A second-generation M1-polarized CAR macrophage with antitumor efficacy.

Chimeric antigen receptor (CAR) T cell therapies have successfully treated hematological malignancies. Macrophages have also gained attention as an immunotherapy owing to their immunomodulatory capacity and ability to infiltrate solid tumors and phagocytize tumor cells. The first-generation CD3ζ-based CAR-macrophages could phagocytose tumor cells in an antigen-dependent manner. Here we engineered induced pluripotent stem cell-derived macrophages (iMACs) with toll-like receptor 4 intracellular toll/IL-1R (TIR) domain-containing CARs resulting in a markedly enhanced antitumor effect over first-generation CAR-macrophages. Moreover, the design of a tandem CD3ζ-TIR dual signaling CAR endows iMACs with both target engulfment capacity and antigen-dependent M1 polarization and M2 resistance in a nuclear factor kappa B (NF-κB)-dependent manner, as well as the capacity to modulate the tumor microenvironment. We also outline a mechanism of tumor cell elimination by CAR-induced efferocytosis against tumor cell apoptotic bodies. Taken together, we provide a second-generation CAR-iMAC with an ability for orthogonal phagocytosis and polarization and superior antitumor functions in treating solid tumors relative to first-generation CAR-macrophages.

Ferroptosis contributes to airway epithelial E-cadherin disruption in a mixed granulocytic asthma mouse model.

Aberrant expression of airway epithelial E-cadherin is a key feature of asthma, yet the underlying mechanisms are largely unknown. Ferroptosis is a novel form of regulated cell death involved in asthma pathogenesis. This study was aimed to evaluate the role of ferroptosis and to investigate whether ferroptosis mediates E-cadherin disruption in mixed granulocyte asthma (MGA). Two murine models of MGA were established using toluene diisocyanate (TDI) or ovalbumin with Complete Freund's Adjuvant (OVA/CFA). Specific antagonists of ferroptosis, including Liproxstatin-1 (Lip-1) and Ferrostatin-1 (Fer-1) were given to the mice. The allergen-exposed mice displayed markedly shrunk mitochondria in the airway epithelia, with decreased volume and denser staining accompanied by down-regulated GPX4 as well as up-regulated FTH1 and malondialdehyde, which are markers of ferroptosis. Decreased pulmonary expression of E-cadherin was also observed, with profound loss of membrane E-cadherin in the airway epithelia, as well as increased secretion of sE-cadherin. Treatment with Lip-1 not only showed potent protective effects against the allergen-induced airway hyperresponsiveness and inflammatory responses, but also rescued airway epithelial E-cadherin expression and inhibited the release of sE-cadherin. Taken together, our data demonstrated that ferroptosis mediates airway epithelial E-cadherin dysfunction in MGA.

PRMT6 deficiency or inhibition alleviates neuropathic pain by decreasing glycolysis and inflammation in microglia.

Microglia induced chronic inflammation is the critical pathology of Neuropathic pain (NP). Metabolic reprogramming of macrophage has been intensively reported in various chronic inflammation diseases. However, the metabolic reprogramming of microglia in chronic pain remains to be elusive. Here, we reported that immuno-metabolic markers (HIF-1α, PKM2, GLUT1 and lactate) were related with increased expression of PRMT6 in the ipsilateral spinal cord dorsal horn of the chronic construction injury (CCI) mice. PRMT6 deficiency or prophylactic and therapeutic intrathecal administration of PRMT6 inhibitor (EPZ020411) ameliorated CCI-induced NP, inflammation and glycolysis in the ipsilateral spinal cord dorsal horn. PRMT6 knockout or knockdown inhibited LPS-induced inflammation, proliferation and glycolysis in microglia cells. While PRMT6 overexpression exacerbated LPS-induced inflammation, proliferation and glycolysis in BV2 cells. Recent research revealed that PRMT6 could interact with and methylate HIF-1α, which increased HIF-1α protein stability. In sum, increased expression of PRMT6 exacerbates NP progress by increasing glycolysis and neuroinflammation through interacting with and stabilizing HIF-1α in a methyltransferase manner, which outlines novel pathological mechanism and drug target for NP.

Cardiovascular disease risk perceptions and influencing factors among Chinese systemic lupus erythematosus patients.

BACKGROUND: Systemic Lupus Erythematosus patients (SLE) are at a higher risk of cardiovascular events than the general population. This study aimed to investigate the risk perception of cardiovascular disease (CVD) and to analyze its influence factors among Chinese SLE patients. METHODS: This was a cross-sectional study. Convenience sampling was used to select 201 patients with SLE who had attended the outpatient and inpatient departments of the Department of Rheumatology and Immunology at the First Affiliated Hospital of the University of Science and Technology of China from November 2022 to March 2023. The following were used in the study: the Chinese version of the Attitudes and Beliefs about Cardiovascular Disease Risk Questionnaire, the Social Support Rating Scale, the Connor-Davidson Resilience Scale, the General Self-Efficacy Scale, the Hospital Anxiety and Depression Scale, the Health Literacy Management Scale, and sociodemographic and disease-related data. RESULTS: The mean (standard deviation) risk perception score of CVD patients with SLE was 57.18 ± 13.02. A Pearson correlation analysis showed that CVD risk perceptions were positively correlated with health literacy (r = 0.152, p < .05) and depression (r = 0.277, p < .05), and negatively correlated with social support (r = -0.393, p < .05) and psychological resilience (r = -0.374, p < .05). A multiple linear regression analysis showed that body mass index (BMI), family history, health literacy, depression, social support, and psychological resilience were the main factors influencing CVD risk perceptions among Chinese SLE patients (p < .05). CONCLUSIONS: Body mass index, family history, health literacy, depression, social support, and psychological resilience influenced CVD risk perceptions among Chinese SLE patients. Healthcare workers should objectively and accurately assess the levels of CVD risk perception among SLE patients, identify the risk factors of CVD, adopt effective health risk communication strategies to help patients develop appropriate risk perceptions, and raise risk awareness to adopt active coping approaches to reduce risk.

GLUT1 regulates the release of VEGF-A in the alveolar epithelium of lipopolysaccharide-induced acute lung injury.

Acute lung injury (ALI) is a severe disease with high mortality and poor prognosis, characterized by excessive and uncontrolled inflammatory response. Vascular endothelial growth factor A (VEGF-A) contributes to the development and progression of ALI. The aim of this study was to evaluate the role of glucose transporter 1 (GLUT1) in alveolar epithelial VEGF-A production in lipopolysaccharide (LPS)-induced ALI. An ALI mouse model was induced by LPS oropharyngeal instillation. Mice were challenged with LPS and then treated with WZB117, a specific antagonist of GLUT1. For the vitro experiments, cultured A549 cells (airway epithelial cell line) were exposed to LPS, with or without the GLUT1 inhibitors WZB117 or BAY876. LPS significantly upregulated of GLUT1 and VEGF-A both in the lung from ALI mice and in cultured A549. In vivo, treatment with WZB117 not only markedly decreased LPS-induced pulmonary edema, injury, neutrophilia, as well as levels of interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α in bronchoalveolar lavage fluid (BALF), but also reduced VEGF-A production. Yet, the maximum tolerated concentration of WZB117 failed to suppress LPS-induced VEGF-A overexpression in vitro. While administration of BAY876 inhibited gene and protein expression as well as secretion of VEGF-A in response to LPS in A549. These results illustrated that GLUT1 upregulates VEGF-A production in alveolar epithelia from LPS-induced ALI, and inhibition of GLUT1 alleviates ALI.

The associations between peripheral inflammatory and lipid parameters, white matter hyperintensity, and cognitive function in patients with non-disabling ischemic cerebrovascular events.

BACKGROUND: The global prevalence of VCI has increased steadily in recent years, but diagnostic biomarkers for VCI in patients with non-disabling ischemic cerebrovascular incidents (NICE) remain indefinite. The primary objective of this research was to investigate the relationship between peripheral serological markers, white matter damage, and cognitive function in individuals with NICE. METHODS: We collected clinical data, demographic information, and medical history from 257 patients with NICE. Using the MoCA upon admission, patients were categorized into either normal cognitive function (NCF) or VCI groups. Furthermore, they were classified as having mild white matter hyperintensity (mWMH) or severe WMH based on Fazekas scores. We then compared the levels of serological markers between the cognitive function groups and the WMH groups. RESULTS: Among 257 patients with NICE, 165 were male and 92 were female. Lymphocyte count (OR = 0.448, P < 0.001) and LDL-C/HDL-C (OR = 0.725, P = 0.028) were protective factors for cognitive function in patients with NICE. The sWMH group had a higher age and inflammation markers but a lower MoCA score, and lymphocyte count than the mWMH group. In the mWMH group, lymphocyte count (AUC = 0.765, P < 0.001) and LDL-C/HDL-C (AUC = 0.740, P < 0.001) had an acceptable diagnostic value for the diagnosis of VCI. In the sWMH group, no significant differences were found in serological markers between the NCF and VCI groups. CONCLUSION: Lymphocyte count, LDL-C/HDL-C were independent protective factors for cognitive function in patients with NICE; they can be used as potential biological markers to distinguish VCI in patients with NICE and are applicable to subgroups of patients with mWMH.

AHNAK2 Regulates NF-κB/MMP-9 Signaling to Promote Pancreatic Cancer Progression.

Early metastasis of pancreatic cancer (PaC) is a major cause of its high mortality rate. Previous studies have shown that AHNAK2 is involved in the progression of some tumors and is predicted to be an independent prognostic factor for PaC; however, the specific mechanisms through which AHNAK2 regulates PaC remain unclear. In this study, we examined the role of AHNAK2 in PaC and its potential molecular mechanisms. AHNAK2 mRNA and protein expression in PaC tissues and cells were measured using qRT-PCR and western blot analysis. After AHNAK2 knockdown using small interfering RNA, PaC cells were subjected to CCK-8 scratch, and Transwell assays to assess cell proliferation, migration, and invasion, respectively. Furthermore, the validation of the mechanistic pathway was achieved by western blot analysis. AHNAK2 mRNA and protein levels were up-regulated in PaC and silencing AHNAK2 significantly inhibited the proliferation, migration, and invasion of PaC cells. Mechanistically, AHNAK2 knockdown decreased the expression of phosphorylated p65, phosphorylated IκBα, and matrix metalloproteinase-9 (MMP-9), suggesting that activation of the NF-κB/MMP-9 signaling pathway was inhibited. Importantly, activation of NF-κB reversed the effects of AHNAK2 knockdown. Our findings indicate that AHNAK2 promotes PaC progression through the NF-kB/MMP-9 pathway and provides a theoretical basis for targeting AHNAK2 for the treatment of PaC.

Uncovering the transcriptional responses of tobacco (Nicotiana tabacum L.) roots to Ralstonia solanacearum infection: a comparative study of resistant and susceptible cultivars.

BACKGROUND: Tobacco bacterial wilt (TBW) caused by Ralstonia solanacearum is the most serious soil-borne disease of tobacco that significantly reduces crop yield. However, the limited availability of resistance in tobacco hinders breeding efforts for this disease. RESULTS: In this study, we conducted hydroponic experiments for the root expression profiles of D101 (resistant) and Honghuadajinyuan (susceptible) cultivars in response to BW infection at 0 h, 6 h, 1 d, 3 d, and 7d to explore the defense mechanisms of BW resistance in tobacco. As a result, 20,711 and 16,663 (total: 23,568) differentially expressed genes (DEGs) were identified in the resistant and susceptible cultivars, respectively. In brief, at 6 h, 1 d, 3 d, and 7 d, the resistant cultivar showed upregulation of 1553, 1124, 2583, and 7512 genes, while the susceptible cultivar showed downregulation of 1213, 1295, 813, and 7735 genes. Similarly, across these time points, the resistant cultivar had downregulation of 1034, 749, 1686, and 11,086 genes, whereas the susceptible cultivar had upregulation of 1953, 1790, 2334, and 6380 genes. The resistant cultivar had more up-regulated genes at 3 d and 7 d than the susceptible cultivar, indicating that the resistant cultivar has a more robust defense response against the pathogen. The GO and KEGG enrichment analysis showed that these genes are involved in responses to oxidative stress, plant-pathogen interactions, cell walls, glutathione and phenylalanine metabolism, and plant hormone signal transduction. Among the DEGs, 239 potential candidate genes were detected, including 49 phenylpropane/flavonoids pathway-associated, 45 glutathione metabolic pathway-associated, 47 WRKY, 48 ERFs, eight ARFs, 26 pathogenesis-related genes (PRs), and 14 short-chain dehydrogenase/reductase genes. In addition, two highly expressed novel genes (MSTRG.61386-R1B-17 and MSTRG.61568) encoding nucleotide-binding site leucine-rich repeat (NBS-LRR) proteins were identified in both cultivars at 7 d. CONCLUSIONS: This study revealed significant enrichment of DEGs in GO and KEGG terms linked to glutathione, flavonoids, and phenylpropane pathways, indicating the potential role of glutathione and flavonoids in early BW resistance in tobacco roots. These findings offer fundamental insight for further exploration of the genetic architecture and molecular mechanisms of BW resistance in tobacco and solanaceous plants at the molecular level.

Effect and mechanism of microRNA-515-5p in proliferation and apoptosis of trophoblast cells in preeclampsia via manipulating histone deacetylase 2.

Preeclampsia (PE) refers to a pregnancy-specific disease that begins with the placenta. Differentially expressed microRNAs (miRs) are a feature of PE. This study tried to elicit the functional mechanism of miR-515-5p in trophoblast cell behaviors in PE. First, HTR-8/SVneo cells were transfected with miR-515-5p mimic or miR-515-5p inhibitor. Then, relative expression levels of miR-515-5p and histone deacetylase 2 (HDAC2) in HTR-8/SVneo cells were determined by reverse transcription-quantitative polymerase chain reaction. The potential binding site of miR-515-5p and HDAC2 was predicted on Targetscan and their binding relationship was verified via dual-luciferase assay. Proliferation, apoptosis, invasion, and migration of HTR-8/SVneo cells were assessed via cell counting kit-8, flow cytometry, Transwell, and wound healing assays, respectively. Protein levels of Cleaved caspase-3, Bcl-2, and Bax were determined via Western blot. Overexpressed miR-515-5p impeded proliferation and stimulated apoptosis of HTR-8/SVneo cells, and decreased levels of Cleaved caspase-3 and Bax and elevated Bcl-2, whilst opposite results were observed after miR-515-5p inhibition. miR-515-5p targeted HDAC2. Knockdown of HDAC2 annulled the promotional action of miR-515-5p inhibition on proliferative, invasive, and migratory abilities and its antiapoptotic action on HTR-8/SVneo cells. In brief, miR-515-5p affected the proliferation, apoptosis, invasion, and migration of HTR-8/SVneo cells by targeting HDAC2.

IRE1α/XBP-1 promotes ß-catenin signaling activation of airway epithelium in lipopolysaccharide-induced acute lung injury.

BACKGROUND: Acute lung injury (ALI), along with the more severe condition--acute respiratory distress syndrome (ARDS), is a major cause of respiratory failure in critically ill patients with high morbidity and mortality. Inositol-requiring protein 1α (IRE1α)/X box protein-1 (XBP1) pathway was proved to regulate lipopolysaccharide (LPS)-induced lung injury and inflammation. Yet, its role on epithelial ß-catenin in LPS-induced ALI remains to be elucidated. METHODS: LPS-induced models were generated in mice (5 mg/kg) and Beas-2B cells (200 µg/mL). Two selective antagonists of IRE1α (4µ8c and STF-083010) were respectively given to LPS-exposed mice and cultured cells. RESULTS: Up-regulated expression of endoplasmic reticulum (ER) stress markers immunoglobulin-binding protein (BIP) and spliced X box protein-1(XBP-1s) was detected after LPS exposure. Besides, LPS also led to a down-regulated total ß-catenin level in the lung and Beas-2B cells, with decreased membrane distribution as well as increased cytoplasmic and nuclear accumulation, paralleled by extensively up-regulated downstream targets of the Wnt/ß-catenin signaling. Treatment with either 4µ8c or STF-083010 not only significantly attenuated LPS-induced lung injury and inflammation, but also recovered ß-catenin expression in airway epithelia, preserving the adhesive function of ß-catenin while blunting its signaling activity. CONCLUSION: These results illustrated that IRE1α/XBP1 pathway promoted the activation of airway epithelial ß-catenin signaling in LPS-induced ALI.

Sedentary Behavior, Physical Activity, Social Participation, and Loneliness Among Community-Dwelling Older Adults in China.

This study examined the relationship between loneliness, sedentary behavior, physical exercise, and social participation in Chinese older adults, and provided ideas to formulate preventive strategies that can help reduce loneliness. Data on demographics, health behavior, social participation, and loneliness were collected from a cross-sectional study of 629 older adults in Hefei, Anhui province, from June to August 2020. After adjusting for age, income, religion, marital status, and chronic illness demographic variables, sedentary behavior (ß = 0.111, SE = 0.671, p = .001), physical exercise (ß = -0.229, SE = 0.358, p < .001), and social participation (ß = -0.329, SE = 0.086, p < .001) were found to be significantly correlated with loneliness in older adults. These findings suggest that a higher level of loneliness may be linked to greater sedentary behavior, less social engagement, and decreased physical exercise among older men and women.

Microcystin-LR-Induced Interaction between M2 Tumor-Associated Macrophage and Colorectal Cancer Cell Promotes Colorectal Cancer Cell Migration through Regulating the Expression of TGF-ß1 and CST3.

Microcystin-LR (MC-LR) is a toxic secondary metabolite produced by cyanobacteria that has been demonstrated to promote colorectal cancer (CRC). However, the mechanism by which MC-LR enhances CRC in the tumor microenvironment (TME) is poorly understood. To elucidate its role in TME, a co-culture system was established using CRC cells and M2 macrophages in a Transwell chamber. The study found that MC-LR promotes CRC cell migration by upregulating TGF-ß1 expression and secretion in M2 macrophages and downregulating CST3 in CRC cells. Neutralizing TGF-ß1 increased CST3 expression in CRC cells, while overexpressing CST3 in CRC cells suppressed TGF-ß1 expression in M2 macrophages, both of which weakened MC-LR-induced cellular motility in the co-culture system. In vivo, the mice in the MC-LR/AOM/DSS group had more tumor nodules, deeper tumor invasion, and higher M2 macrophage infiltration compared to the AOM/DSS group, and the expression of TGF-ß1 and CST3 in tumors was consistent with the cellular level. Overall, this study provides insights into the regulatory mechanism of MC-LR on TME, revealing that MC-LR upregulates the expression and secretion of TGF-ß1 in M2 macrophages, which in turn inhibits the expression of CST3 in CRC cells to promote migration.

Metabolic Engineering of Microorganisms to Produce Pyruvate and Derived Compounds.

Pyruvate is a hub of various endogenous metabolic pathways, including glycolysis, TCA cycle, amino acid, and fatty acid biosynthesis. It has also been used as a precursor for pyruvate-derived compounds such as acetoin, 2,3-butanediol (2,3-BD), butanol, butyrate, and L-alanine biosynthesis. Pyruvate and derivatives are widely utilized in food, pharmaceuticals, pesticides, feed additives, and bioenergy industries. However, compounds such as pyruvate, acetoin, and butanol are often chemically synthesized from fossil feedstocks, resulting in declining fossil fuels and increasing environmental pollution. Metabolic engineering is a powerful tool for producing eco-friendly chemicals from renewable biomass resources through microbial fermentation. Here, we review and systematically summarize recent advances in the biosynthesis pathways, regulatory mechanisms, and metabolic engineering strategies for pyruvate and derivatives. Furthermore, the establishment of sustainable industrial synthesis platforms based on alternative substrates and new tools to produce these compounds is elaborated. Finally, we discuss the potential difficulties in the current metabolic engineering of pyruvate and derivatives and promising strategies for constructing efficient producers.

Combined assessment of health hazard and odour impact of soils at a contaminated site: a case study on a defunct pharmaceuticals factory in China.

Surveys and assessments of contaminated sites primarily focus on hazardous pollutants in the soil with less attention paid to odorants. This makes the management of contaminated sites difficult. In this study, hazardous and odorous pollutants in the soil were assessed for a large site that was previously used for production of pharmaceuticals to determine the degree and characteristics of soil contamination at pharmaceutical production sites, for undertaking rational remediation measures. The main hazardous pollutants at the study site were triethylamine, n-butyric acid, benzo(a)pyrene (BaP), N-nitrosodimethylamine (NDMA), dibenzo(a,h)anthracene (DBA), total petroleum hydrocarbons (C10-C40) (TPH), and 1,2-dichloroethane; TEA, BA, and isovaleric acid (IC) were the main odorants. As the type and distribution of hazardous and odorous pollutants differ, it is necessary to separately assess the impact of these pollutants at a contaminated site. Soils in the surface layer pose significant non-carcinogenic (HI = 68.30) and carcinogenic risks (RT = 3.56E-5), whereas those in the lower layer only pose non-carcinogenic risks (HI > 7.43). Odorants were found at considerable concentrations both in the surface and lower layers, with the maximum concentrations being 29,309.91 and 41.27, respectively. The findings of this study should improve our understanding of soil contamination at former pharmaceutical production sites and should inform the assessment of the risks posed by contaminated sites, with problems associated with odour, and possible remediation strategies.

Identification and primary application of hybridomas cell secreting monoclonal antibodies against mink (Neovison vison) interferon-gamma.

Due to their susceptibility to several human viruses, the mink has been proposed as potential animal models for the study of human viral infections. However, there are no specific monoclonal antibody (mAbs) currently available for the detection of mink-specific interferon-gamma (miIFN-γ). The BALB/c mice were immunized intraperitoneally with purified recombinant miIFN-γ protein. The splenocytes were obtained and fused with murine myeloma cells. Five of 24 hybridoma clones were obtained to produce mAbs steadily with the strongest affinity to recombinant miIFN-γ protein. The isotype of the 31A, 31B and 31G were lgG 2b. The isotype of 44 and 46 were lgG 2a and 1. All five mAbs were κ light chains. Western blotting and indirect ELISA method showed that 5 mAbs were positive to miIFN-γ. Immunofluorescence showed that 2 mAbs (44 and 46) had a positive reaction to miIFN-γ. The hybridoma clone 46 had the highest sensitivity for the detection of miIFN-γ. Most importantly, our primary sandwich ELISA system (mAbs 46 and polyclonal antiserum) detected endogenous IFN-γ in mink lymphocytes infected with canine distemper virus (CDV). We have thus developed a novel mAbs could recognize miIFN-γ, and have demonstrated the first ELISA-based measurement of IFN-γ in lymphocyte of the mink.

Coarse-Grained Molecular Dynamics Simulations of Paclitaxel-Loaded Polymeric Micelles.

A continuous manufacturing technology based on coaxial turbulent jet in coflow was previously developed to produce paclitaxel-loaded polymeric micelles. Herein, coarse-grained molecular dynamics (CG-MD) simulations were implemented to better understand the effect of the material attributes (i.e., the drug-polymer ratio and the ethanol concentration) and process parameters (i.e., temperature) on the self-assembly process of polymeric micelles as well as to provide molecular details on micelle instability. An all-atom (AA) poly (ethylene glycol)-poly (lactic acid) (PEG-PLA) polymer model was developed as the reference for parameterizing a coarse-grained (CG) model, and the AA polymer model was further validated with experimental glass transition temperature (Tg). The model transferability was verified by comparing structural properties between the AA and CG models. The CG model was further validated with experimental data, including micelle particle size measurements and drug encapsulation efficiency. Furthermore, the encapsulation of paclitaxel into the polymeric micelles was included in the simulations, taking into consideration the interactions between the paclitaxel and the polymers. The results from various points of view demonstrated a strong dependence of the shape of the micelles on the drug encapsulation, with micelles transitioning from spherical to ellipsoidal structures with an increasing paclitaxel amount. Simulation data were also used to identify the critical aggregation number (i.e., the number of polymer and drug molecules required for transition from one shape to another). Improved micellar structural stability was found with a larger micellar size and less solvent accessibility. Lastly, an evaluation was performed on the micellar dissociation free energy using a steered molecular dynamics simulation over a range of temperatures and ethanol concentrations. These simulations revealed that at higher ethanol and temperature conditions, micelles become destabilized, resulting in greater paclitaxel release. The increased drug release was determined to originate from the solvation of the hydrophobic core, which promoted micellar swelling and an associated reduction in hydrophobic interactions, leading to a loosely packed micellar structure.

Red blood cell biomimetic nanoparticle with anti-inflammatory, anti-oxidative and hypolipidemia effect ameliorated atherosclerosis therapy.

A main pathogenic factor of atherosclerosis is the local oxidative stress microenvironment. Probucol (PU) has anti-inflammatory, antioxidative and hypolipidemic effects, showing great potential to treat atherosclerosis. However, its low bioavailability limits its development. Herein, PU was encapsulated to form RP-PU with star-shaped polymers and red blood cell membranes. Star-shaped polymers show lower solution viscosity, a smaller hydrodynamic radius and a higher drug loading content than linear polymers. RP-PU had a good sustained-release effect and excellent biocompatibility. RP-PU can be efficiently internalized by cells to improve biodistribution. ApoE-/- mice were treated with RP-PU, and the contents of lipids and related metabolic enzymes were effectively reduced. The collagen fibers in the aortic root sections were reduced by RP-PU compared with control and PU. Moreover, RP-PU inhibited foam cell formation, decreased ICAM-1 and MCP-1 expression and delayed lesion formation. Consequently, RP-PU biomimetic nanoparticles can be developed as an anti-atherosclerotic nanotherapeutic.

Metabolic Engineering of Shikimic Acid Biosynthesis Pathway for the Production of Shikimic Acid and Its Branched Products in Microorganisms: Advances and Prospects.

The shikimate pathway is a necessary pathway for the synthesis of aromatic compounds. The intermediate products of the shikimate pathway and its branching pathway have promising properties in many fields, especially in the pharmaceutical industry. Many important compounds, such as shikimic acid, quinic acid, chlorogenic acid, gallic acid, pyrogallol, catechol and so on, can be synthesized by the shikimate pathway. Among them, shikimic acid is the key raw material for the synthesis of GS4104 (Tamiflu®), an inhibitor of neuraminidase against avian influenza virus. Quininic acid is an important intermediate for synthesis of a variety of raw chemical materials and drugs. Gallic acid and catechol receive widespread attention as pharmaceutical intermediates. It is one of the hotspots to accumulate many kinds of target products by rationally modifying the shikimate pathway and its branches in recombinant strains by means of metabolic engineering. This review considers the effects of classical metabolic engineering methods, such as central carbon metabolism (CCM) pathway modification, key enzyme gene modification, blocking the downstream pathway on the shikimate pathway, as well as several expansion pathways and metabolic engineering strategies of the shikimate pathway, and expounds the synthetic biology in recent years in the application of the shikimate pathway and the future development direction.

MUC16 promotes EOC proliferation by regulating GLUT1 expression.

As a common malignancy in females with a higher incidence rate, epithelial ovarian cancer (EOC) is a heterogeneous disease with complexity and diversity in histology and therapeutic response. Although great progress has been made in diagnosis and therapeutic strategies, novel therapeutic strategies are required to improve survival. Although the promoting effect of mucin 16 (MUC16) on tumour progression has been reported, the potential mechanisms remain unclear. In our study, we reported that overexpression of MUC16 was significantly related to cell proliferation and disease progression in EOC. Results from clinical specimen analysis and cell experiment support this conclusion. Patients with a high MUC16 expression usually had a worse prognosis that those with a low expression. Cell proliferation ability was significantly decreased in EOC cell lines when the knockdown of MUC16. Further study shows that the function of MUC16 in cell proliferation is based on the regulation of glucose transporter 1 (GLUT1) expression. MUC16 can control glucose uptake by regulating GLUT1 in EOC cells, thereby promoting glycogen synthesis, so that tumour cells produce more energy for proliferation. This conclusion is based on two findings. First, the significant correlation between MUC16 and GLUT1 was verified by clinical specimen and TCGA data analysis. Then, alteration of MUC16 expression levels can affect the expression of GLUT1 and glucose uptake was also verified. Finally, this conclusion is further verified in vivo by tumour-bearing mice model. To summarize, our results suggest that MUC16 promotes EOC proliferation and disease progression by regulating GLUT1 expression.