Foodomics uncovers functional and volatile metabolite dynamics in red raspberry chewable tablet optimized processing.

Raspberries are known to contain valuable metabolites and possess a robust antioxidant capacity. However, the impact of different tablet processing stages on the nutritional content and flavor profile of raspberries remains unclear. The dynamic profile of functional and volatile metabolites was investigated through foodomics combined with UPLC-MS/MS-based widely targeted metabolomics and HS-SPME-GC-MS, and antioxidant capacities were assessed during tablet processing. 1336 functional metabolites and 645 volatile metabolites were identified. Results indicated tablets retained 34% âˆ¼ 61% of the total volatile contents. In addition, the conversion intensity of functional metabolites was consistent with the order of "Tableting > Freeze-drying > Crushing". Compared to raspberry, tablets showed higher antioxidant activity, which was positively correlated with vitamin contents. This study elucidated that tablet formation demonstrated advantages in antioxidation and aroma retention, which may provide insights for enhancing quality during the tableting process.

Impact of indigenous Oenococcus oeni and Lactiplantibacillus plantarum species co-culture on Cabernet Sauvignon wine malolactic fermentation: Kinetic parameters, color and aroma.

Malolactic fermentation (MLF) is a crucial process to enhance wine quality, and the utilization of indigenous microorganisms has the potential to enhance wine characteristics distinct to a region. Here, the MLF performance of five indigenous Oenococcus oeni strains and six synthetic microbial communities (SynComs), were comparatively evaluated in Cabernet Sauvignon wine. In terms of malate metabolism rate and wine aroma diversity, the strain of O. oeni Oe114-46 demonstrated comparable MLF performance to the commercial strain of O. oeni Oe450 PreAc. Furthermore, the corresponding SynComs (Oe144-46/LpXJ25) exhibited improved fermentation properties, leading to increased viable cell counts of both species, more rapid and thorough MLF, and increased concentrations of important aroma compounds, such as linalool, 4-terpinenol, α-terpineol, diethyl succinate, and ethyl lactate. These findings highlight the remarkable MLF performance of indigenous O. oeni and O. oeni-L. plantarum microbial communities, emphasizing their immense potential in improving MLF efficiency and wine quality.

Miz1 represses type I interferon production and limits viral clearance during influenza A virus infection.

Type I interferons (IFNs) are critical for the antiviral immune response, and fine-tuning type I IFN production is critical to effectively clearing viruses without causing harmful immunopathology. We showed that the transcription factor Miz1 epigenetically repressed the expression of genes encoding type I IFNs in mouse lung epithelial cells by recruiting histone deacetylase 1 (HDAC1) to the promoters of Ifna and Ifnb. Loss of function of Miz1 resulted in augmented production of these type I IFNs during influenza A virus (IAV) infection, leading to improved viral clearance in vitro and in vivo. IAV infection induced Miz1 accumulation by promoting the cullin-4B (CUL4B)-mediated ubiquitylation and degradation of the E3 ubiquitin ligase Mule (Mcl-1 ubiquitin ligase E3; also known as Huwe1 or Arf-BP1), which targets Miz1 for degradation. As a result, Miz1 accumulation limited type I IFN production and favored viral replication. This study reveals a previously unrecognized function of Miz1 in regulating antiviral defense and a potential mechanism for influenza viruses to evade host immune defense.

LATS2 degradation promoted fibrosis damage and rescued by vitamin K3 in lupus nephritis.

BACKGROUND: Lupus nephritis (LN) is the most common complication of systemic lupus erythematosus (SLE). The limited treatment options for LN increase the economic burdens on patients. Because fibrotic progression leads to irreversible renal damage in LN patients and further progresses to chronic kidney disease (CKD) and the end stage of renal disease (ESRD), developing new targets to prevent LN fibrotic progression could lead to a feasible treatment strategy for LN patients. METHODS: In this study, we examined YAP activation and LATS2 downregulation in LN kidney biopsy samples (LN: n = 8, normal: n = 2) and lupus-prone MRL/lpr mice (n = 8 for each disease stage). The function of LATS2 was further investigated by in situ injection of Ad-LATS2 into mice with LN (n = 6 mice per group). We examined the role of SIAH2-LATS2 regulation by IP-MS and co-IP, and the protective effect of the SIAH2 inhibitor was investigated in mice with LN. RESULTS: Restoring LATS2 by an adenovirus in vivo alleviated renal fibrotic damage in mice with LN. Moreover, we found that LATS2 was degraded by a K48 ubiquitination-proteasome pathway mediated by SIAH2 and promoted YAP activation to worsen fibrosis progression in LN. The H150 region of the substrate binding domain (SBD) is an important site for SIAH2-LATS2 binding. The SIAH2-specific inhibitor vitamin K3 protected against LN-associated fibrotic damage in vivo. CONCLUSION: In summary, we identified the SIAH2-LATS2 axis as an attractive intervention target in LN to alter the resistance to fibrosis.

Comparative analysis of the organelle genomes of Aconitum carmichaelii revealed structural and sequence differences and phylogenetic relationships.

In this study, we conducted an assembly and analysis of the organelle genomes of Aconitum carmichaelii. Our investigation encompassed the examination of organelle genome structures, gene transfer events, and the environmental selection pressures affecting A. carmichaelii. The results revealed distinct evolutionary patterns in the organelle genomes of A. carmichaelii. Especially, the plastome exhibited a more conserved structure but a higher nucleotide substitution rate (NSR), while the mitogenome displayed a more complex structure with a slower NSR. Through homology analysis, we identified several instances of unidirectional protein-coding genes (PCGs) transferring from the plastome to the mitogenome. However, we did not observe any events which genes moved from the mitogenome to the plastome. Additionally, we observed multiple transposable element (TE) fragments in the organelle genomes, with both organelles showing different preferences for the type of nuclear TE insertion. Divergence time estimation suggested that rapid differentiation occurred in Aconitum species approximately 7.96 million years ago (Mya). This divergence might be associated with the reduction in CO2 levels and the significant uplift of the Qinghai-Tibet Plateau (QTP) during the late Miocene. Selection pressure analysis indicated that the dN/dS values of both organelles were less than 1, suggested that organelle PCGs were subject to purification selection. However, we did not detect any positively selected genes (PSGs) in Subg. Aconitum and Subg. Lycoctonum. This observation further supports the idea that stronger negative selection pressure on organelle genes in Aconitum results in a more conserved amino acid sequence. In conclusion, this study contributes to a deeper understanding of organelle evolution in Aconitum species and provides a foundation for future research on the genetic mechanisms underlying the structure and function of the Aconitum plastome and mitogenome.

Female frogs communicate with males through blinking.

Blinking is a behavior unique to animal taxa with motile eyelids, such as most amphibians and reptiles as well as all birds and mammals1. Eyelid movement has physiological functions, such as lubricating the cornea and washing away dust, but its potential signaling functions are not well understood1,2. The use of eyeblinks as a social signal is currently thought to be restricted to some primates, especially humans and their companion animals, but has not been verified in other taxa1,3,4. Here, through field observation and experiments, we demonstrate that female concave-eared torrent frogs (Odorrana tormota), which inhabit noisy streams, use eyeblinks to communicate with males to urge them to initiate amplexus for mating. Our findings reveal that eyeblinks may serve as a social signal in non-primate species.

gp120-derived amyloidogenic peptides form amyloid fibrils that increase HIV-1 infectivity.

Apart from mediating viral entry, the function of the free HIV-1 envelope protein (gp120) has yet to be elucidated. Our group previously showed that EP2 derived from one ß-strand in gp120 can form amyloid fibrils that increase HIV-1 infectivity. Importantly, gp120 contains ~30 ß-strands. We examined whether gp120 might serve as a precursor protein for the proteolytic release of amyloidogenic fragments that form amyloid fibrils, thereby promoting viral infection. Peptide array scanning, enzyme degradation assays, and viral infection experiments in vitro confirmed that many ß-stranded peptides derived from gp120 can indeed form amyloid fibrils that increase HIV-1 infectivity. These gp120-derived amyloidogenic peptides, or GAPs, which were confirmed to form amyloid fibrils, were termed gp120-derived enhancers of viral infection (GEVIs). GEVIs specifically capture HIV-1 virions and promote their attachment to target cells, thereby increasing HIV-1 infectivity. Different GAPs can cross-interact to form heterogeneous fibrils that retain the ability to increase HIV-1 infectivity. GEVIs even suppressed the antiviral activity of a panel of antiretroviral agents. Notably, endogenous GAPs and GEVIs were found in the lymphatic fluid, lymph nodes, and cerebrospinal fluid (CSF) of AIDS patients in vivo. Overall, gp120-derived amyloid fibrils might play a crucial role in the process of HIV-1 infectivity and thus represent novel targets for anti-HIV therapeutics.

Engineered extracellular vesicles efficiently deliver CRISPR-Cas9 ribonucleoprotein (RNP) to inhibit herpes simplex virus1 infection in vitro and in vivo.

Extracellular vesicles (EVs) have recently emerged as a promising delivery platform for CRISPR/Cas9 ribonucleoproteins (RNPs), owing to their ability to minimize off-target effects and immune responses. However, enhancements are required to boost the efficiency and safety of Cas9 RNP enrichment within EVs. In response, we employed the Fc/Spa interaction system, in which the human Fc domain was fused to the intracellular domain of PTGFRN-Δ687 and anchored to the EV membrane. Simultaneously, the B domain of the Spa protein was fused to the C domain of cargos such as Cre or spCas9. Due to the robust interaction between Fc and Spa, this method enriched nearly twice the amount of cargo within the EVs. EVs loaded with spCas9 RNP targeting the HSV1 genome exhibited significant inhibition of viral replication in vitro and in vivo. Moreover, following neuron-targeting peptide RVG modification, the in vivo dosage in neural tissues substantially increased, contributing to the clearance of the HSV1 virus in neural tissues and exhibiting a lower off-target efficiency. These findings establish a robust platform for efficient EV-based SpCas9 delivery, offering potential therapeutic advantages for HSV1 infections and other neurological disorders.

A panel of multivalent nanobodies broadly neutralizing Omicron subvariants and recombinant.

The emerging Omicron subvariants have a remarkable ability to spread and escape nearly all current monoclonal antibody (mAb) treatments. Although the virulence of SARS-CoV-2 has now diminished, it remains a significant threat to public health due to its high transmissibility and susceptibility to mutation. Therefore, it is urgent to develop broad-acting and potent therapeutics targeting current and emerging Omicron variants. Here, we identified a panel of Omicron BA.1 spike receptor-binding domain (RBD)-targeted nanobodies (Nbs) from a naive alpaca VHH library. This panel of Nbs exhibited high binding affinity to the spike RBD of wild-type, Alpha B.1.1.7, Beta B.1.351, Delta plus, Omicron BA.1, and BA.2. Through multivalent Nb construction, we obtained a subpanel of ultrapotent neutralizing Nbs against Omicron BA.1, BA.2, BF.7 and even emerging XBB.1.5, and XBB.1.16 pseudoviruses. Protein structure prediction and docking analysis showed that Nb trimer 2F2E5 targets two independent RBD epitopes, thus minimizing viral escape. Taken together, we obtained a panel of broad and ultrapotent neutralizing Nbs against Omicron BA.1, Omicron BA.2, BF.7, XBB.1.5, and XBB.1.16. These multivalent Nbs hold great promise for the treatment against SARS-CoV-2 infection and could possess a superwide neutralizing breadth against novel omicron mutants or recombinants.

Dynamic proteomic changes in tumor and immune organs reveal systemic immune response to tumor development.

In orthotopic mouse tumor models, tumor progression is a complex process, involving interactions among tumor cells, host cell derived stromal cells and immune cells. Much attention has been focused on the tumor and its tumor microenvironment, while the host's macroenvironment including immune organs in response to tumorigenesis is poorly understood. Here, we report a temporal proteomic analysis on a subcutaneous tumor and three immune organs (LN, MLN and spleen) collected on Days 0, 3, 7, 10, 14 and 21 after inoculation of mouse forestomach cancer (MFC) cells in a syngeneic mouse model. Bioinformatics analysis identified key biological processes during distinct tumor development phases, including an initial acute immune response, the attack by the host immune system, followed by the adaptive immune activation and the build-up of extracellular matrix. Proteomic changes in LN and spleen largely recapitulated the dynamics of the immune response in the tumor, consistent with an acute defense response on D3, adaptive immune response on D10 and the immune evasion by D21. In contrast, the immune response in MLN showed a gradual and sustained activation, suggesting a delayed response from a distal immune organ. Combined analyses of tumors and host immune organs allowed the identification of potential therapeutic targets. A proof-of concept experiment demonstrated that significant growth reduction can be achieved by dual inhibition of MEK and DDR2. Together, our temporal proteomic dataset of tumors and immune organs provides a useful resource to understand the interaction between tumors and the immune system, and has the potential for identifying new therapeutic targets for cancer treatment.

MDFI promotes the proliferation and tolerance to chemotherapy of colorectal cancer cells by binding ITGB4/LAMB3 to activate the AKT signaling pathway.

Colorectal cancer (CRC) is one of the most lethal cancers. Single-cell RNA sequencing (scRNA-seq) and protein-protein interactions (PPIs) have enabled the systematic study of CRC. In our research, the activation of the AKT pathway in CRC was analyzed by KEGG using single-cell sequencing data from the GSE144735 dataset. The correlation and PPIs of MDFI and ITGB4/LAMB3 were examined. The results were verified in the TCGA and CCLE and further tested by coimmunoprecipitation experiments. The effect of MDFI on the AKT pathway via ITGB4/LAMB3 was validated by knockdown and lentiviral overexpression experiments. The effect of MDFI on oxaliplatin/fluorouracil sensitivity was probed by colony formation assay and CCK8 assay. We discovered that MDFI was positively associated with ITGB4/LAMB3. In addition, MDFI was negatively associated with oxaliplatin/fluorouracil sensitivity. MDFI upregulated the AKT pathway by directly interacting with LAMB3 and ITGB4 in CRC cells, and enhanced the proliferation of CRC cells via the AKT pathway. Finally, MDFI reduced the sensitivity of CRC cells to oxaliplatin and fluorouracil. In conclusion, MDFI promotes the proliferation and tolerance to chemotherapy of colorectal cancer cells, partially through the activation of the AKT signaling pathway by the binding to ITGB4/LAMB3. Our findings provide a possible molecular target for CRC therapy.

Model-guided metabolic rewiring to bypass pyruvate oxidation for pyruvate derivative synthesis by minimizing carbon loss.

Engineering microbial hosts to synthesize pyruvate derivatives depends on blocking pyruvate oxidation, thereby causing severe growth defects in aerobic glucose-based bioprocesses. To decouple pyruvate metabolism from cell growth to improve pyruvate availability, a genome-scale metabolic model combined with constraint-based flux balance analysis, geometric flux balance analysis, and flux variable analysis was used to identify genetic targets for strain design. Using translation elements from a ~3,000 cistronic library to modulate fxpK expression in a bicistronic cassette, a bifido shunt pathway was introduced to generate three molecules of non-pyruvate-derived acetyl-CoA from one molecule of glucose, bypassing pyruvate oxidation and carbon dioxide generation. The dynamic control of flux distribution by T7 RNAP-mediated synthetic small RNA decoupled pyruvate catabolism from cell growth. Adaptive laboratory evolution and multi-omics analysis revealed that a mutated isocitrate dehydrogenase functioned as a metabolic switch to activate the glyoxylate shunt as the only C4 anaplerotic pathway to generate malate from two molecules of acetyl-CoA input and bypass two decarboxylation reactions in the tricarboxylic acid cycle. A chassis strain for pyruvate derivative synthesis was constructed to reduce carbon loss by using the glyoxylate shunt as the only C4 anaplerotic pathway and the bifido shunt as a non-pyruvate-derived acetyl-CoA synthetic pathway and produced 22.46, 27.62, and 6.28 g/L of l-leucine, l-alanine, and l-valine by a controlled small RNA switch, respectively. Our study establishes a novel metabolic pattern of glucose-grown bacteria to minimize carbon loss under aerobic conditions and provides valuable insights into cell design for manufacturing pyruvate-derived products.IMPORTANCEBio-manufacturing from biomass-derived carbon sources using microbes as a cell factory provides an eco-friendly alternative to petrochemical-based processes. Pyruvate serves as a crucial building block for the biosynthesis of industrial chemicals; however, it is different to improve pyruvate availability in vivo due to the coupling of pyruvate-derived acetyl-CoA with microbial growth and energy metabolism via the oxidative tricarboxylic acid cycle. A genome-scale metabolic model combined with three algorithm analyses was used for strain design. Carbon metabolism was reprogrammed using two genetic control tools to fine-tune gene expression. Adaptive laboratory evolution and multi-omics analysis screened the growth-related regulatory targets beyond rational design. A novel metabolic pattern of glucose-grown bacteria is established to maintain growth fitness and minimize carbon loss under aerobic conditions for the synthesis of pyruvate-derived products. This study provides valuable insights into the design of a microbial cell factory for synthetic biology to produce industrial bio-products of interest.

Engineering of novel hemagglutinin biosensors for rapid detection and drug screening of Influenza A H7N9 virus.

New pathogenic influenza virus strains are constantly emerging, posing a serious risk to both human health and economic growth. To effectively control the spread of this virus, there is an urgent need for early, rapid, sensitive, simple, and cost-effective detection technologies, as well as new and effective antiviral drugs. In this study, we have successfully achieved a significant milestone by successfully fusing the H7N9 influenza virus hemagglutinin (HA) protein with the nano-luciferase component, resulting in the development of a novel set of biosensors. This remarkable achievement marks the first instance of utilizing this biosensor technology for influenza antibody detection. Our biosensor technology also has the potential to facilitate the development of antiviral drugs targeting specific epitopes of the HA protein, providing a promising avenue for the treatment of H7N9 influenza virus infections. Furthermore, our biosensors have broad applications beyond H7N9 influenza virus detection, as they can be expanded for the detection of other pathogens and drug screening applications in the future. By providing a novel and effective solution to the detection and treatment of influenza viruses, our biosensors have the potential to revolutionize the field of infectious disease control.

Optimization and biological evaluation of l-DOPA derivatives as potent influenza PAN endonuclease inhibitors with multi-site binding characteristics.

Emerging and potential influenza pandemics still are an enormous worldwide public health challenge. The PAN endonuclease has been proved to be a promising target for anti-influenza drug design. Here, we report the discovery and optimization of potent Y-shaped PAN inhibitors featuring multi-site binding characteristics with l-DOPA as a starting point. We systematically modified the hit 1 bearing two-binding characteristics based on structure-based rational design combined with multisite binding and conformational constraint strategies, generating four families of l-DOPA derivatives for SARs analysis. Among these substances, N, 3-di-substituted 1, 2, 3, 4-tetrahydroisoquinoline derivative T-31 displayed superior properties as a lead PAN endonuclease inhibitor and antiviral agent. The lead T-31 inhibited PAN endonuclease activity with an IC50 value of 0.15 µM and showed broad and submicromolar anti-influenza potency in cell-based assays. More importantly, T-31 could simultaneously target both influenza HA and the RdRp complex, thus interfering with virus entry into host cells and viral replication. This study offers a set of novel PAN endonuclease inhibitors with multi-site binding characteristics starting from the l-DOPA skeleton.

A mutant GH3 family ß-glucosidase from Oenococcus oeni exhibits superior adaptation to wine stresses and potential for improving wine aroma and phenolic profiles.

In this study, we conducted a comprehensive investigation into a GH3 family ß-glucosidase (BGL) from the wild-type strain of Oenococcus oeni and its mutated counterpart from the acid-tolerant mutant strain. Our analysis revealed the mutant BGL's remarkable capacity to adapt to wine-related stress conditions, including heightened tolerance to low pH, elevated ethanol concentrations, and metal ions. Additionally, the mutant BGL exhibited superior hydrolytic activity towards various substrates. Through de novo modeling, we identified specific amino acid mutations responsible for its resilience to low pH and high ethanol environments. In simulated wine conditions, the mutant BGL outperformed both wild-type and commercial BGLs, efficiently releasing terpene and phenolic aglycones from glycosides in wine grapes. These findings not only expand our understanding of O. oeni BGLs but also highlight their potential in enhancing wine production. The mutant BGL's enhanced adaptation to wine stress conditions opens promising avenue for improving wine quality and flavor.

The volume regulated anion channel VRAC regulates NLRP3 inflammasome by modulating itaconate efflux and mitochondria function.

The NLRP3 inflammasome is a supramolecular complex that is linked to sterile and pathogen-dependent inflammation, and its excessive activation underlies many diseases. Ion flux disturbance and cell volume regulation are both reported to mediate NLRP3 inflammasome activation, but the underlying orchestrating signaling remains not fully elucidated. The volume-regulated anion channel (VRAC), formed by LRRC8 proteins, is an important constituent that controls cell volume by permeating chloride and organic osmolytes in response to cell swelling. We now demonstrate that Lrrc8a, the essential component of VRAC, plays a central and specific role in canonical NLRP3 inflammasome activation. Moreover, VRAC acts downstream of K+ efflux for NLRP3 stimuli that require K+ efflux. Mechanically, our data demonstrate that VRAC modulates itaconate efflux and damaged mitochondria production for NLRP3 inflammasome activation. Further in vivo experiments show mice with Lrrc8a deficiency in myeloid cells were protected from lipopolysaccharides (LPS)-induced endotoxic shock. Taken together, this work identifies VRAC as a key regulator of NLRP3 inflammasome and innate immunity by regulating mitochondrial adaption for macrophage activation and highlights VRAC as a prospective drug target for the treatment of NLRP3 inflammasome and itaconate related diseases.

Production, surface modification, physicochemical properties, biocompatibility, and bioimaging applications of nanodiamonds.

Nanodiamonds (ND) are chemically inert and stable owing to their sp3 covalent bonding structure, but their surface sp2 graphitic carbons can be easily homogenized with diverse functional groups via oxidation, reduction, hydrogenation, amination, and halogenation. Further surface conjugation of NDs with hydrophilic ligands can boost their colloidal stability and functionality. In addition, NDs are non-toxic as they are made of carbons. They exhibit stable fluorescence without photobleaching. They also possess paramagnetic and ferromagnetic properties, making them suitable for use as a new type of fluorescence imaging (FI) and magnetic resonance imaging (MRI) probe. In this review, we focused on recently developed ND production methods, surface homogenization and functionalization methods, biocompatibilities, and biomedical imaging applications as FI and MRI probes. Finally, we discussed future perspectives.

Heavy Metal-Based Nanoparticles as High-Performance X-ray Computed Tomography Contrast Agents.

X-ray computed tomography (CT) contrast agents offer extremely valuable tools and techniques in diagnostics via contrast enhancements. Heavy metal-based nanoparticles (NPs) can provide high contrast in CT images due to the high density of heavy metal atoms with high X-ray attenuation coefficients that exceed that of iodine (I), which is currently used in hydrophilic organic CT contrast agents. Nontoxicity and colloidal stability are vital characteristics in designing heavy metal-based NPs as CT contrast agents. In addition, a small particle size is desirable for in vivo renal excretion. In vitro phantom imaging studies have been performed to obtain X-ray attenuation efficiency, which is a critical parameter for CT contrast agents, and the imaging performance of CT contrast agents has been demonstrated via in vivo experiments. In this review, we focus on the in vitro and in vivo studies of various heavy metal-based NPs in pure metallic or chemical forms, including Au, Pt, Pd, Ag, Ce, Gd, Dy, Ho, Yb, Ta, W, and Bi, and provide an outlook on their use as high-performance CT contrast agents.

High-Quantum-Yield Ultrasmall Ln2O3 (Ln = Eu, Tb, or Dy) Nanoparticle Colloids in Aqueous Media Obtained via Photosensitization.

Fluorescent nanoparticles used in biomedical applications should be stable in their colloidal form in aqueous media and possess a high quantum yield (QY). We report ultrasmall Ln2O3 (Ln = Eu, Tb, or Dy) nanoparticle colloids with high QYs in aqueous media. The nanoparticles are grafted with hydrophilic and biocompatible poly(acrylic acid) (PAA) to ensure colloidal stability and biocompatibility and with organic photosensitizer 2,6-pyridinedicarboxylic acid (PDA) for achieving a high QY. The PAA/PDA-Ln2O3 nanoparticle colloids were nearly monodispersed and ultrasmall (particle diameter: ∼2 nm). They exhibited excellent colloidal stability with no precipitation after synthesis (>1.5 years) in aqueous media, very low cellular toxicity, and very high absolute QYs of 87.6, 73.6, and 2.8% for Ln = Eu, Tb, and Dy, respectively. These QYs are the highest reported so far for lanthanides in aqueous media. Therefore, the results suggest their high potential as sensitive optical or imaging probes in biomedical applications.

Discovery of novel aporphine alkaloid derivative as potent TLR2 antagonist reversing macrophage polarization and neutrophil infiltration against acute inflammation.

Toll-like receptor 2 (TLR2) mediated macrophages regulate the protective immune response to infectious microorganisms, but the aberrant activation of macrophages often leads to pathological inflammation, including tissue damage. In this study, we identified antagonists of TLR2 by screening 2100 natural products and subsequently identified Taspine, an aporphine alkaloid, as an excellent candidate. Furthermore, analysis of the 10 steps chemical synthesis route and structural optimization yielded the Taspine derivative SMU-Y6, which has higher activity, better solubility, and improved drug-feasible property. Mechanistic studies and seq-RNA analysis revealed that SMU-Y6 inhibited TLR2 over other TLRs, hindered the formation of TLR2/MyD88 complex, and blocked the downstream NF-κB and MAPK signaling pathway, thus suppressing the release of inflammatory cytokines. SMU-Y6 could stabilize TLR2 and bind to TLR2 protein with a Kd of 0.18 µmol/L. Additionally, SMU-Y6 could efficiently reverse the M1 phenotype macrophage polarization, reduce the production of cytokines as well as infiltration of neutrophiles and alleviate the local inflammation in mice with acute paw edema and colitis. Collectively, we reported the first aporphine alkaloid derivative that selectively inhibits TLR2 with high binding affinity and superior drug-feasible property, thus providing an urgently-needed molecular probe and potential drug candidate for inflammatory and autoimmune disease therapy.