for transfer hydrogenation (TH). Notably, the NN-systems based on N-R functionalized 5,6,7,8-tetrahydroquinoline-8-amines, proved the most effective in the manganese-promoted conversion of acetophenone to 1-phenylethanol. In particular, the N-isopropyl derivative, Mn1, when conducted in combination with t-BuONa, was the standout performer mediating not only the reduction of acetophenone but also a range of carbonyl substrates including (hetero)aromatic-, aliphatic- and cycloalkyl-containing ketones and aldehydes with especially high values of TON (up to 17 200; TOF of 3550 h-1). These findings, obtained through a systematic variation of the N-R group of the NN ligand, are consistent with an outer-sphere mechanism for the hydrogen transfer. As a more general point, this Mn-based catalytic TH protocol offers an attractive and sustainable alternative for producing alcoholic products from carbonyl substrates.

Emerging Roles of Non-proteolytic Ubiquitination in Tumorigenesis.

Ubiquitination is a critical type of protein post-translational modification playing an essential role in many cellular processes. To date, more than eight types of ubiquitination exist, all of which are involved in distinct cellular processes based on their structural differences. Studies have indicated that activation of the ubiquitination pathway is tightly connected with inflammation-related diseases as well as cancer, especially in the non-proteolytic canonical pathway, highlighting the vital roles of ubiquitination in metabolic programming. Studies relating degradable ubiquitination through lys48 or lys11-linked pathways to cellular signaling have been well-characterized. However, emerging evidence shows that non-degradable ubiquitination (linked to lys6, lys27, lys29, lys33, lys63, and Met1) remains to be defined. In this review, we summarize the non-proteolytic ubiquitination involved in tumorigenesis and related signaling pathways, with the aim of providing a reference for future exploration of ubiquitination and the potential targets for cancer therapies.

Efficient transfer hydrogenation of ketones using molybdenum complexes by comprehensively verifying the auxiliary ligands.

Molybdenum complexes ligated with N1,N1-dialkyl-N2-(5,6,7,8-tetrahydroquinolin-8-yl)ethane-1,2-diamines and auxiliary ligands, providing various structural features, were developed: [NNH/NNHN]Mo(CO)4/3 (Mo1-Mo3), [NNHN]Mo(CO)2Br (Mo4-Mo5), [NNH]Mo(CO)(η3-C3H5)Br (Mo6) and [NNHN/S]Mo(CO)(PPh3)2 (Mo7-Mo8). All the complexes were highly active in the transfer hydrogenation (TH) of a model substrate (acetophenone), providing excellent yields of 1-phenylethanol. The structural variation in the ligand framework had a modest effect on the catalyst performance as compared to the changes in the auxiliary ligands Br, PPh3 and CO. This structural evolution provided the complex [Mo(NNH)(η3-C3H5)(CO)2Br] (Mo6) as the most effective catalyst not only for the transfer hydrogenation of acetophenone but also for a wide range of diverse ketones (up to 43 examples). Moreover, easy purification of the products by only removing the acetone byproduct is another noteworthy feature of this environmentally friendly route.

An Initial Covalent Organic Polymer with Closed-F Edges Directly for Proton-Exchange-Membrane Fuel Cells.

Covalent organic polymers (COPs) are a class of rising electrocatalysts for the oxygen reduction reaction (ORR) due to the atomically metrical control of the organic molecular components along with highly architectural robustness and thermodynamic stability even in acid or alkaline media. However, the direct application of pristine COPs as acidic ORR electrocatalysts, especially in device manner, e.g., in proton-exchange-membrane fuel cells (PEMFCs), remains a big challenge. Currently, the decoration toward electronic structures of active sites is considered a vital pathway to enhancing the acidic ORR activity of carbon-based electrocatalysts. Here, an initial F-decorated fully closed π-conjugated quasi-phthalocyanine COP (denoted as COPBTC -F) is reported. The introduction of the closed-F edges stepwise drags more electrons from FeN4 sites in COPBTC -F into the catalyst margin, which weakens the occupied numbers of bonding orbitals between COPBTC -F and OH* intermediates at the rate-determining step, exhibiting over five times intrinsic performance beyond the counterpart without F functionalities (termed as COPBTC ). Significantly, the maximum power density utilizing COPBTC -F as a cathode catalyst in PEMFCs is remarkably increased by an order of magnitude compared with COPBTC , which is a stride forward among catalysts based on a pyrolysis-free conjugated-polymer network in device manner to date.

Bone-targeted nanoplatform enables efficient modulation of bone tumor microenvironment for prostate cancer bone metastasis treatment.

As there is currently no effective therapy for patients with prostate cancer (PCa) bone metastasis, it was stringent to explore the relevant treatment strategies. Actually, the interaction between cancer cells and bone microenvironment plays important role in prostate cancer bone metastasis, especially the Sonic hedgehog protein (SHH) signaling in the bone microenvironment. The SHH promotes osteoblast maturation and osteoblast then secretes RANKL to induce osteoclastogenesis. Herein, this study develops bone-targeting calcium phosphate lipid hybrid nanoparticles (NPs) loaded with docetaxel (DTXL) and SHH siRNA for PCa bone metastasis treatment. For bone targeting purposes, the nanoplatform was modified with alendronate (ALN). (DTXL + siRNA)@NPs-ALN NPs effectively change the bone microenvironment by inhibiting the SHH paracrine and autocrine signaling, enhancing the anti-tumor effects of DTXL. Besides showing good in vitro cellular uptake, the NPs-ALN also inhibited tumor growth both in vitro and in vivo by inducing apoptosis, cell cycle arrest, and autophagy. This DDS comprised of (DTXL + siRNA)-loaded NPs provides an excellent strategy to treat PCa bone metastasis.