Itaconate in host inflammation and defense.

Immune cells undergo rapid and extensive metabolic changes during inflammation. In addition to contributing to energetic and biosynthetic demands, metabolites can also function as signaling molecules. Itaconate (ITA) rapidly accumulates to high levels in myeloid cells under infectious and sterile inflammatory conditions. This metabolite binds to and regulates the function of diverse proteins intracellularly to influence metabolism, oxidative response, epigenetic modification, and gene expression and to signal extracellularly through binding the G protein-coupled receptor (GPCR). Administration of ITA protects against inflammatory diseases and blockade of ITA production enhances antitumor immunity in preclinical models. In this article, we review ITA metabolism and its regulation, discuss its target proteins and mechanisms, and conjecture a rationale for developing ITA-based therapeutics to treat inflammatory diseases and cancer.

Dynamics of Nanocomposite Hydrogel Alignment during 3D Printing to Develop Tissue Engineering Technology.

Taking inspiration from spider silk protein spinning, we developed a method to produce tough filaments using extrusion-based 3D bioprinting and salting-out of the protein. To enhance both stiffness and ductility, we have designed a blend of partially crystalline, thermally sensitive natural polymer gelatin and viscoelastic G-polymer networks, mimicking the components of spider silk. Additionally, we have incorporated inorganic nanoparticles as a rheological modifier to fine-tune the 3D printing properties. This self-healing nanocomposite hydrogel exhibits exceptional mechanical properties, biocompatibility, shear thinning behavior, and a well-controlled gelation mechanism for 3D printing.

Mechanism of HMGB1 in scarring after glaucoma drainage valve implantation / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To explore the dynamic expression of high mobility group box 1(HMGB1)in scar tissues after glaucoma drainage valve implantation, and to further reveal the role and possible mechanism of HMGB1 in scarring after glaucoma surgery.METHODS: A total of 60 New Zealand white rabbits were randomly divided into control group(n=20), model group(n=20, silicone implantation under conjunctival sac)and model with drug administration group(n=20, silicone implantation under conjunctival sac combined with 5-fluorouracil injection). The conjunctival tissues were collected at 4 and 8 wk after surgery. HE staining and Masson staining were used to detect the proliferation and distribution of fibroblasts and collagen fibers in conjunctival tissues. Immunohistochemistry was utilized to detect the distribution and changes of HMGB1, transforming growth factor(TGF)-β1, Smad3 and α-smooth muscle actin(SMA)in conjunctival tissues. RT-PCR and Western blot were adopted to detect the mRNA and protein expression of HMGB1, TGF-β1, Smad3 and α-SMA in conjunctival tissues.RESULTS: HE staining and Masson staining showed that the proliferation of inflammatory cells, fibroblasts and collagen fibers in the model group was significantly higher than that in the control group at both 4 and 8 wk. Meanwhile, the proliferation of fibroblasts and collagen fibers in the model with drug administration group was significantly lower than that in the model group. Immunohistochemical staining showed that the expression of HMGB1, TGF-β1, Smad3 and α-SMA protein was observed in the conjunctival tissues of the model group both 4 and 8 wk, with brown and significantly deeper staining of the model group at 8 wk. Meanwhile, the positive staining in the model with drug administration group at both 4 and 8 wk was significantly lower than that in the model group. There was positive correlations between the number of fibroblasts stained with HE and the expression of HMGB1 in the conjunctival tissue of the model group at both 4 and 8 wk(r=0.602, 0.703, all P<0.05). RT-PCR and Western blot revealed that the mRNA and protein expression levels of HMGB1, TGF-β1, Smad3 and α-SMA in the model group were significantly higher than those in the control group at both 4 and 8 wk(all P<0.05). Meanwhile, the mRNA and protein expression levels of HMGB1, TGF-β1, Smad3 and α-SMA in the model with drug administration group were significantly lower than those in the model group(all P<0.05). There was positive correlations between mRNA expressions of HMGB1 and TGF-β1, Smad3 in the model group and the model with drug administration group(all P<0.05).CONCLUSION: The expression of HMGB1 increased at a time-dependent manner after glaucoma valve implantation. HMGB1 acts an indispensable role in the initiation and progression of scar formation after glaucoma surgery, which may be involved in the regulation of TGF-β/Smad signaling pathway.

Targeting FLT3-TAZ signaling to suppress drug resistance in blast phase chronic myeloid leukemia.

BACKGROUND: Although the development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast phase (BP) progression remains a critical challenge. Here, we reposition FLT3, one of the most frequently mutated drivers of acute myeloid leukemia (AML), as a prognostic marker and therapeutic target of BP-CML. METHODS: We generated FLT3 expressing BCR::ABL1 TKI-resistant CML cells and enrolled phase-specific CML patient cohort to obtain unpaired and paired serial specimens and verify the role of FLT3 signaling in BP-CML patients. We performed multi-omics approaches in animal and patient studies to demonstrate the clinical feasibility of FLT3 as a viable target of BP-CML by establishing the (1) molecular mechanisms of FLT3-driven drug resistance, (2) diagnostic methods of FLT3 protein expression and localization, (3) association between FLT3 signaling and CML prognosis, and (4) therapeutic strategies to tackle FLT3+ CML patients. RESULTS: We reposition the significance of FLT3 in the acquisition of drug resistance in BP-CML, thereby, newly classify a FLT3+ BP-CML subgroup. Mechanistically, FLT3 expression in CML cells activated the FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway, which conferred resistance to a wide range of BCR::ABL1 TKIs that was independent of recurrent BCR::ABL1 mutations. Notably, FLT3+ BP-CML patients had significantly less favorable prognosis than FLT3- patients. Remarkably, we demonstrate that repurposing FLT3 inhibitors combined with BCR::ABL1 targeted therapies or the single treatment with ponatinib alone can overcome drug resistance and promote BP-CML cell death in patient-derived FLT3+ BCR::ABL1 cells and mouse xenograft models. CONCLUSION: Here, we reposition FLT3 as a critical determinant of CML progression via FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway that promotes TKI resistance and predicts worse prognosis in BP-CML patients. Our findings open novel therapeutic opportunities that exploit the undescribed link between distinct types of malignancies.

Drug-eluting beads versus conventional transarterial chemoembolization for the treatment of unresectable hepatocellular carcinoma: A meta-analysis.

BACKGROUND: Transarterial chemoembolization (TACE) consists of conventional TACE (cTACE) and drug-eluting beads TACE (DEB-TACE). The benefits of the 2 treatments remain controversial. We conduct this meta-analysis to assess the efficacy and safety of the 2 methods for the patients with unresectable hepatocellular carcinoma. METHODS: In order to get a sound conclusion, we did thorough search all relevant studies with clear and stringent keyword criteria on the main databases. Objective tumor response rate, overall survival (OS) rate and adverse events were calculated and analyzed by RevMan 5.3 software. The random-effects or fixed-effects model was applied to pool the estimates according to Cochran Q test and I2 statistics. RESULTS: Twenty-four studies involving 2987 patients were eligible. DEB-TACE significantly improved objective tumor response rate (OR) (risk ratio [RR] = 1.27, 95% confidence interval [CI] [1.08, 1.48]; P = .003). While as for 1-year, 2-year, 3-year, 5-year OS rates, there were no evidences to indicate that DEB-TACE was significantly better than cTACE (RR = 1.05, 95% CI [0.99, 1.11]; P = .08), (RR = 1.02, 95% CI [0.93, 1.11]; P = .68), (RR = 0.92, 95% CI [0.77, 1.10]; P = .37), (RR = 0.92, 95% CI [0.47, 1.80]; P = .81), respectively. Adverse events rate (AE) was also similar in both groups (RR = 1.11, 95% CI [0.99,1.26]; P = .08). CONCLUSION: This meta-analysis demonstrates that DEB-TACE is not superior than cTACE regarding to OS and AE. However, DEB-TACE still be considered to provide a better objective tumor response rate for patients with unresectable hepatocellular carcinoma.

YAP silencing by RB1 mutation is essential for small-cell lung cancer metastasis.

Small cell lung cancer (SCLC) is highly lethal due to its prevalent metastasis. Most SCLCs have inactivating mutations in TP53 and RB1. We find that loss of YAP expression is key for SCLC cells to acquire rapid ameboid migration and high metastatic potential. YAP functions through its target genes CCN1/CCN2 to inhibit SCLC ameboid migration. RB1 mutation contributes to YAP transcriptional silencing via E2F7, which recruits the RCOR co-repressor complex to YAP promoter. We discover that benzamide family HDAC inhibitors stimulate YAP expression by inhibiting the RCOR-HDAC complex, thereby suppressing SCLC metastasis and improving survival in a mouse model. Our study unveils the molecular and cellular basis underlying SCLC's high metastatic potential, the previously unrecognized role of YAP in suppressing ameboid migration and tumor metastasis, and the mechanism of YAP transcription regulation involving E2F7, RCOR, and Sin3 HDAC. This study reveals a therapeutic potential of benzamides for SCLC treatment.

Application of novel nanobubble-contained electrolyzed catalytic water to cleanup petroleum-hydrocarbon contaminated soils and groundwater: A pilot-scale and performance evaluation study.

Soil and groundwater contamination caused by petroleum hydrocarbons is a severe environmental problem. In this study, a novel electrolyzed catalytic system (ECS) was developed to produce nanobubble-contained electrolyzed catalytic (NEC) water for the remediation of petroleum-hydrocarbon-contaminated soils and groundwater. The developed ECS applied high voltage (220 V) with direct current, and titanium electrodes coated with iridium dioxide were used in the system. The developed ECS prototype contained 21 electrode pairs (with a current density of 20 mA/cm2), which were connected in series to significantly enhance the hydroxyl radical production rate. Iron-copper hybrid oxide catalysts were laid between each electrode pair to improve the radical generation efficiency. The electron paramagnetic resonance (EPR) and Rhodamine B (RhB) methods were applied for the generated radical species and concentration determination. During the operation of the ECS, high concentrations of nanobubbles (nanobubble density = 3.7 × 109 particles/mL) were produced due to the occurrence of the cavitation mechanism. Because of the negative zeta potential and nano-scale characteristics of nanobubbles (mean diameter = 28 nm), the repelling force would prevent the occurrence of bubble aggregations and extend their lifetime in NEC water. The radicals produced after the bursting of the nanobubbles would be beneficial for the increase of the radical concentration and subsequent petroleum hydrocarbon oxidation. The highly oxidized NEC water (oxidation-reduction potential = 887 mV) could be produced with a radical concentration of 9.5 × 10-9 M. In the pilot-scale study, the prototype system was applied to clean up petroleum-hydrocarbon polluted soils at a diesel-oil spill site via an on-site slurry-phase soil washing process. The total petroleum hydrocarbon (TPH)-contaminated soils were excavated and treated with the NEC water in a slurry-phase reactor. Results show that up to 74.4% of TPH (initial concentration = 2846 mg/kg) could be removed from soils after four rounds of NEC water treatment (soil and NEC water ratio for each batch = 10 kg: 40 L and reaction time = 10 min). Within the petroleum-hydrocarbon plume, one remediation well (RW) and two monitor wells (located 1 m and 3 m downgradient of the RW) were installed along the groundwater flow direction. The produced NEC water was injected into the RW and the TPH concentrations in groundwater (initial concentrations = 12.3-15.2 mg/L) were assessed in these three wells. Compared to the control well, TPH concentrations in RW and MW1 dropped to below 0.4 and 2.1 mg/L after 6 m3 of NEC water injection in RW, respectively. Results from the pilot-scale study indicate that the NEC water could effectively remediate TPH-contaminated soils and groundwater without secondary pollution production. The main treatment mechanisms included (1) in situ chemical oxidation via produced radicals, (2) desorption of petroleum hydrocarbons from soil particles due to the dispersion of nanobubbles into soil pores, and (3) enhanced TPH oxidation due to produced radicals and energy after nanobubble bursting.

Insights into recent findings and clinical application of YAP and TAZ in cancer.

Decades of research have mapped out the basic mechanics of the Hippo pathway. The paralogues Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), as the central transcription control module of the Hippo pathway, have long been implicated in the progression of various human cancers. The current literature regarding oncogenic YAP and TAZ activities consists mostly of context-specific mechanisms and treatments of human cancers. Furthermore, a growing number of studies demonstrate tumour-suppressor functions of YAP and TAZ. In this Review we aim to synthesize an integrated perspective of the many disparate findings regarding YAP and TAZ in cancer. We then conclude with the various strategies for targeting and treating YAP- and TAZ-dependent cancers.

Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy.

Immune-responsive gene 1 (IRG1) encodes aconitate decarboxylase (ACOD1) that catalyzes the production of itaconic acids (ITAs). The anti-inflammatory function of IRG1/ITA has been established in multiple pathogen models, but very little is known in cancer. Here, we show that IRG1 is expressed in tumor-associated macrophages (TAMs) in both human and mouse tumors. Mechanistically, tumor cells induce Irg1 expression in macrophages by activating NF-κB pathway, and ITA produced by ACOD1 inhibits TET DNA dioxygenases to dampen the expression of inflammatory genes and the infiltration of CD8+ T cells into tumor sites. Deletion of Irg1 in mice suppresses the growth of multiple tumor types and enhances the efficacy of anti-PD-(L)1 immunotherapy. Our study provides a proof of concept that ACOD1 is a potential target for immune-oncology drugs and IRG1-deficient macrophages represent a potent cell therapy strategy for cancer treatment even in pancreatic tumors that are resistant to T cell-based immunotherapy.

Reprogramming anchorage dependency by adherent-to-suspension transition promotes metastatic dissemination.

BACKGROUND: Although metastasis is the foremost cause of cancer-related death, a specialized mechanism that reprograms anchorage dependency of solid tumor cells into circulating tumor cells (CTCs) during metastatic dissemination remains a critical area of challenge. METHODS: We analyzed blood cell-specific transcripts and selected key Adherent-to-Suspension Transition (AST) factors that are competent to reprogram anchorage dependency of adherent cells into suspension cells in an inducible and reversible manner. The mechanisms of AST were evaluated by a series of in vitro and in vivo assays. Paired samples of primary tumors, CTCs, and metastatic tumors were collected from breast cancer and melanoma mouse xenograft models and patients with de novo metastasis. Analyses of single-cell RNA sequencing (scRNA-seq) and tissue staining were performed to validate the role of AST factors in CTCs. Loss-of-function experiments were performed by shRNA knockdown, gene editing, and pharmacological inhibition to block metastasis and prolong survival. RESULTS: We discovered a biological phenomenon referred to as AST that reprograms adherent cells into suspension cells via defined hematopoietic transcriptional regulators, which are hijacked by solid tumor cells to disseminate into CTCs. Induction of AST in adherent cells 1) suppress global integrin/ECM gene expression via Hippo-YAP/TEAD inhibition to evoke spontaneous cell-matrix dissociation and 2) upregulate globin genes that prevent oxidative stress to acquire anoikis resistance, in the absence of lineage differentiation. During dissemination, we uncover the critical roles of AST factors in CTCs derived from patients with de novo metastasis and mouse models. Pharmacological blockade of AST factors via thalidomide derivatives in breast cancer and melanoma cells abrogated CTC formation and suppressed lung metastases without affecting the primary tumor growth. CONCLUSION: We demonstrate that suspension cells can directly arise from adherent cells by the addition of defined hematopoietic factors that confer metastatic traits. Furthermore, our findings expand the prevailing cancer treatment paradigm toward direct intervention within the metastatic spread of cancer.

The Arf family GTPases: Regulation of vesicle biogenesis and beyond.

The Arf family proteins are best known for their roles in the vesicle biogenesis. However, they also play fundamental roles in a wide range of cellular regulation besides vesicular trafficking, such as modulation of lipid metabolic enzymes, cytoskeleton remodeling, ciliogenesis, lysosomal, and mitochondrial morphology and functions. Growing studies continue to expand the downstream effector landscape of Arf proteins, especially for the less-studied members, revealing new biological functions, such as amino acid sensing. Experiments with cutting-edge technologies and in vivo functional studies in the last decade help to provide a more comprehensive view of Arf family functions. In this review, we summarize the cellular functions that are regulated by at least two different Arf members with an emphasis on those beyond vesicle biogenesis.

The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response.

Pathogens and inflammatory conditions rapidly induce the expression of immune-responsive gene 1 (IRG1) in cells of myeloid lineage. IRG1 encodes an aconitate decarboxylase (ACOD1) that produces the immunomodulatory metabolite itaconate (ITA). In addition to rapid intracellular accumulation, ITA is also secreted from the cell, but whether secreted ITA functions as a signaling molecule is unclear. Here, we identified ITA as an orthosteric agonist of the GPCR OXGR1, with an EC50 of approximately 0.3 mM, which was in the same range as the physiological concentration of extracellular ITA upon macrophage activation. ITA activated OXGR1 to induce Ca2+ mobilization, ERK phosphorylation, and endocytosis of the receptor. In a mouse model of pulmonary infection with bacterial Pseudomonas aeruginosa, ITA stimulated Oxgr1-dependent mucus secretion and transport in respiratory epithelium, the primary innate defense mechanism of the airway. Our study thus identifies ITA as a bona fide ligand for OXGR1 and the ITA/OXGR1 paracrine signaling pathway during the pulmonary innate immune response.

Tanshinone functions as a coenzyme that confers gain of function of NQO1 to suppress ferroptosis.

Ferroptosis is triggered by the breakdown of cellular iron-dependent redox homeostasis and the abnormal accumulation of lipid ROS. Cells have evolved defense mechanisms to prevent lipid ROS accumulation and ferroptosis. Using a library of more than 4,000 bioactive compounds, we show that tanshinone from Salvia miltiorrhiza (Danshen) has very potent inhibitory activity against ferroptosis. Mechanistically, we found that tanshinone functions as a coenzyme for NAD(P)H:quinone oxidoreductase 1 (NQO1), which detoxifies lipid peroxyl radicals and inhibits ferroptosis both in vitro and in vivo. Although NQO1 is recognized as an oxidative stress response gene, it does not appear to have a direct role in ferroptosis inhibition in the absence of tanshinone. Here, we demonstrate a gain of function of NQO1 induced by tanshinone, which is a novel mechanism for ferroptosis inhibition. Using mouse models of acute liver injury and ischemia/reperfusion heart injury, we observed that tanshinone displays protective effects in both the liver and the heart in a manner dependent on NQO1. Our results link the clinical use of tanshinone to its activity in ferroptosis inhibition.

Short-term clinical outcomes of different courses of antenatal corticosteroids for preterm twins / 中国新生儿科杂志

Objective:To study the short-term clinical outcomes of different courses of antenatal corticosteroids (ACS) for preterm twins.Methods:From January 2017 to December 2021, preterm twins with gestational age (GA) 24-34 weeks admitted to the neonatal ward of our hospital and received ACS were retrospectively studied. The infants were assigned into single-course group, partial-course group and multiple-course group according to ACS courses. The short-term clinical outcomes were compared among the groups. SPSS software version 25.0 was used for statistical analysis.Results:A total of 286 infants were enrolled in this study, including 128 in single-course group, 89 in partial-course group and 69 in multiple-course group. Compared with single-course group, the risks of neonatal respiratory distress syndrome (RDS) in both partial-course group ( OR=2.332, 95% CI 1.028-5.293, P=0.043) and multiple-course group ( OR=3.872, 95% CI 1.104-13.584, P=0.034) were higher. The birth length in multiple-course group ( β=-0.016, 95% CI -0.029 - -0.002, P=0.024) was lower than single-course group. Conclusions:The risks of neonatal RDS in preterm twins are higher in partial-course and multiple-course of ACS. A full course of ACS should be used to prevent neonatal RDS until further evidence of effectiveness is available.

Results analysis of mNGS applied to infectious diseases / 中华预防医学杂志

The application of metagenomic second-generation sequencing (mNGS) is shifting from research to clinical laboratories due to rapid technological advances and significant cost reductions. Although many studies and case reports have confirmed that the success of mNGS in improving the prevention, diagnosis, treatment and tracking of infectious diseases, there are still some obstacles that must be overcome. The results of mNGS show all the possible pathogens in the sample, however, in the face of thousands of microbes that can infect humans, it remains challenging to accurately identify the key pathogens. So far, there is no unified interpretation standard for mNGS in clinical practice. This article reviews the interpretation of mNGS results for pathogen infection in different systems, the clinical interpretation and application regulations of mNGS results, and the challenges of mNGS interpretation in pathogen diagnosis.

Lipid-lowering effect of drug pair Scutellariae Radix-Coptidis Rhizoma based on lipomics / 中国中药杂志

This study investigated the mechanism of action of Scutellariae Radix-Coptidis Rhizoma(SR-CR) in intervening in non-alcoholic fatty liver disease(NAFLD) in rats based on lipidomics. Thirty-six SD rats were divided into a control group, a model group, SR-CR groups of different doses, and a simvastatin group, with six rats in each group. Rats in the control group were fed on a normal diet, while those in the remaining groups were fed on a high-lipid diet. After four weeks of feeding, drug treatment was carried out and rats were sacrificed after 12 weeks. Serum liver function and lipid indexes were detected using kits, and the pathomorphology of liver tissues was evaluated by hematoxylin-eosin(HE) staining and oil red O staining. Changes in lipid levels in rats were detected using the LC-MS technique. Differential lipid metabolites were screened by multivariate statistical analysis, and lipid metabolic pathways were plotted. The changes in lipid-related protein levels were further verified by Western blot. The results showed that compared with the control group, the model group showed increased levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), total cholesterol(TC), triglyceride(TG), and low-density lipoprotein cholesterol(LDL-c)(P<0.01), and decreased levels of γ-glutamyl transferase(γ-GT) and high-density lipoprotein cholesterol(HDL-c)(P<0.01), which were significantly recovered by the intervention of SR-CR. HE staining and oil red O staining showed that different doses of SR-CR could reverse the steatosis in the rat liver in a dose-dependent manner. After lipidomics analysis, there were significant differences in lipid metabolism between the model group and the control group, with 54 lipids significantly altered, mainly including glycerolipids, phosphatidylcholine, and sphingolipids. After administration, 44 differential lipids tended to normal levels, which indicated that SR-CR groups of different doses significantly improved the lipid metabolism level in NAFLD rats. Western blot showed that SR-CR significantly decreased TG-synthesis enzyme 1(DGAT1), recombinant lipin 1(LPIN1), fatty acid synthase(FASN), acetyl-CoA carboxylase 1(ACC1), and increased the phosphorylation level of ACC1. These changes significantly decreased the synthesis of TG and increased the rate of its decomposition, which enhanced the level of lipid metabolism in the body and finally achieved the lipid-lowering effect. SR-CR can improve NAFLD by inhibiting the synthesis of fatty acids and TG.

The Hippo signalling pathway and its implications in human health and diseases.

As an evolutionarily conserved signalling network, the Hippo pathway plays a crucial role in the regulation of numerous biological processes. Thus, substantial efforts have been made to understand the upstream signals that influence the activity of the Hippo pathway, as well as its physiological functions, such as cell proliferation and differentiation, organ growth, embryogenesis, and tissue regeneration/wound healing. However, dysregulation of the Hippo pathway can cause a variety of diseases, including cancer, eye diseases, cardiac diseases, pulmonary diseases, renal diseases, hepatic diseases, and immune dysfunction. Therefore, therapeutic strategies that target dysregulated Hippo components might be promising approaches for the treatment of a wide spectrum of diseases. Here, we review the key components and upstream signals of the Hippo pathway, as well as the critical physiological functions controlled by the Hippo pathway. Additionally, diseases associated with alterations in the Hippo pathway and potential therapies targeting Hippo components will be discussed.