SNX5-Rab11a protects against cardiac hypertrophy through regulating LRP6 membrane translocation.

BACKGROUNDS: Pathological cardiac hypertrophy is considered one of the independent risk factors for heart failure, with a rather complex pathogenic machinery. Sorting nexins (SNXs), denoting a diverse family of cytoplasmic- and membrane-associated phosphoinositide-binding proteins, act as a pharmacological target against specific cardiovascular diseases including heart failure. Family member SNX5 was reported to play a pivotal role in a variety of biological processes. However, contribution of SNX5 to the development of cardiac hypertrophy, remains unclear. METHODS: Mice underwent transverse aortic constriction (TAC) to induce cardiac hypertrophy and simulate pathological conditions. TAC model was validated using echocardiography and histological staining. Expression of SNX5 was assessed by western blotting. Then, SNX5 was delivered through intravenous administration of an adeno-associated virus serotype 9 carrying cTnT promoter (AAV9-cTnT-SNX5) to achieve SNX5 cardiac-specific overexpression. To assess the impact of SNX5, morphological analysis, echocardiography, histological staining, hypertrophic biomarkers, and cardiomyocyte contraction were evaluated. To unravel potential molecular events associated with SNX5, interactome analysis, fluorescence co-localization, and membrane protein profile were evaluated. RESULTS: Our results revealed significant downregulated protein level of SNX5 in TAC-induced hypertrophic hearts in mice. Interestingly, cardiac-specific overexpression of SNX5 improved cardiac function, with enhanced left ventricular ejection fraction, fraction shortening, as well as reduced cardiac fibrosis. Mechanistically, SNX5 directly bound to Rab11a, increasing membrane accumulation of Rab11a (a Rab GTPase). Afterwards, this intricate molecular interaction upregulated the membrane content of low-density lipoprotein receptor-related protein 6 (LRP6), a key regulator against cardiac hypertrophy. Our comprehensive assessment of siRab11a expression in HL-1 cells revealed its role in antagonism of LRP6 membrane accumulation under SNX5 overexpression. CONCLUSIONS: This study revealed that binding of SNX5 with LRP6 triggers their membrane translocation through Rab11a assisting, defending against cardiac remodeling and cardiac dysfunction under pressure overload. These findings provide new insights into the previously unrecognized role of SNX5 in the progression of cardiac hypertrophy.

Nano co-delivery of doxorubicin and plumbagin achieves synergistic chemotherapy of hepatocellular carcinoma.

Doxorubicin (DOX) is a chemotherapy drug used for hepatocellular carcinoma (HCC) treatment, but its effectiveness can be dramatically dampened by cancer cell chemoresistance. Signal transducer and activator of transcription 3 (STAT3) is implicated with drug resistance in a range of cancers (e.g., HCC), and the STAT3 inhibition can reverse the resistance of cancer cells to chemotherapeutic drugs. In the present study, a combination regimen to improve the efficiency of DOX was provided via the STAT3 blockade using plumbagin (PLB). A poly(lactic-co-glycolic acid) decorated by polyethylene glycol and aminoethyl anisamide was produced in the present study with the hope of generating the nanoparticles for co-delivery of DOX and PLB. The resulting co-formulation suppressed the STAT3 activity and achieved the synergistic chemotherapy, which led to tumor inhibition in the mice with subcutaneous DOX-resistant HCC, without causing any toxicity. The present study reveals the synergism of DOX and PLB, and demonstrates a promising combinatorial approach for treating HCC.

Mechanisms of conjugative transfer of antibiotic resistance genes induced by extracellular polymeric substances: Insights into molecular diversities and electron transfer properties.

Dissemination of antibiotic resistance genes (ARGs) has become a critical threat to public health. Activated sludge, rich in extracellular polymeric substances (EPS), is an important pool of ARGs. In this study, mechanisms of conjugation transfer of ARGs induced by EPS, including tightly bound EPS (TBEPS), soluble EPS (SEPS), and loosely bound EPS (LBEPS), were explored in terms of molecular diversities and electron transfer properties of EPS. Conjugation transfer frequency was increased by 9.98-folds (SEPS), 4.21-folds (LBEPS), and 15.75-folds (TBEPS) versus the control, respectively. Conjugation-related core genes involving SOS responses (9 genes), membrane permeability (18 genes), intercellular contact (17 genes), and energy metabolism pathways (13 genes) were all upregulated, especially in the presence of TBEPS. Carbohydrates and aliphatic substances in SEPS and LBEPS were contributors to ARG transfer, via influencing reactive oxygen species (ROS) formation (SEPS) and ROS and adenosine triphosphate (ATP) production (LBEPS). TBEPS had the highest redox potential and greatest lability and facilitated electron transfer and alternated respiration between cells, thus promoting ARG transfer by producing ATP. Generally, the chemical molecular characteristics and redox properties of EPS facilitated ARG transfer mainly by influencing lipid peroxidation and ATP, respectively.

Cytotoxic xanthanolide sesquiterpenes from the fruits of Xanthium italicum Moretti.

One previously undescribed xanthanolide sesquiterpene dimer pungiolide P (1), possessing an unprecedented scaffold with a 5/7/5/7/5 ring system skeleton and its intermediate pungiolide Q (2), ten xanthanolide sesquiterpenes (3-12), two eudesmene sesquiterpene derivatives (13-14), one phenylpropionic acid derivative (15), together with eleven known compounds (16-26) were obtained from the fruits of Xanthium italicum Moretti. A possible biosynthetic pathway for pungiolide P (1) was also proposed, which was supported by its bio-synthetic intermediate (2). Compounds 1, 4-5, 18-21, and 25 exhibited cytotoxic activity against a variety of human cancer cell lines. Furthermore, compounds 1, 4-5, could cause blockage of the cell cycle in the G2/M phase and induce apoptosis in H460 cells. Notably, pungiolide P (1) exhibited significantly superior cytotoxicity compared to previously reported compounds, providing valuable insights for natural anti-tumor sources.

SPP1 represents a therapeutic target that promotes the progression of oesophageal squamous cell carcinoma by driving M2 macrophage infiltration.

BACKGROUND: Tumour-associated macrophages (TAMs) are an important component of the tumour microenvironment (TME). However, the crosstalk between oesophageal squamous cell carcinoma (ESCC) cells and TAMs remains largely unexplored. METHODS: Clinical samples and the TCGA database were used to evaluate the relevance of SPP1 and TAM infiltration in ESCC. Mouse models were constructed to investigate the roles of macrophages educated by SPP1 in ESCC. Macrophage phenotypes were determined using qRT‒PCR and immunohistochemical staining. RNA sequencing was performed to elucidate the mechanism. RESULTS: Increasing expression of SPP1 correlated with M2-like TAM accumulation in ESCC, and they both predicted poor prognosis in the ESCC cohort. Knockdown of SPP1 significantly inhibited the infiltration of M2 TAMs in xenograft tumours. In vivo mouse model experiments showed that SPP1-mediated education of macrophages plays an essential role in the progression of ESCC. Mechanistically, SPP1 recruited macrophages and promoted M2 polarisation via CD44/PI3K/AKT signalling activation and then induced VEGFA and IL6 secretion to sustain ESCC progression. Finally, blockade of SPP1 with RNA aptamer significantly inhibited tumour growth and M2 TAM infiltration in xenograft mouse models. CONCLUSIONS: This study highlights SPP1-mediated crosstalk between ESCC cells and TAMs in ESCC. SPP1 could serve as a potential target in ESCC therapy.

A review of the clinical efficacy of FDA-approved antibody‒drug conjugates in human cancers.

While strategies such as chemotherapy and immunotherapy have become the first-line standard therapies for patients with advanced or metastatic cancer, acquired resistance is still inevitable in most cases. The introduction of antibody‒drug conjugates (ADCs) provides a novel alternative. ADCs are a new class of anticancer drugs comprising the coupling of antitumor mAbs with cytotoxic drugs. Compared with chemotherapeutic drugs, ADCs have the advantages of good tolerance, accurate target recognition, and small effects on noncancerous cells. ADCs occupy an increasingly important position in the therapeutic field. Currently, there are 13 Food and Drug Administration (FDA)‒approved ADCs and more than 100 ADC drugs at different stages of clinical trials. This review briefly describes the efficacy and safety of FDA-approved ADCs, and discusses the related problems and challenges to provide a reference for clinical work.

CeO2 for modulating the electronic structure of nickel-cobalt bimetallic phosphides to promote efficient overall water splitting.

The discovery of earth-abundant electrocatalysts to replace platinum and iridium for overall water splitting is a crucial step in reducing the cost of green hydrogen production. Transition metal phosphides have drawn wide attention due to their non-toxicity, good chemical stability, low cost, and stable catalytic activity in alkaline electrolytes. We report a three-dimensional flower-like structure composed of core-shell nanoneedles as catalysts, in which CeO2 is introduced on the surface of nickel cobalt bimetallic phosphide through electrodeposition. And X-ray photoelectron spectroscopy testing and DFT calculations show electron coupling and transfer between CeO2 and CoP3, thereby modulating the electronic structure of the catalyst surface and reducing the adsorption energy of H atoms during the catalytic process, resulting in enhanced catalytic activity. In 1 M KOH, it exhibits a low overpotential of 109 and 296 mV to achieve the current density of 50 mA cm-2 for HER and OER, respectively. When used as both cathode and anode as a bifunctional catalyst, a voltage of only 1.77 V is required to achieve a current density of 50 mA cm-2, demonstrating great industrial potential.

Steady regime of radiation pressure acceleration with foil thickness adjustable within micrometers under a 10-100 PW laser.

Quasimonoenergetic GeV-scale protons are predicted to be efficiently generated via radiation pressure acceleration (RPA) when the foil thickness is matched with the laser intensity, e.g., L_{mat} of several nm to 100 nm for 10^{19}-10^{22}Wcm^{-2} available in laboratory. However, nonmonoenergetic protons with much lower energies than predicted were usually observed in RPA experiments because of too small foil thickness which cannot support insufficient laser contrast and foil surface roughness. Besides the technical problems, we here find that there is an upper-limit thickness L_{up} derived from the requirement that the laser energy should dominate over the ion source energy in the effective laser-proton interaction zone, and L_{up} is lower than L_{mat} with the intensity below 10^{22}Wcm^{-2}, which causes inefficient or unsteady RPA. As the intensity is enhanced to ≥10^{23}Wcm^{-2} provided by 10-100 PW laser facilities, L_{up} can significantly exceed L_{mat}, and therefore RPA becomes efficient. In this regime, L_{mat} acts as a lower-limit thickness for efficient RPA, so the matching thickness can be extended to a continuous range from L_{mat} to L_{up}; the range can reach micrometers, within which foil thickness is adjustable. This makes RPA steady and meanwhile the above technical problems can be overcome. Particle-in-cell simulation shows that multi-GeV quasimonoenergetic proton beams can be steadily generated and the fluctuation of the energy peaks and the energy conversation efficiency remains stable although the thickness is taken in a larger range with increasing intensity. This work predicts that near future RPA experiments with 10-100 PW facilities will enter a new regime with a large range of usable foil thicknesses that can be adjusted to the interaction conditions for steady acceleration.

Identification of a 9-gene signature to enhance biochemical recurrence prediction in primary prostate cancer: A benchmarking study using ten machine learning methods and twelve patient cohorts.

Prostate cancer (PCa) is a prevalent malignancy among men worldwide, and biochemical recurrence (BCR) after radical prostatectomy (RP) is a critical turning point commonly used to guide the development of treatment strategies for primary PCa. However, the clinical parameters currently in use are inadequate for precise risk stratification and informing treatment choice. To address this issue, we conducted a study that collected transcriptomic data and clinical information from 1662 primary PCa patients across 12 multicenter cohorts globally. We leveraged 101 algorithm combinations that consisted of 10 machine learning methods to develop and validate a 9-gene signature, named BCR SCR, for predicting the risk of BCR after RP. Our results demonstrated that BCR SCR generally outperformed 102 published prognostic signatures. We further established the clinical significance of these nine genes in PCa progression at the protein level through immunohistochemistry on Tissue Microarray (TMA). Moreover, our data showed that patients with higher BCR SCR tended to have higher rates of BCR and distant metastasis after radical radiotherapy. Through drug target prediction analysis, we identified nine potential therapeutic agents for patients with high BCR SCR. In conclusion, the newly developed BCR SCR has significant translational potential in accurately stratifying the risk of patients who undergo RP, monitoring treatment courses, and developing new therapies for the disease.

Preimplantation genetic testing for X-linked chronic granulomatous disease induced by a CYBB gene variant: A case report.

INTRODUCTION: X-linked recessive chronic granulomatous disease (XR-CGD) is a severe primary immunodeficiency principally caused by a CYBB (OMIM: 300481) gene variant. Recurrent fatal bacterial or fungal infections are the main clinical manifestations of XR-CGD. PATIENT CONCERNS: In the current case, in vitro fertilization (IVF) associated with preimplantation genetic testing for monogenic disorder (PGT-M) was applied for a Chinese couple who had given birth to a boy with XR-CGD. DIAGNOSIS: Next-generation sequencing-based SNP haplotyping and Sanger-sequencing were used to detect the CYBB gene variant (c.804 + 2T>C, splicing) in this family. INTERVENTIONS: The patient was treated with IVF and PGT-M successively. OUTCOMES: In this IVF cycle, 7 embryos were obtained, and 2 of them were euploid and lacked the CYBB gene variant (c.804 + 2T>C). The PGT results were verified by prenatal diagnosis after successful pregnancy, and a healthy girl was eventually born. CONCLUSION: PGT-M is an effective method for helping families with these fatal and rare inherited diseases to have healthy offspring. It can availably block the transmission of disease-causing loci to descendant.

Structural characterization and osteogenic differentiation-promoting activity of polysaccharide purified from Chroogomphus rutilus.

Chroogomphus rutilus (CR) possesses anti-inflammatory, antioxidant, and hypoglycemic properties. However, studies are yet to evaluate the anti-osteoporotic activity of the fungi and its polysaccharides. Therefore, this study is aimed at characterizing and evaluating the anti-osteoporotic effects of a novel polysaccharide from CR. The neutral polysaccharide CRP2 extracted and purified from the fruiting body of CR had a molecular weight of 20.41 kDa. Monosaccharide composition analysis revealed that CRP2 is composed of galactose, glucose, fucose, and mannose. The backbone of CRP2 primarily consisted of →6)-α-D-Galp-(1 â†’ residues, with specific site substitutions speculated at partial positions, such as O-CH3 substitution at H-3 position, or a branch site located at C-2, including α-L-Fucp-(1 â†’ 6)-ß-D-Glcp-(1 â†’ and α-D-Manp-(1→. CRP2 treatment increased trabecular bone density, restored a network-shaped structure, and upregulated the expression of osteoblast differentiation markers, including runt-related transcription factor 2, osterix, osteocalcin, and osteopontin in the femoral tissue of mice with osteoporosis (OP). Additionally, CRP2 treatment suppressed the expression of tumor necrosis factor-α and interleukin-1ß in the femoral tissue of mice with OP. Mechanistically, CRP2 exerted anti-OP effect by inhibiting inflammation and promoting osteogenesis through the transforming growth factor ß-1/Smad pathway. Conclusively, these findings augment our understanding of the potential role of CRP2 in OP treatment.

Methodology for Good Machine Learning with Multi-Omics Data.

In 2020, Novartis Pharmaceuticals Corporation and the U.S. Food and Drug Administration (FDA) started a 4-year scientific collaboration to approach complex new data modalities and advanced analytics. The scientific question was to find novel radio-genomics-based prognostic and predictive factors for HR+/HER- metastatic breast cancer under a Research Collaboration Agreement. This collaboration has been providing valuable insights to help successfully implement future scientific projects, particularly using artificial intelligence and machine learning. This tutorial aims to provide tangible guidelines for a multi-omics project that includes multidisciplinary expert teams, spanning across different institutions. We cover key ideas, such as "maintaining effective communication" and "following good data science practices," followed by the four steps of exploratory projects, namely (1) plan, (2) design, (3) develop, and (4) disseminate. We break each step into smaller concepts with strategies for implementation and provide illustrations from our collaboration to further give the readers actionable guidance.

Development of a bacterial gene transcription activating strategy based on transcriptional activator positive feedback.

INTRODUCTION: Transcription of biological nitrogen fixation (nif) genes is activated by the NifA protein which recognizes specific activating sequences upstream of σ54-dependent nif promoters. The large quantities of nitrogenase which can make up 20% of the total proteins in the cell indicates high transcription activating efficiency of NifA and high transcription level of nifHDK nitrogenase genes. OBJECTIVES: Development of an efficient gene transcription activating strategy in bacteria based on positive transcription regulatory proteins and their regulating DNA sequences. METHODS: We designed a highly efficient gene transcription activating strategy in which the nifA gene was placed directly downstream of its regulating sequences. The NifA protein binds its regulating sequences and stimulates transcription of itself and downstream genes. Overexpressed NifA causes transcription activation by positive reinforcement. RESULTS: When this gene transcription activating strategy was used to overexpress NifA in Pseudomonas stutzeri DSM4166 containing the nif gene cluster, the nitrogenase activity was increased by 368 folds which was 16 times higher than that obtained by nifA driven by the strongest endogenous constitutive promoter. When this strategy was used to activate transcription of exogenous biosynthetic genes for the plant auxin indole-3-acetic acid and the antitumor alkaloid pigment prodigiosin in DSM4166, both of them resulted in better performance than the strongest endogenous constitutive promoter and the highest reported productions in heterologous hosts to date. Finally, we demonstrated the universality of this strategy using the positive transcriptional regulator of the psp operon, PspF, in E. coli and the pathway-specific positive transcription regulator of the polyene antibiotic salinomycin biosynthesis, SlnR, in Streptomyces albus. CONCLUSION: Many positive transcription regulatory proteins and their regulating DNA sequences have been identified in bacteria. The gene transcription activating strategy developed in this study will have broad applications in molecular biology and biotechnology.

Glutamic Acid Enhances the Corrosion Inhibition of Polyaspartic Acid on Q235 Carbon Steel.

Currently, poly(aspartic acid) (PASP) is used with traditional toxic agents for corrosion inhibition, which greatly reduces the environmental significance of PASP as a green inhibitor. Amino acids, small-molecule compounds with amino and carboxyl groups, may react with PASP and act as chains to link PASP molecules, which might enhance the inhibition of PASP on metal corrosion. In this study, we selected glutamic acid (GLU) as a typical amino acid to explore the potential synergistic effect of the amino acid and PASP on corrosion inhibition via electrochemical experiments and molecular dynamics simulation. The corrosion inhibition of PASP was promoted by GLU with less weight loss and less pitting. The results of molecular dynamics simulation showed that GLU could bind with PASP at carboxyl groups and amino groups via donor-acceptor interactions and accelerate the diffusion of PASP to the carbon steel surface. Furthermore, the binding between PASP and the carbon steel surface can be enhanced by GLU, resulting in a dense and stable protective film. To the best of our knowledge, this is the first investigation into the mechanism of an amino acid as an enhancer to improve corrosion inhibition. This work provides a new strategy to enhance existing green inhibitors, which would significantly reduce the cost of cooling water treatment and its adverse environmental impacts.

Antioxidant and Anti-Aging Properties of Polyphenol-Polysaccharide Complex Extract from Hizikia fusiforme.

Hizikia fusiforme has a long history of consumption and medicinal use in China. It has been found that natural plants containing polyphenol-polysaccharide complexes have better activity compared with polyphenols and polysaccharides. Therefore, in this study on enzymatic hydrolysis and fractional alcohol precipitation, two kinds of polyphenol-polysaccharide complexes (PPC), PPC1 and PPC2, were initially obtained from Hizikia fusiforme, while the dephenolization of PPC1 and PPC2 produced PPC3 and PPC4. Through in vitro assays, PPC2 and PPC4 were found to have higher antioxidant activity, and thus were selected for testing the PPCs' anti-aging activity in a subsequent in vivo experiment with D-gal-induced aging in mice. The results indicated that PPCs could regulate the expressions of antioxidant enzymes and products of oxidation, elevate the expressions of genes and proteins related to the Nrf2 pathway in the mouse brain, enrich the gut microbiota species and increase the Bacteroidota-Firmicute (B/F) ratio. Above all, the Hizikia fusiforme polyphenol-polysaccharide complex has potential in the development of natural anti-aging drugs.

A long-read sequencing and SNP haplotype-based novel preimplantation genetic testing method for female ADPKD patient with de novo PKD1 mutation.

The autosomal dominant form of polycystic kidney disease (ADPKD) is the most common hereditary disease that causes late-onset renal cyst development and end-stage renal disease. Preimplantation genetic testing for monogenic disease (PGT-M) has emerged as an effective strategy to prevent pathogenic mutation transmission rely on SNP linkage analysis between pedigree members. Yet, it remains challenging to establish reliable PGT-M methods for ADPKD cases or other monogenic diseases with de novo mutations or without a family history. Here we reported the application of long-read sequencing for direct haplotyping in a female patient with de novo PKD1 c.11,526 G > C mutation and successfully established the high-risk haplotype. Together with targeted short-read sequencing of SNPs for the couple and embryos, the carrier status for embryos was identified. A healthy baby was born without the PKD1 pathogenic mutation. Our PGT-M strategy based on long-read sequencing for direct haplotyping combined with targeted SNP haplotype can be widely applied to other monogenic disease carriers with de novo mutation.

Recent Strategies to Develop Conjugated Polymers for Detection and Therapeutics.

The infectious diseases resulting from pathogenic microbes are highly contagious and the source of infection is difficult to control, which seriously endangers life and public health safety. Although the emergence of antibiotics has a good therapeutic effect in the early stage, the massive abuse of antibiotics has brought about the evolution of pathogens with drug resistance, which has gradually weakened the lethality and availability of antibiotics. Cancer is a more serious disease than pathogenic bacteria infection, which also threatens human life and health. Traditional treatment methods have limitations such as easy recurrence, poor prognosis, many side effects, and high toxicity. These two issues have led to the exploration and development of novel therapeutic agents (such as conjugated polymers) and therapeutic strategies (such as phototherapy) to avoid the increase of drug resistance and toxic side effects. As a class of organic polymer biological functional materials with excellent photoelectric properties, Conjugated polymers (CPs) have been extensively investigated in biomedical fields, such as the detection and treatment of pathogens and tumors due to their advantages of easy modification and functionalization, good biocompatibility and low cost. A rare comprehensive overview of CPs-based detection and treatment applications has been reported. This paper reviews the design strategies and research status of CPs used in biomedicine in recent years, introduces and discusses the latest progress of their application in the detection and treatment of pathogenic microorganisms and tumors according to different detection or treatment methods, as well as the limitations and potential challenges in prospective exploration.

Phytochemicals for the prevention and treatment of pancreatic cancer: Current progress and future prospects.

Pancreatic cancer is the third leading cause of cancer-related deaths in the United States, owing to its aggressive nature and suboptimal treatment options, emphasizing the need for novel therapeutic approaches. Emerging studies have exhibited promising results regarding the therapeutic utility of plant-derived compounds (phytochemicals) in pancreatic cancer. The purpose of this review is to evaluate the potential of phytochemicals in the treatment and prevention of pancreatic cancer. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses was applied to collect articles for this review. Scholarly databases, including PubMed, Scopus and ScienceDirect, were queried for relevant studies using the following keywords: phytochemicals, phenolics, terpenoids, alkaloids, sulfur-containing compounds, in vitro, in vivo, clinical studies, pancreatic cancer, tumour, treatment and prevention. Aggregate results pooled from qualified studies indicate phytochemicals can inhibit pancreatic cancer cell growth or decrease tumour size and volume in animal models. These effects have been attributed to various mechanisms, such as increasing proapoptotic factors, decreasing antiapoptotic factors, or inducing cell death and cell cycle arrest. Notable signalling pathways modulated by phytochemicals include the rat sarcoma/mitogen activated protein kinase, wingless-related integration site/ß-catenin and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signal transduction pathways. Clinically, phytochemicals have been found to increase survival while being well-tolerated and safe, though research is scarce. While these promising results have produced great interest in this field, further in-depth studies are required to characterize the anticancer activities of phytochemicals before they can be utilized to prevent or treat pancreatic cancer in clinical practice.

Facile Synthesis of Iron and Nitrogen Co-Doped Carbon Dot Nanozyme as Highly Efficient Peroxidase Mimics for Visualized Detection of Metabolites.

Visual detection based on nanozymes has great potential for the rapid detection of metabolites in clinical analysis or home-based health management. In this work, iron and nitrogen co-doped carbon dots (Fe,N-CDs) were conveniently synthesized as a nanozyme for the visual detection of glucose (Glu) or cholesterol (Chol). Using inexpensive and readily available precursors, Fe,N-CDs with peroxidase-like activity were conveniently prepared through a simple hydrothermal method. Co-doping of Fe and N atoms enhanced the catalytic activity of the nanozyme. The nanozyme had a low Michaelis constant (Km) of 0.23 mM when hydrogen peroxide (H2O2) was used as the substrate. Free radical trapping experiments revealed that the reactive oxygen species (ROS) generated in the nanozyme-catalyzed process were superoxide anion radicals (•O2-), which can oxidize colorless 3,3',5,5'-tetramethylbenzidine (TMB) to generate blue oxidation product (ox-TMB) with characteristics absorbance at 652 nm. Based on this mechanism, a colorimetric sensor was constructed to detect H2O2 ranging from 0.1 µM to 200 µM with a detection limit (DL) of 75 nM. In the presence of glucose oxidase (Gox) or Chol oxidase (Chox), Glu or Chol was oxidized, respectively, and generated H2O2. Based on this, indirect detection of Glu and Chol was realized with linear detection ranges of 5-160 µM and 2-200 µM and DLs of 2.8 µM and 0.8 µM, respectively. A paper-based visual detection platform was fabricated using Fe,N-CDs as nanozyme ink to prepare testing paper by inkjet printing. Using a smartphone to record the RGB values of the testing paper after the reaction, visual detection of Glu and Chol can be achieved with linear detection ranges of 5-160 µM (DL of 3.3 µM) and 2-200 µM (DL of 1.0 µM), respectively.

d-lactate modulates M2 tumor-associated macrophages and remodels immunosuppressive tumor microenvironment for hepatocellular carcinoma.

The polarization of tumor-associated macrophages (TAMs) from M2 to M1 phenotype demonstrates great potential for remodeling the immunosuppressive tumor microenvironment (TME) of hepatocellular carcinoma (HCC). d-lactate (DL; a gut microbiome metabolite) acts as an endogenous immunomodulatory agent that enhances Kupffer cells for clearance of pathogens. In this study, the potential of DL for transformation of M2 TAMs to M1 was confirmed, and the mechanisms underlying such polarization were mainly due to the modulation of phosphatidylinositol 3-kinase/protein kinase B pathway. A poly(lactide-co-glycolide) nanoparticle (NP) was used to load DL, and the DL-loaded NP was modified with HCC membrane and M2 macrophage-binding peptide (M2pep), forming a nanoformulation (DL@NP-M-M2pep). DL@NP-M-M2pep transformed M2 TAMs to M1 and remodeled the immunosuppressive TME in HCC mice, promoting the efficacy of anti-CD47 antibody for long-term animal survival. These findings reveal a potential TAM modulatory function of DL and provide a combinatorial strategy for HCC immunotherapy.