Orphan Nuclear Receptor NR4A3 Promotes Vascular Calcification via Histone Lactylation.

BACKGROUND: Medial arterial calcification is a chronic systemic vascular disorder distinct from atherosclerosis and is commonly observed in patients with chronic kidney disease, diabetes, and aging individuals. We previously showed that NR4A3 (nuclear receptor subfamily 4 group A member 3), an orphan nuclear receptor, is a key regulator in apo (apolipoprotein) A-IV-induced atherosclerosis progression; however, its role in vascular calcification is poorly understood. METHODS: We generated NR4A3-/- mice and 2 different types of medial arterial calcification models to investigate the biological roles of NR4A3 in vascular calcification. RNA-seq was performed to determine the transcriptional profile of NR4A3-/- vascular smooth muscle cells under ß-glycerophosphate treatment. We integrated Cleavage Under Targets and Tagmentation analysis and RNA-seq data to further investigate the gene regulatory mechanisms of NR4A3 in arterial calcification and target genes regulated by histone lactylation. RESULTS: NR4A3 expression was upregulated in calcified aortic tissues from chronic kidney disease mice, 1,25(OH)2VitD3 overload-induced mice, and human calcified aorta. NR4A3 deficiency preserved the vascular smooth muscle cell contractile phenotype, inhibited osteoblast differentiation-related gene expression, and reduced calcium deposition in the vasculature. Further, NR4A3 deficiency lowered the glycolytic rate and lactate production during the calcification process and decreased histone lactylation. Mechanistic studies further showed that NR4A3 enhanced glycolysis activity by directly binding to the promoter regions of the 2 glycolysis genes ALDOA and PFKL and driving their transcriptional initiation. Furthermore, histone lactylation promoted medial calcification both in vivo and in vitro. NR4A3 deficiency inhibited the transcription activation and expression of Phospho1 (phosphatase orphan 1). Consistently, pharmacological inhibition of Phospho1 attenuated calcium deposition in NR4A3-overexpressed vascular smooth muscle cells, whereas overexpression of Phospho1 reversed the anticalcific effect of NR4A3 deficiency in vascular smooth muscle cells. CONCLUSIONS: Taken together, our findings reveal that NR4A3-mediated histone lactylation is a novel metabolome-epigenome signaling cascade mechanism that participates in the pathogenesis of medial arterial calcification.

HIF-1 Transcriptionally Regulates Basal Expression of STING to Maintain Cellular Innate Immunity.

Stimulator of IFN genes (STING) is a critical component of the innate immune system, playing an essential role in defending against DNA virus infections. However, the mechanisms governing basal STING regulation remain poorly understood. In this study, we demonstrate that the basal level of STING is critically maintained by hypoxia-inducible factor 1 (HIF-1)α through transcription. Under normal conditions, HIF-1α binds constitutively to the promoter region of STING, actively promoting its transcription. Knocking down HIF-1α results in a decrease in STING expression in multiple cell lines and zebrafish, which in turn reduces cellular responses to synthetic dsDNAs, including cell signaling and IFN production. Moreover, this decrease in STING levels leads to an increase in cellular susceptibility to DNA viruses HSV-1 and pseudorabies virus. These findings unveil a (to our knowledge) novel role of HIF-1α in maintaining basal STING levels and provide valuable insights into STING-mediated antiviral activities and associated diseases.

eRNAbase: a comprehensive database for decoding the regulatory eRNAs in human and mouse.

Enhancer RNAs (eRNAs) transcribed from distal active enhancers serve as key regulators in gene transcriptional regulation. The accumulation of eRNAs from multiple sequencing assays has led to an urgent need to comprehensively collect and process these data to illustrate the regulatory landscape of eRNAs. To address this need, we developed the eRNAbase (http://bio.liclab.net/eRNAbase/index.php) to store the massive available resources of human and mouse eRNAs and provide comprehensive annotation and analyses for eRNAs. The current version of eRNAbase cataloged 10 399 928 eRNAs from 1012 samples, including 858 human samples and 154 mouse samples. These eRNAs were first identified and uniformly processed from 14 eRNA-related experiment types manually collected from GEO/SRA and ENCODE. Importantly, the eRNAbase provides detailed and abundant (epi)genetic annotations in eRNA regions, such as super enhancers, enhancers, common single nucleotide polymorphisms, expression quantitative trait loci, transcription factor binding sites, CRISPR/Cas9 target sites, DNase I hypersensitivity sites, chromatin accessibility regions, methylation sites, chromatin interactions regions, topologically associating domains and RNA spatial interactions. Furthermore, the eRNAbase provides users with three novel analyses including eRNA-mediated pathway regulatory analysis, eRNA-based variation interpretation analysis and eRNA-mediated TF-target gene analysis. Hence, eRNAbase is a powerful platform to query, browse and visualize regulatory cues associated with eRNAs.

Efficient catalysts of surface hydrophobic Cu-BTC with coordinatively unsaturated Cu(I) sites for the direct oxidation of methane.

Selective oxidation of methane to organic oxygenates over metal-organic frameworks (MOFs) catalysts at low temperature is a challenging topic in the field of C1 chemistry because of the inferior stability of MOFs. Modifying the surface of Cu-BTC via hydrophobic polydimethylsiloxane (PDMS) at 235 °C under vacuum not only can dramatically improve its catalytic cycle stability in a liquid phase but also generate coordinatively unsaturated Cu(I) sites, which significantly enhances the catalytic activity of Cu-BTC catalyst. The results of spectroscopy characterizations and theoretical calculation proved that the coordinatively unsaturated Cu(I) sites made H2O2 dissociative into •OH, which formed Cu(II)-O active species by combining with coordinatively unsaturated Cu(I) sites for activating the C-H bond of methane. The high productivity of C1 oxygenates (CH3OH and CH3OOH) of 10.67 mmol gcat.-1h-1 with super high selectivity of 99.6% to C1 oxygenates was achieved over Cu-BTC-P-235 catalyst, and the catalyst possessed excellent reusability.

Promoting C-F bond activation via proton donor for CF4 decomposition.

Tetrafluoromethane (CF4), the simplest perfluorocarbons, is a permanently potent greenhouse gas due to its powerful infrared radiation adsorption capacity. The highly symmetric and robust C-F bond structure makes its activation a great challenge. Herein, we presented an innovated approach that efficiently activates C-F bond utilizing protonated sulfate (-HSO4) modified Al2O3@ZrO2 (S-Al2O3@ZrO2) catalyst, resulting in highly efficient CF4 decomposition. By combining in situ infrared spectroscopy tests and density function theory simulations, we demonstrate that the introduced -HSO4 proton donor has a stronger interaction on the C-F bond than the hydroxyl (-OH) proton donor, which can effectively stretch the C-F bond for its activation. Consequently, the obtained S-Al2O3@ZrO2 catalyst achieved a stable 100% CF4 decomposition at a record low temperature of 580 °C with a turnover frequency value of ~8.3 times higher than the Al2O3@ZrO2 catalyst without -HSO4 modification, outperforming the previously reported results. This work paves a new way for achieving efficient C-F bond activation to decompose CF4 at a low temperature.

Urea transporter UT-A1 as a novel drug target for hyponatremia.

Hyponatremia is the most common disorder of electrolyte imbalances. It is necessary to develop new type of diuretics to treat hyponatremia without losing electrolytes. Urea transporters (UT) play an important role in the urine concentrating process and have been proved as a novel diuretic target. In this study, rat and mouse syndromes of inappropriate antidiuretic hormone secretion (SIADH) models were constructed and analyzed to determine if UTs are a promising drug target for treating hyponatremia. Experimental results showed that 100 mg/kg UT inhibitor 25a significantly increased serum osmolality (from 249.83 ± 5.95 to 294.33 ± 3.90 mOsm/kg) and serum sodium (from 114 ± 2.07 to 136.67 ± 3.82 mmol/L) respectively in hyponatremia rats by diuresis. Serum chemical examination showed that 25a neither caused another electrolyte imbalance nor influenced the lipid metabolism. Using UT-A1 and UT-B knockout mouse SIADH model, it was found that serum osmolality and serum sodium were lowered much less in UT-A1 knockout mice than in UT-B knockout mice, which suggest UT-A1 is a better therapeutic target than UT-B to treat hyponatremia. This study provides a proof of concept that UT-A1 is a diuretic target for SIADH-induced hyponatremia and UT-A1 inhibitors might be developed into new diuretics to treat hyponatremia.

Soluble TREM2 triggers microglial dysfunction in neuromyelitis optica spectrum disorders.

Microglia-mediated neuroinflammation contributes to acute demyelination in neuromyelitis optica spectrum disorders (NMOSD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the CSF has been associated with microglial activation in several neurodegenerative diseases. However, the basis for this immune-mediated attack and the pathophysiological role of sTREM2 in NMOSD remain to be elucidated. Here, we performed Mendelian randomization analysis and identified a genetic association between increased CSF sTREM2 and NMOSD risk. CSF sTREM2 was elevated in patients with NMOSD and was positively correlated with neural injury and other neuroinflammation markers. Single-cell RNA sequencing of human macrophage/microglia-like cells in CSF, a proxy for microglia, showed that increased CSF sTREM2 was positively associated with microglial dysfunction in patients with NMOSD. Furthermore, we demonstrated that sTREM2 is a reliable biomarker of microglial activation in a mouse model of NMOSD. Using unbiased transcriptomic and lipidomic screens, we identified that excessive activation, overwhelmed phagocytosis of myelin debris, suppressed lipid metabolism and enhanced glycolysis underlie sTREM2-mediated microglial dysfunction, possibly through the nuclear factor kappa B (NF-κB) signalling pathway. These molecular and cellular findings provide a mechanistic explanation for the genetic association between CSF sTREM2 and NMOSD risk and indicate that sTREM2 could be a potential biomarker of NMOSD progression and a therapeutic target for microglia-mediated neuroinflammation.

Utilizing non-coding RNA-mediated regulation of ATP binding cassette (ABC) transporters to overcome multidrug resistance to cancer chemotherapy.

Multidrug resistance (MDR) is one of the primary factors that produces treatment failure in patients receiving cancer chemotherapy. MDR is a complex multifactorial phenomenon, characterized by a decrease or abrogation of the efficacy of a wide spectrum of anticancer drugs that are structurally and mechanistically distinct. The overexpression of the ATP-binding cassette (ABC) transporters, notably ABCG2 and ABCB1, are one of the primary mediators of MDR in cancer cells, which promotes the efflux of certain chemotherapeutic drugs from cancer cells, thereby decreasing or abolishing their therapeutic efficacy. A number of studies have suggested that non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), play a pivotal role in mediating the upregulation of ABC transporters in certain MDR cancer cells. This review will provide updated information about the induction of ABC transporters due to the aberrant regulation of ncRNAs in cancer cells. We will also discuss the measurement and biological profile of circulating ncRNAs in various body fluids as potential biomarkers for predicting the response of cancer patients to chemotherapy. Sequence variations, such as alternative polyadenylation of mRNA and single nucleotide polymorphism (SNPs) at miRNA target sites, which may indicate the interaction of miRNA-mediated gene regulation with genetic variations to modulate the MDR phenotype, will be reviewed. Finally, we will highlight novel strategies that could be used to modulate ncRNAs and circumvent ABC transporter-mediated MDR.

Resistance to gemcitabine is mediated by the circ_0036627/miR-145/S100A16 axis in pancreatic cancer.

The development of gemcitabine (GEM) resistance severely limits the treatment efficacy in pancreatic cancer (PC) and increasing evidence highlights the vital roles of circular RNAs (circRNAs) in the tumorigenesis, progression and drug resistance of PC. However, the circRNAs underlying GEM resistance development of PC remains to be clarified. The current research aims to unveil the roles of circ_0036627 in dictating the aggressiveness and GEM sensitivity in PC. We reported the increased expression of circ_0036627 in PC tissues and PC cell lines. Elevated circ_0036627 expression level was correlated with advanced tumour grade and poor overall survival in PC patients. Functional assays and in vivo experiments demonstrated that circ_0036627 overexpression was required for the proliferation, migration invasion and GEM resistance in PC cells. circ_0036627 knockdown suppressed tumour development in vivo. The molecular analysis further showed that circ_0036627 increased S100A16 expression by sponging microRNA-145 (miR-145), a tumour-suppressive miRNA that could significantly attenuate PC cell proliferation, migration, invasion and GEM resistance. Furthermore, our findings suggested that S100A16 acted as an oncogenic factor to promote aggressiveness and GEM resistance in PC cells. In conclusion, the current findings provide new mechanistic insights into PC aggressiveness and GEM resistance, suggesting the critical role of circ_0036627/miR-145/S100A16 axis in PC progression and drug resistance development and offering novel therapeutic targets for PC therapy.

A LcDOF5.6-LcRbohD regulatory module controls the reactive oxygen species-mediated fruitlet abscission in litchi.

Reactive oxygen species (ROS) have been emerging as a key regulator in plant organ abscission. However, the mechanism underlying the regulation of ROS homeostasis in the abscission zone (AZ) is not completely established. Here, we report that a DOF (DNA binding with one finger) transcription factor LcDOF5.6 can suppress the litchi fruitlet abscission through repressing the ROS accumulation in fruitlet AZ (FAZ). The expression of LcRbohD, a homolog of the Arabidopsis RBOHs that are critical for ROS production, was significantly increased during the litchi fruitlet abscission, in parallel with an increased accumulation of ROS in FAZ. In contrast, silencing of LcRbohD reduced the ROS accumulation in FAZ and decreased the fruitlet abscission in litchi. Using in vitro and in vivo assays, we revealed that LcDOF5.6 was shown to inhibit the expression of LcRbohD via direct binding to its promoter. Consistently, silencing of LcDOF5.6 increased the expression of LcRbohD, concurrently with higher ROS accumulation in FAZ and increased fruitlet abscission. Furthermore, the expression of key genes (LcIDL1, LcHSL2, LcACO2, LcACS1, and LcEIL3) in INFLORESCENCE DEFICIENT IN ABSCISSION signaling and ethylene pathways were altered in LcRbohD-silenced and LcDOF5.6-silenced FAZ cells. Taken together, our results demonstrate an important role of the LcDOF5.6-LcRbohD module during litchi fruitlet abscission. Our findings provide new insights into the molecular regulatory network of organ abscission.

Facile Mechanophore Integration in Heterogeneous Biologically Derived Materials via "Dip-Conjugation".

Mechanical forces play critical roles in a wide variety of biological processes and diseases, yet measuring them directly at the molecular level remains one of the main challenges of mechanobiology. Here, we show a strategy to "Dip-conjugate" biologically derived materials at the chemical level to mechanophores, force-responsive molecular entities, using Click-chemistry. Contrary to classical prepolymerization mechanophore incorporation, this new protocol leads to detectable mechanochromic response with as low as 5% strain, finally making mechanophores relevant for many biological processes that have previously been inaccessible. Our results demonstrate the ubiquity of the technique with activation in synthetic polymers, carbohydrates, and proteins under mechanical force, with alpaca wool fibers as a key example. These results push the limits for mechanophore use in far more types of polymeric materials in applications ranging from molecular-level force damage detection to direct and quantitative 3D force measurements in mechanobiology.

Effect of Laparoscopic and Open Pancreaticoduodenectomy for Pancreatic or Periampullary Tumors: Three-year Follow-up of a Randomized Clinical Trial.

OBJECTIVE: This study aimed to estimate whether the potential short-term advantages of laparoscopic pancreaticoduodenectomy (LPD) could allow patients to recover in a more timely manner and achieve better long-term survival than with open pancreaticoduodenectomy (OPD) in patients with pancreatic or periampullary tumors. BACKGROUND: LPD has been demonstrated to be feasible and may have several potential advantages over OPD in terms of shorter hospital stay and accelerated recovery than OPD. METHODS: This noninferiority, open-label, randomized clinical trial was conducted in 14 centers in China. The initial trial included 656 eligible patients with pancreatic or periampullary tumors enrolled from May 18, 2018, to December 19, 2019. The participants were randomized preoperatively in a 1:1 ratio to undergo either LPD (n=328) or OPD (n=328). The 3-year overall survival (OS), quality of life, which was assessed using the 3-level version of the European Quality of Life-5 Dimensions, depression, and other outcomes were evaluated. RESULTS: Data from 656 patients [328 men (69.9%); mean (SD) age: 56.2 (10.7) years] who underwent pancreaticoduodenectomy were analyzed. For malignancies, the 3-year OS rates were 59.1% and 54.3% in the LPD and OPD groups, respectively ( P =0.33, hazard ratio: 1.16, 95% CI: 0.86-1.56). The 3-year OS rates for others were 81.3% and 85.6% in the LPD and OPD groups, respectively ( P =0.40, hazard ratio: 0.70, 95% CI: 0.30-1.63). No significant differences were observed in quality of life, depression and other outcomes between the 2 groups. CONCLUSION: In patients with pancreatic or periampullary tumors, LPD performed by experienced surgeons resulted in a similar 3-year OS compared with OPD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03138213.

Rapid Glutathione Analysis with SERS Microneedles for Deep Glioblastoma Tissue Differentiation.

Rapid tissue differentiation at the molecular level is a prerequisite for precise surgical resection, which is of special value for the treatment of malignant tumors, such as glioblastoma (GBM). Herein, a SERS-active microneedle is prepared by modifying glutathione (GSH)-responsive molecules, 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), on the surface of Au@Ag substrates for the distinction of different GBM tissues. Since the Raman signals on the surface of the DTNB@Au@Ag microneedle can be collected by both portable and benchtop Raman spectrometers, the distribution of GSH in different tissues at centimeter scale can be displayed through Raman spectroscopy and Raman imaging, and the entire analysis process can be accomplished within 12 min. Accordingly, in vivo brain tissues of orthotopic GBM xenograft mice and ex vivo tissues of GBM patients are accurately differentiated with the microneedle, and the results are well consistent with tissue staining and postoperative pathological reports. In addition, the outline of tumor, peritumoral, and normal tissues can be indicated by the DTNB@Au@Ag microneedle for at least 56 days. Considering that the tumor tissues are quickly discriminated at the molecular level without the restriction of depth, the DTNB@Au@Ag microneedle is promising to be a powerful intraoperative diagnostic tool for surgery navigation.

Electrophoretic Microplate Protein Identification Based on Gold Staining of Molybdenum Disulfide Hydrogels.

Numerous high-performance nanotechnologies have been developed, but their practical applications are largely restricted by the nanomaterials' low stabilities and high operation complexity in aqueous substrates. Herein, we develop a simple and high-reliability hydrogel-based nanotechnology based on the in situ formation of Au nanoparticles in molybdenum disulfide (MoS2)-doped agarose (MoS2/AG) hydrogels for electrophoresis-integrated microplate protein recognition. After the incubation of MoS2/AG hydrogels in HAuCl4 solutions, MoS2 nanosheets spontaneously reduce Au ions, and the hydrogels are remarkably stained with the color of as-synthetic plasmonic Au hybrid nanomaterials (Au staining). Proteins can precisely mediate the morphologies and optical properties of Au/MoS2 heterostructures in the hydrogels. Consequently, Au staining-based protein recognition is exhibited, and hydrogels ensure the comparable stabilities and sensitivities of protein analysis. In comparison to the fluorescence imaging and dye staining, enhanced sensitivity and recognition performances of proteins are implemented by Au staining. In Au staining, exfoliated MoS2 semiconductors directly guide the oriented growth of plasmonic Au nanostructures in the presence of formaldehyde, showing environment-friendly features. The Au-stained hydrogels merge the synthesis and recognition applications of plasmonic Au nanomaterials. Significantly, the one-step incubation of the electrophoretic hydrogels leads to high simplicity of operation, largely challenging those multiple-step Ag staining routes which were performed with high complexity and formaldehyde toxicity. Due to its toxic-free, simple, and sensitive merits, the Au staining integrated with electrophoresis-based separation and microplate-based high-throughput measurements exhibits highly promising and improved practicality of those developing nanotechnologies and largely facilitates in-depth understanding of biological information.

Single-cell RNA sequencing in donor and end-stage heart failure patients identifies NLRP3 as a therapeutic target for arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Dilation may be the first right ventricular change and accelerates the progression of threatening ventricular tachyarrhythmias and heart failure for patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), but the treatment for right ventricular dilation remains limited. METHODS: Single-cell RNA sequencing (scRNA-seq) of blood and biventricular myocardium from 8 study participants was performed, including 6 end-stage heart failure patients with ARVC and 2 normal controls. ScRNA-seq data was then deeply analyzed, including cluster annotation, cellular proportion calculation, and characterization of cellular developmental trajectories and interactions. An integrative analysis of our single-cell data and published genome-wide association study-based data provided insights into the cell-specific contributions to the cardiac arrhythmia phenotype of ARVC. Desmoglein 2 (Dsg2)mut/mut mice were used as the ARVC model to verify the therapeutic effects of pharmacological intervention on identified cellular cluster. RESULTS: Right ventricle of ARVC was enriched of CCL3+ proinflammatory macrophages and TNMD+ fibroblasts. Fibroblasts were preferentially affected in ARVC and perturbations associated with ARVC overlap with those reside in genetic variants associated with cardiac arrhythmia. Proinflammatory macrophages strongly interact with fibroblast. Pharmacological inhibition of Nod-like receptor protein 3 (NLRP3), a transcriptional factor predominantly expressed by the CCL3+ proinflammatory macrophages and several other myeloid subclusters, could significantly alleviate right ventricular dilation and dysfunction in Dsg2mut/mut mice (an ARVC mouse model). CONCLUSIONS: This study provided a comprehensive analysis of the lineage-specific changes in the blood and myocardium from ARVC patients at a single-cell resolution. Pharmacological inhibition of NLRP3 could prevent right ventricular dilation and dysfunction of mice with ARVC.

Deeply Discharged, Quiescently Stable, and Long-Life Zn Anode by Spontaneous SEI Formation.

Zn ion batteries (ZIBs) are a promising candidate in safe and low-cost large-scale energy storage applications. However, significantly deteriorated cycling stability of Zn anode in high depth of charge or after long-term quiescence impedes the practical application of ZIBs. Aiming at the above issue, a spontaneous solid electrolyte interphase (SEI) formation of Zn4(OH)6SO4·xH2O (ZHS) on Zn powder is achieved in pure ZnSO4 electrolyte by facile and rational interface design. The stable and ultrathin ZHS SEI plays a crucial part in insulating water molecules and conducting Zn2+ ions, intrinsically suppressing the severe hydrogen evolution and dendrite formation on the Zn powder anode. The ZHS-Zn anode delivers a stable cycling at a high DOD of 50% for over 500 h, as well as a lifespan of over 200 h after 40-days of resting at a DOD of 25%. Benefiting from the high utilization of Zn anode, the energy density of the Zn-MnxV2O5 full cell is up to 118 Wh Kg-1. This facile method can fabricate the ZHS-Zn anode as long as 1 m, revealing its feasibility in large-scale production and commercialization.

Fragmented QRS complex could predict all-cause mortality in patients with connective tissue disease-associated pulmonary arterial hypertension.

OBJECTIVES: To investigate the prognostic impact and pathophysiological characteristics of fragmented QRS complex (fQRS) on patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH). METHODS: This was a multicentre retrospective study recruiting 141 patients with CTD-PAH diagnosed by right heart catheterization (114 cases in the discovery cohort and 27 cases in the validation cohort). fQRS and ST-T change were detected on conventional 12-lead electrocardiogram (ECG). Patients were followed up every 3 months to update their status and the primary end point was all-cause death. Clinical information and ECG characteristics were compared between survival and death groups and Kaplan-Meier curve was used for survival analysis. RESULTS: There were significant differences in age, gender, 6-min walk distance, NT-proBNP, WHO class, presence of fQRS and presence of ST-T change in inferior leads between survival group and death group. Inferior fQRS and ST-T change were significantly associated with right ventricular (RV) dilatation and reduced RV ejection fraction (RVEF). Kaplan-Meier curve showed that all-cause mortality was higher in CTD-PAH with fQRS (p= 0.003) and inferior ST-T change (p= 0.012). Low- and intermediate-risk CTD-PAH with inferior ST-T change had higher all-cause mortality (p= 0.005). The prognostic value of fQRS and inferior ST-T change was validated in external validation cohort. CONCLUSION: The presence of inferior fQRS and ST-T change could predict poor prognosis in CTD-PAH. CLINICAL TRIAL REGISTRATION NUMBER: NCT05980728, https://clinicaltrials.gov.

Performance evaluation of rhamnolipid biosurfactant produced by Pseudomonas aeruginosa and its effect on marine oil-spill remediation.

This study aimed to reveal that the effect of biosurfactant on the dispersion and degradation of crude oil. Whole genome analysis showed that Pseudomonas aeruginosa GB-3 contained abundant genes involved in biosurfactant synthesis and metabolic processes and had the potential to degrade oil. The biosurfactant produced by strain GB-3 was screened by various methods. The results showed that the surface tension reduction activity was 28.6 mN·m-1 and emulsification stability was exhibited at different pH, salinity and temperature. The biosurfactant was identified as rhamnolipid by LC-MS and FTIR. The fermentation conditions of strain GB-3 were optimized by response surface methodology, finally the optimal system (carbon source: glucose, nitrogen source: ammonium sulfate, C/N ratio:16:1, pH: 7, temperature: 30-35 °C) was determined. Compared with the initial fermentation, the yield of biosurfactant increased by 4.4 times after optimization. In addition, rhamnolipid biosurfactant as a dispersant could make the dispersion of crude oil reach 38% within seven days, which enhanced the bioavailability of crude oil. As a biostimulant, it could also improve the activity of indigenous microorganism and increase the degradation rate of crude oil by 10-15%. This study suggested that rhamnolipid biosurfactant had application prospect in bioremediation of marine oil-spill.

CDK inhibitor Palbociclib targets STING to alleviate autoinflammation.

Aberrant activation of stimulator of interferon genes (STING) is tightly associated with multiple types of disease, including cancer, infection, and autoimmune diseases. However, the development of STING modulators for the therapy of STING-related diseases is still an unmet clinical need. We employed a high-throughput screening approach based on the interaction of small-molecule chemical compounds with recombinant STING protein to identify functional STING modulators. Intriguingly, the cyclin-dependent protein kinase (CDK) inhibitor Palbociclib was found to directly bind STING and inhibit its activation in both mouse and human cells. Mechanistically, Palbociclib targets Y167 of STING to block its dimerization, its binding with cyclic dinucleotides, and its trafficking. Importantly, Palbociclib alleviates autoimmune disease features induced by dextran sulphate sodium or genetic ablation of three prime repair exonuclease 1 (Trex1) in mice in a STING-dependent manner. Our work identifies Palbociclib as a novel pharmacological inhibitor of STING that abrogates its homodimerization and provides a basis for the fast repurposing of this Food and Drug Administration-approved drug for the therapy of autoinflammatory diseases.

AGCM-22, a novel cetuximab-based EGFR-targeting antibody-drug-conjugate with highly selective anti-glioblastoma efficacy.

The epidermal growth factor receptor (EGFR) has received significant attention as a potential target for glioblastoma (GBM) therapeutics in the past two decades. However, although cetuximab, an antibody that specifically targets EGFR, exhibits a high affinity for EGFR, it has not yet been applied in the treatment of GBM. Antibody-drug conjugates (ADCs) utilize tumor-targeting antibodies for the selective delivery of cytotoxic drugs, resulting in improved efficacy compared to conventional chemotherapy drugs. However, the effectiveness of cetuximab as a targeted antibody for ADCs in the treatment of GBM remains uncertain. In this study, we synthesized AGCM-22, an EGFR-targeted ADC derived from cetuximab, by conjugating it with the tubulin inhibitor monomethyl auristatin E (MMAE) using our Valine-Alanine Cathepsin B cleavable linker. In vitro experiments demonstrated that AGCM-22 effectively inhibited GBM cell proliferation through increased levels of apoptosis and autophagy-related cell death, whereas cetuximab alone had no anti-GBM effects. Additionally, both mouse and human orthotopic tumor models exhibited the selective tumor-targeting efficacy of AGCM-22, along with favorable metabolic properties and superior anti-GBM activity compared to temozolomide (TMZ). In summary, this study presents a novel ADC for GBM therapy that utilizes cetuximab as the tumor-targeting antibody, resulting in effective delivery of the cytotoxic drug payload.