Integrated production of xylose and docosahexaenoic acid from hemicellulose and cellulose in corncob.

Exploring efficient and comprehensive utilization of agricultural waste to produce high value-added products has been global research hotspot. In this study, a novel process for integrated production of xylose and docosahexaenoic acid (DHA) from hemicellulose and cellulose in corncob was developed. Corncob was treated with dilute H2SO4 at 121 °C for 1 h and xylose was readily produced with a recovery yield of 79.35 %. The corncob residue was then subject to alkali pretreatment under optimized conditions of 0.1 g NaOH/g dry solid, 60 °C for 2 h, and the contents of cellulose, hemicellulose, and lignin in the resulting residue were 87.49 %, 7.58 % and 2.31 %, respectively. The cellulose in the residue was easily hydrolyzed by cellulase, yielding 74.87 g/L glucose with hydrolysis efficiency of 77.02 %. Remarkably, the corncob residue hydrolysate supported cell growth and DHA production in Schizochytrium sp. ATCC 20888 well, and the maximum biomass of 32.71 g/L and DHA yield of 4.63 g/L were obtained, with DHA percentage in total fatty acids of 36.89 %. This study demonstrates that the corncob residue generated during xylose production, rich in cellulose, can be effectively utilized for DHA production by Schizochytrium sp., offering a cost-effective and sustainable alternative to pure glucose.

PRMT1 and TDRD3 promote stress granule assembly by rebuilding the protein-RNA interaction network.

Stress granules (SGs) are membrane-less organelles (MLOs) or cytosolic compartments formed upon exposure to environmental cell stress-inducing stimuli. SGs are based on ribonucleoprotein complexes from a set of cytoplasmic proteins and mRNAs, blocked in translation due to stress cell-induced polysome disassembly. Post-translational modifications (PTMs) such as methylation, are involved in SG assembly, with the methylation writer PRMT1 and its reader TDRD3 colocalizing to SGs. However, the role of this writer-reader system in SG assembly remains unclear. Here, we found that PRMT1 methylates SG constituent RNA-binding proteins (RBPs) on their RGG motifs. Besides, we report that TDRD3, as a reader of asymmetric dimethylarginines, enhances RNA binding to recruit additional RNAs and RBPs, lowering the percolation threshold and promoting SG assembly. Our study enriches our understanding of the molecular mechanism of SG formation by elucidating the functions of PRMT1 and TDRD3. We anticipate that our study will provide a new perspective for comprehensively understanding the functions of PTMs in liquid-liquid phase separation driven condensate assembly.

A Passive-Active Anti/Deicing Coating Integrating Superhydrophobicity, Thermal Insulation, and Photo/Electrothermal Conversion Effects.

Anti/deicing coatings that combine active and passive methods can utilize various energy sources to achieve anti/deicing effects. However, poor photothermal or electrothermal performance and inevitable heat loss often reduce their anti/deicing efficiency. Herein, copper sulfide loaded activated biochar (AC@CuS) as photo/electric material, polydimethylsiloxane as hydrophobic component, thermally expandable microspheres as foaming agent, and an anti/deicing coating integrating thermal insulation, superhydrophobicity, photo/electrothermal effects was successfully constructed. Benefiting from the synergistic effect of superhydrophobicity and thermal insulation, the freezing time of water droplets on the coating surface is extended from 150 to 2140 s, showing excellent passive anti-icing performance. AC@CuS exhibits photo/electrothermal effects, and porous expanded microspheres reduce heat loss, which endows the coating with desirable photo/electrothermal conversion performance. Under the conditions of 0.2 W/cm2 electric power density (EPD) and 0.1 W/cm2 optical power density (OPD), the temperature of the coating increases from 24 to 96.4 and 113 °C, respectively. Interestingly, with a coheating of 0.05 W/cm2 weaker OPD and 0.05 W/cm2 lower EPD, the ice on the coating surface can be quickly melted in 2.5 min, showing synergistic deicing performance. In addition, the WCA of the prepared coating remains above 150° after mechanical damage, rain impact, UV irradiation, chemical corrosion, and high-temperature treatment, and good superhydrophobic durability ensures the anti/deicing durability of the coating.

SIRT4 is associated with microvascular infiltration, immune cell infiltration, and epithelial mesenchymal transition in hepatocellular carcinoma.

AIMS: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. In the present study, we evaluated SIRT4 expression levels in HCC specimens and investigated the relationships between SIRT4 expression levels, clinicopathological factors, and microvascular infiltration (MVI) in HCC. METHODS: The expression levels of SIRT4 in 108 HCC specimens were examined by immunohistochemical staining. MVI in HCC specimens was divided into three subtypes: M0, M1, and M2. Comprehensive bioinformatics analysis was carried out to demonstrate SIRT4's biological functions and expression-related prognostic value. RESULTS: The diffuse cytoplasmic expression pattern of SIRT4 was observed in all adjacent nonneoplastic liver tissues. The levels of SIRT4 were higher in HCC than in any other type of cancer and normal tissues. In addition, the expression levels of SIRT4 were significantly decreased in HCC tissues when MVI was M1 or M2 (P=0.003) but were not related to the overall clinical outcome. To explain MVI regulated by SIRT4, we also found that SIRT4 expression correlated with epithelial-mesenchymal transition (EMT) markers and CD4+ T/NK cells and downregulated cancer-associated fibroblast cells. Also, there was a significant relationship between MVI and degree of cell differentiation (P=0.003), tumor size (P<0.001), alpha fetoprotein (AFP) (P=0.001), alanine aminotransferase (ALT) (P=0.024), and γ-glutamyl transferase (γ-GT) (P=0.024). However, SIRT4 was not an independent prognostic marker of HCC. CONCLUSIONS: Our results demonstrated an association between SIRT4 expression levels, MVI, immune cell infiltration, and potential biological functions, including EMT in the progression of HCC.

Caprin1 Bridges PRMT1 to G3BP1 and Spaces Them to Ensure Proper Stress Granule Formation.

Stress granules (SGs) are dynamic biomolecular condensates that form in the cytoplasm in response to cellular stress, encapsulating proteins and RNAs. Methylation is a key factor in the assembly of SGs, with PRMT1, which acts as an arginine methyltransferase, localizing to SGs. However, the precise mechanism of PRMT1 localization within SGs remains unknown. In this study, we identified that Caprin1 plays a primary role in the recruitment of PRMT1 to SGs, particularly through its C-terminal domain. Our findings demonstrate that Caprin1 serves a dual function as both a linker, facilitating the formation of a PRMT1-G3BP1 complex, and as a spacer, preventing the aberrant formation of SGs under non-stress conditions. This study sheds new lights on the regulatory mechanisms governing SG formation and suggests that Caprin1 plays a critical role in cellular responses to stress.

Fragment-based discovery of small molecule inhibitors of the HDGFRP2 PWWP domain.

The PWWP domain of hepatoma-derived growth factor-related protein 2 (HDGFRP2) recognizes methylated histones to initiate the recruitment of homologous recombination repair proteins to damaged silent genes. The combined depletion of HDGFRP2 and its paralog PSIP1 effectively impedes the onset and progression of diffuse intrinsic pontine glioma (DIPG). Here, we discovered varenicline and 4-(4-bromo-1H-pyrazol-3-yl) pyridine (BPP) as inhibitors of the HDGFRP2 PWWP domain through a fragment-based screening method. The complex crystal structures reveal that both Varenicline and BPP engage with the aromatic cage of the HDGFRP2 PWWP domain, albeit via unique binding mechanisms. Notably, BPP represents the first single-digit micromolar inhibitor of the HDGFRP2 PWWP domain with a high ligand efficiency. As a dual inhibitor targeting both HDGFRP2 and PSIP1 PWWP domains, BPP offers an exceptional foundation for further optimization into a chemical tool to dissect the synergetic function of HDGFRP2 and PSIP1 in DIPG pathogenesis.

5HT2A modulation attenuates pancreatic cancer induced pain mouse model by inhibiting HDAC.

PURPOSE: Patients have been severely suffered from cancer associated pain, and pancreatic cancer is the most severe form of cancer associated with pain. There are very few options available to manage it. The present report evaluated the effect of 5HT2A on pancreatic cancer associated pain. METHODS: Pancreatic cancer was induced by injecting SW 1,990 cells (~3×106 in a 20 µL suspension) into the pancreas and formed a 2-3-mm vesicle using an inoculator fitted with a 26-gauge needle in BALB/c-nu mice. Survival rate and body weight of the mice were observed. Pain behaviour testing was performed at the end of each week (third and fourth week) after surgery. Inflammatory mediators and HDAC 2 proteins were determined in the spinal tissue using quantitative real-time polymerase chain reaction. RESULTS: There was improvement in the survival rate and body weight in 5HT2A antagonist treated group than pancreatic cancer group of mice. Moreover, 5HT2A antagonist ameliorated the alteration in pain behaviour of pancreatic cancer mice. mRNA expression of HDAC2 and level of inflammatory cytokines were reduced in the spinal tissue of 5HT 2A antagonist treated group than pancreatic cancer group of mice. CONCLUSIONS: Data revealed that 5HT2A antagonist ameliorates pain associated with pancreatic cancer mice by HDAC inhibition and inflammatory cytokines. The result of investigation supports that modulation of 5HT2A receptor could be used clinically to protects neuropathic pain in pancreatic cancer.

Two new sesquiterpene glycosides from Dendrobium findleyanum.

One new ylangene-type sesquiterpene glycoside, findlayanoside C (1), and one new picrotoxane-type sesquiterpene glycoside, findlayanoside D (3), together with five known sesquiterpene glycosides, dendrofindlayanoside C (2), dendronobiloside B (4), dendronobiloside A (5), dendroside F (6) and dendromoniliside D (7), have been isolated from the stems of Dendrobium findleyanum. The structures of compounds 1 and 3 were elucidated by means of extensive spectroscopic analyses, and their absolute configuration were confirmed by electronic circular dichroism (ECD) calculations. Cytotoxic activity assays against SMMC-7721, A-549 and MCF-7 human cancer cell lines revealed IC50 values of 10.12, 12.32 and 14.13 µM for compound 1, and of 9.25, 13.16 and 16.26 µM for compound 2. This study enriches the anti-tumour sesquiterpenoids composition of D. findleyanum.

A TLR4/TRAF6-dependent signaling pathway mediates NCoR coactivator complex formation for inflammatory gene activation.

The nuclear receptor corepressor (NCoR) forms a complex with histone deacetylase 3 (HDAC3) that mediates repressive functions of unliganded nuclear receptors and other transcriptional repressors by deacetylation of histone substrates. Recent studies provide evidence that NCoR/HDAC3 complexes can also exert coactivator functions in brown adipocytes by deacetylating and activating PPARγ coactivator 1α (PGC1α) and that signaling via receptor activator of nuclear factor kappa-B (RANK) promotes the formation of a stable NCoR/HDAC3/PGC1ß complex that coactivates nuclear factor kappa-B (NFκB)- and activator protein 1 (AP-1)-dependent genes required for osteoclast differentiation. Here, we demonstrate that activation of Toll-like receptor (TLR) 4, but not TLR3, the interleukin 4 (IL4) receptor nor the Type I interferon receptor, also promotes assembly of an NCoR/HDAC3/PGC1ß coactivator complex. Receptor-specific utilization of TNF receptor-associated factor 6 (TRAF6) and downstream activation of extracellular signal-regulated kinase 1 (ERK1) and TANK-binding kinase 1 (TBK1) accounts for the common ability of RANK and TLR4 to drive assembly of an NCoR/HDAC3/PGC1ß complex in macrophages. ERK1, the p65 component of NFκB, and the p300 histone acetyltransferase (HAT) are also components of the induced complex and are associated with local histone acetylation and transcriptional activation of TLR4-dependent enhancers and promoters. These observations identify a TLR4/TRAF6-dependent signaling pathway that converts NCoR from a corepressor of nuclear receptors to a coactivator of NFκB and AP-1 that may be relevant to functions of NCoR in other developmental and homeostatic processes.

Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function.

BACKGROUND: Cardiac metabolic dysfunction is a hallmark of heart failure (HF). Estrogen-related receptors ERRα and ERRγ are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for HF. However, in vivo studies demonstrating the potential usefulness of ERR agonist for HF treatment are lacking, because compounds with pharmacokinetics appropriate for in vivo use have not been available. METHODS: Using a structure-based design approach, we designed and synthesized 2 structurally distinct pan-ERR agonists, SLU-PP-332 and SLU-PP-915. We investigated the effect of ERR agonist on cardiac function in a pressure overload-induced HF model in vivo. We conducted comprehensive functional, multi-omics (RNA sequencing and metabolomics studies), and genetic dependency studies both in vivo and in vitro to dissect the molecular mechanism, ERR isoform dependency, and target specificity. RESULTS: Both SLU-PP-332 and SLU-PP-915 significantly improved ejection fraction, ameliorated fibrosis, and increased survival associated with pressure overload-induced HF without affecting cardiac hypertrophy. A broad spectrum of metabolic genes was transcriptionally activated by ERR agonists, particularly genes involved in fatty acid metabolism and mitochondrial function. Metabolomics analysis showed substantial normalization of metabolic profiles in fatty acid/lipid and tricarboxylic acid/oxidative phosphorylation metabolites in the mouse heart with 6-week pressure overload. ERR agonists increase mitochondria oxidative capacity and fatty acid use in vitro and in vivo. Using both in vitro and in vivo genetic dependency experiments, we show that ERRγ is the main mediator of ERR agonism-induced transcriptional regulation and cardioprotection and definitively demonstrated target specificity. ERR agonism also led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocytes. CONCLUSIONS: ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced HF in vivo. Our results provide direct pharmacologic evidence supporting the further development of ERR agonists as novel HF therapeutics.

A bivalent inhibitor against TDRD3 to suppress phase separation of methylated G3BP1.

The formation of membrane-less organelles is driven by multivalent weak interactions while mediation of such interactions by small molecules remains an unparalleled challenge. Here, we uncovered a bivalent inhibitor that blocked the recruitment of TDRD3 by the two methylated arginines of G3BP1. Relative to the monovalent inhibitor, this bivalent inhibitor demonstrated an enhanced binding affinity to TDRD3 and capability to suppress the phase separation of methylated G3BP1, TDRD3, and RNAs, and in turn inhibit the stress granule growth in cells. Our result paves a new path to mediate multivalent interactions involved in SG assembly for potential combinational chemotherapy by bivalent inhibitors.

5HT2A modulation attenuates pancreatic cancer induced pain mouse model by inhibiting HDAC

Purpose Patients have been severely suffered from cancer associated pain, and pancreatic cancer is the most severe form of cancer associated with pain. There are very few options available to manage it. The present report evaluated the effect of 5HT2A on pancreatic cancer associated pain. Methods Pancreatic cancer was induced by injecting SW 1,990 cells (~3×106 in a 20 µL suspension) into the pancreas and formed a 2­3-mm vesicle using an inoculator fitted with a 26-gauge needle in BALB/c-nu mice. Survival rate and body weight of the mice were observed. Pain behaviour testing was performed at the end of each week (third and fourth week) after surgery. Inflammatory mediators and HDAC 2 proteins were determined in the spinal tissue using quantitative real-time polymerase chain reaction. Results There was improvement in the survival rate and body weight in 5HT2A antagonist treated group than pancreatic cancer group of mice. Moreover, 5HT2A antagonist ameliorated the alteration in pain behaviour of pancreatic cancer mice. mRNA expression of HDAC2 and level of inflammatory cytokines were reduced in the spinal tissue of 5HT 2A antagonist treated group than pancreatic cancer group of mice. Conclusions Data revealed that 5HT2A antagonist ameliorates pain associated with pancreatic cancer mice by HDAC inhibition and inflammatory cytokines. The result of investigation supports that modulation of 5HT2A receptor could be used clinically to protects neuropathic pain in pancreatic cancer.

Engineering contact curved interface with high-electronic-state active sites for high-performance potassium-ion batteries.

Potassium-ion batteries (PIBs) have attracted ever-increasing interest due to the abundant potassium resources and low cost, which are considered a sustainable energy storage technology. However, the graphite anodes employed in PIBs suffer from low capacity and sluggish reaction kinetics caused by the large radius of potassium ions. Herein, we report nitrogen-doped, defect-rich hollow carbon nanospheres with contact curved interfaces (CCIs) on carbon nanotubes (CNTs), namely CCI-CNS/CNT, to boost both electron transfer and potassium-ion adsorption. Density functional theory calculations validate that engineering CCIs significantly augments the electronic state near the Fermi level, thus promoting electron transfer. In addition, the CCIs exhibit a pronounced affinity for potassium ions, promoting their adsorption and subsequently benefiting potassium storage. As a result, the rationally designed CCI-CNS/CNT anode shows remarkable cyclic stability and rate capability. This work provides a strategy for enhancing the potassium storage performance of carbonaceous materials through CCI engineering, which can be further extended to other battery systems.

Ginseng-derived nanoparticles reprogram macrophages to regulate arginase-1 release for ameliorating T cell exhaustion in tumor microenvironment.

BACKGROUND: Lines of evidence indicated that, immune checkpoints (ICs) inhibitors enhanced T cell immune response to exert anti-tumor effects. However, T cell exhaustion has been so far a major obstacle to antitumor immunotherapy in colorectal cancer patients. Our previous studies showed that ginseng-derived nanoparticles (GDNPs) inhibited the growth of various tumors by reprograming tumor-associated macrophages (TAMs) and downregulated the ICs expression on T cells in tumor microenvironment (TME), but the underlying effector mechanisms remained unclear. METHODS: The correlation between arginase-1 (ARG1) and T cells was computed based on the colorectal cancer patients in TCGA database. In vitro, we observed that GDNPs reprogrammed TAMs inhibited ARG1 release and ultimately ameliorated T cell exhaustion according to several techniques including WB, PCR, ELISA and flow cytometry. We also used an in vivo MC38 tumor-bearing model and administered GDNPs to assess their anti-tumor effects through multiple indices. The mechanism that GDNPs improved T cell exhaustion was further clarified using the bioinformatics tools and flow cytometry. RESULTS: GDNPs reprogramed TAMs via reducing ARG1 production. Moreover, normalized arginine metabolism ameliorated T cell exhaustion through mTOR-T-bet axis, resulting in reduced ICs expression and enhanced CD8+ T cells expansion. CONCLUSIONS: By regulating the mTOR-T-bet axis, GDNPs reprogramed macrophages to regulate ARG1 release, which further ameliorated T cell exhaustion in TME. These findings provided new insights into comprehending the mechanisms underlying the mitigation of T cell exhaustion, which may facilitate the development of innovative therapeutic strategies in the field of cancer treatment.

RANK ligand converts the NCoR/HDAC3 co-repressor to a PGC1ß- and RNA-dependent co-activator of osteoclast gene expression.

The nuclear receptor co-repressor (NCoR) complex mediates transcriptional repression dependent on histone deacetylation by histone deacetylase 3 (HDAC3) as a component of the complex. Unexpectedly, we found that signaling by the receptor activator of nuclear factor κB (RANK) converts the NCoR/HDAC3 co-repressor complex to a co-activator of AP-1 and NF-κB target genes that are required for mouse osteoclast differentiation. Accordingly, the dominant function of NCoR/HDAC3 complexes in response to RANK signaling is to activate, rather than repress, gene expression. Mechanistically, RANK signaling promotes RNA-dependent interaction of the transcriptional co-activator PGC1ß with the NCoR/HDAC3 complex, resulting in the activation of PGC1ß and inhibition of HDAC3 activity for acetylated histone H3. Non-coding RNAs Dancr and Rnu12, which are associated with altered human bone homeostasis, promote NCoR/HDAC3 complex assembly and are necessary for RANKL-induced osteoclast differentiation in vitro. These findings may be prototypic for signal-dependent functions of NCoR in other biological contexts.

In situ construction of Fe3O4@PDA@Au multi hotspot SERS probe for trace detection of benzodiazepines in serum.

The abuse of benzodiazepines is a serious health hazard that can cause damage to the central nervous system.Trace monitoring of benzodiazepines in serum can effectively prevent the damage caused by these drugs. Therefore, in this study, a Fe3O4@PDA@Au core-shell satellite nanomaterial SERS(Surface-Enhanced Raman Scattering) probe that integrates magnetic separation techniques and a multi-hotspot structure was synthetized by in situ growth of gold nanoparticles on the surface of PDA(Polymerized dopamine)-coated Fe3O4. The size and gap of Au nanoparticles on the surface of the SERS probe can be modulated by regulating the amount of HAuCl4 to create 3D multi-hotspot structures. The good dispersion and superparamagnetic properties of this SERS probe enable it to fully contact and load the target molecules in the serum, and the applied magnetic field facilitates separation and enrichment.This process increases the molecular density and number of SERS hotspots, thereby enhancing detection sensitivity. Based on the above considerations, this SERS probe can detect traces of eszopiclone and diazepam in serum at concentrations as low as 1 µg/ml with good linearity, offering promising applications in clinical monitoring of drug concentrations in blood.

[Change of drinking water quality in Shijiazhuang South-to-North Water Diversion area from 2014 to 2021].

OBJECTIVE: To analyze the change of drinking water quality in the receiving area of Shijiazhuang South-to-North Water Transfer Project. METHODS: 2029 monitoring data of drinking water in the receiving areas of the South-to-North Water Transfer Project in Shijiazhuang from 2014 to 2021 were collected and collated according to the Sanitary Standard for Drinking Water(GB 5749-2006). Off-work water and pipe water before and after the total coliform group of South-to-North Water Transfer Project, heat-resistant coliform bacteria, escherichia coli, the total number of colonies, arsenic, cadmium, chromium, lead, mercury, nitrate, fluoride, selenium, cyanide, chloroform, carbon tetrachloride, chromaticity and turbidity, odor and taste, visible to the naked eye, pH, aluminum, iron, manganese, copper, zinc, chloride, sulfate, total soluble solids, total hardness, oxygen consumption, volatile phenols, anionic synthetic detergent, ammonia nitrogen, residual chlorine and chlorine dioxide were evaluated and compared. χ~2 test was used to compare the qualified rate, Mann-Whitney rank sum test was used to compare the test values of each index, and simple superposition comprehensive water environmental quality index method was used to evaluate the water quality comprehensively. RESULTS: Before the South-to-North Water Transfer Project, the total qualified rate of drinking water was 84.21%, that of factory water was 81.29%, and that of end water was 85.97%. The total qualified rate of drinking water after the South-to-North Water Transfer Project was 98.72%, that of factory water was 98.89%, and that of end water was 98.66%. The total qualified rate of water quality, the qualified rate of factory water and the qualified rate of end water after the South-to-North water transfer were higher than those before the transfer(P<0.05). The qualified rates of microbial indexes and total hardness of ex-factory water before the South-to-North Water Transfer Project were 94.37% and 89.94%, and those of microbial indexes and total hardness of end water were 94.32% and 93.35%, respectively. After the South-to-North Water Transfer, the qualified rates of microbial indexes and total hardness of the ex-factory water were 100.00% and 98.90%, and the qualified rates of microbial indexes and total hardness of the end water were 100.00% and 99.24%, respectively. After the South-to-North water transfer, the qualified rate of microbial indexes and total hardness of factory water and peripheral water were higher than those before the transfer(P<0.05). After the South-to-North Water Transfer, the M of total coliform group, total colony number, total hardness, fluoride, nitrate nitrogen, chloride, sulfate and dissolved total solids were lower than those before water transfer(For example, the median number of colonies and total hardness of factory water before the South-to-North Water Transfer were 20.00 CFU/100 mL and 248.00 mg/L, respectively. After the South-to-North Water Transfer, the median number of colonies and total hardness were 1.00 CFU/100 mL and 129.00 mg/L, respectively), while the M of trichloromethane, aluminum, pH and oxygen consumption were higher than those before water transfer(For example, the median of trichloromethane and aluminum before the South-to-North Water Transfer is 0.04×10~(-2) and 0.04×10~(-1) mg/L, respectively. After the South-to-North Water Transfer, the median of chloroform and aluminum were 0.06×10~(-2) and 0.25×10~(-1) mg/L, respectively)(P<0.05). The median WQI of comprehensive water environmental quality index before and after the South-to-North Water Transfer was 4.58 and 2.37(P<0.05), respectively. CONCLUSION: The introduction of the South-to-North Water Transfer has significantly improved the quality of drinking water in Shijiazhuang city. Microbial contamination and total hardness exceedance have been greatly improved.

PAIP1 regulates expression of immune and inflammatory response associated genes at transcript level in liver cancer cell.

Poly(A) binding protein interacting protein 1 (PAIP1) is a translation regulator and also regulate the decay of mRNA. PAIP1 has also been reported to be a marker of increased invasive potential of liver cancer. However, the roles and underlying molecular mechanism of PAIP1 in liver cancer is still unclear. Here, cell viability and the gene expression profile of liver cancer line HepG2 transfected with PAIP1 siRNA was compared with cells transfected with non-targeting control siRNA. The results showed that PAIP1 knockdown inhibited cell viability, and extensively affects expression of 893 genes at transcriptional level in HepG2 cells. Gene function analysis showed that a large number of PAIP1 up-regulated genes were enriched in term of DNA-dependent transcription and the down-regulated genes were enriched in some pathways including immune response and inflammatory response. qPCR confirmed that PAIP1 knockdown positively regulated the expression of selected immune and inflammatory factor genes in HepG2 cells. Expression analysis of TCGA revealed that PAIP1 had positive correlations with two immune associated genes IL1R2 and PTAFR in liver tumor tissue. Taken together, our results demonstrated that PAIP1 was not only a translation regulator, but also a transcription regulator in liver cancer. Moreover, PAIP1 could function as a regulatory factor of immune and inflammatory genes in liver cancer. Thus, our study provides important cues for further study on the regulatory mechanism of PAIP1 in liver cancer.

Construction of a TTN Mutation-Based Prognostic Model for Evaluating Immune Microenvironment, Cancer Stemness, and Outcomes of Colorectal Cancer Patients.

Background: Colorectal cancer (CRC) is one of the commonest cancers worldwide. As conventional biomarkers cannot clearly define the heterogeneity of CRC, it is essential to establish novel prognostic models. Methods: For the training set, data pertaining to mutations, gene expression profiles, and clinical parameters were obtained from the Cancer Genome Atlas. Consensus clustering analysis was used to identify the CRC immune subtypes. CIBERSORT was used to analyze the immune heterogeneity across different CRC subgroups. Least absolute shrinkage and selection operator regression was used to identify the genes for constructing the immune feature-based prognostic model and to determine their coefficients. Result: A gene prognostic model was then constructed to predict patient outcomes; the model was then externally validated using data from the Gene Expression Omnibus. As a high-frequency somatic mutation, the titin (TTN) mutation has been identified as a risk factor for CRC. Our results demonstrated that TTN mutations have the potential to modulate the tumor microenvironment, converting it into the immunosuppressive type. In this study, we identified the immune subtypes of CRC. Based on the identified subtypes, 25 genes were selected for prognostic model construction; a prediction model was also constructed, and its prediction accuracy was tested using the validation dataset. The potential of the model in predicting immunotherapy responsiveness was then explored. Conclusion: TTN-mutant and TTN-wild-type CRC demonstrated different microenvironment features and prognosis. Our model provides a robust immune-related gene prognostic tool and a series of gene signatures for evaluating the immune features, cancer stemness, and prognosis of CRC.

Edible and cation-free kiwi fruit derived vesicles mediated EGFR-targeted siRNA delivery to inhibit multidrug resistant lung cancer.

Clinically, activated EGFR mutation associated chemo-drugs resistance has severely threaten NSCLC patients. Nanoparticle based small interfering RNA (siRNA) therapy representing another promising alternative by silencing specific gene while still suffered from charge associated toxicity, strong immunogenicity and poor targetability. Herein, we reported a novel EGFR-mutant NSCLC therapy relying on edible and cation-free kiwi-derived extracellular vesicles (KEVs), which showed sevenfold enhancement of safe dosage compared with widely used cationic liposomes and could be further loaded with Signal Transducer and Activator of Transcription 3 interfering RNA (siSTAT3). siSTAT3 loaded KEVs (STAT3/KEVs) could be easily endowed with EGFR targeting ability (STAT3/EKEVs) and fluorescence by surface modification with tailor-making aptamer through hydrophobic interaction. STAT3/EKEVs with a controlled size of 186 nm displayed excellent stability, high specificity and good cytotoxicity towards EGFR over-expressing and mutant PC9-GR4-AZD1 cells. Intriguingly, the systemic administration of STAT3/EKEVs significantly suppressed subcutaneous PC9-GR4-AZD1 tumor xenografts in nude mice by STAT3 mediated apoptosis. This safe and robust KEVs has emerged as the next generation of gene delivery platform for NSCLC therapy after multiple drug-resistance.