Microbial gatekeepers: unraveling the role of the gut microbiota enzyme DPP4 in diabetes management.

Wang et al. identified dipeptidyl peptidase 4 (DPP4) as a gut microbe-derived enzyme that impacts on host glucose metabolism. They further introduced a novel therapeutic, daurisoline-d4 (Dau-d4), a selective microbial DPP4 (mDPP4) inhibitor that shows promise in improving glucose tolerance, highlighting the potential of therapies that target both host enzymes and gut microbial enzymes.

Bioinformatic Approaches Identify Hybrid Antibiotics against Tuberculosis via d-Amino Acid-Activating Adenylation Domains from Cordyceps militaris.

The development of tuberculosis (TB) therapy has been marked by the discovery of natural-product-derived streptomycin, followed by the introduction of NP-derived rifampicin, representing a significant milestone in the history of TB management. However, TB remains a global challenge, with the emergence of multidrug-resistant Mycobacterium tuberculosis highlighting the need for novel therapeutic agents. In this study, a bioinformatic approach was employed to investigate d-amino acid-activating adenylation domains, leading to the identification of cordysetin A (1), a novel trans-decalin tetramic acid antibiotic from the ascomycete fungi Cordyceps militaris. Cordysetin A (1) exhibits considerable activity against M. tuberculosis in vitro and in vivo while maintaining low cytotoxicity. These results reveal that the d-configuration of the amino acid within this hybrid polyketide-nonribosomal antibiotic is crucial for preserving its anti-tuberculosis efficacy. These findings emphasize the significant translational potential of cordysetin A as a promising candidate for TB treatment, furthering our understanding of bioinformatic approaches in the development of effective anti-tuberculosis agents.

Transcriptome sequencing and metabolome analysis reveal the metabolic reprogramming of partial hepatectomy and extended hepatectomy.

Surgical resection remains a critical treatment option for many patients with primary and secondary hepatic neoplasms. Extended hepatectomy (eHx) may be required for some patients with large tumors, which may cause liver failure and death. Partial hepatectomy (pHx) and eHx mouse models were constructed, liver tissues were sampled at 18, 36, and 72 h posthepatectomy. Transcriptome and metabolome analyses were employed to explore the different potential mechanisms in regeneration and injury between pHx and eHx. The results showed that eHx was associated with more severe liver injury and lower survival rates than pHx. Transcriptomics data showed there were 1842, 2129, and 1277 differentially expressed genes (DEGs) in eHx and 962, 1305, and 732 DEGs in pHx at 18, 36, and 72 h posthepatectomy, respectively, compared with the those in the sham groups. Compared with pHx, the number of DEGs in the eHx group reached a maximum of 230 at 18 h after surgery and decreased sequentially to 87 and 43 at 36 and 72 h. Metabolomics analysis identified a total of 1399 metabolites, and 48 significant differentially produced metabolites (DPMs) were screened between eHx and pHx. Combined analysis of DEGs and DPMs indicated that cholesterol metabolism and insulin resistance may be two important pathways for liver regeneration and mouse survival postextended hepatectomy. Our results showed the global influence of pHx and eHx on the transcriptome and metabolome in mouse liver, and revealed cholesterol metabolism and insulin resistance pathways might be involved in regeneration post-pHx and -eHx.

Generation and Screening of Antigen-Specific Nanobodies from Mammalian Cells Expressing the BCR Repertoire Library Using Droplet-Based Microfluidics.

Nanobodies, also known as VHHs, originate from the serum of Camelidae. Nanobodies have considerable advantages over conventional antibodies, including smaller size, more modifiable, and deeper tissue penetration, making them promising tools for immunotherapy and antibody-drug development. A high-throughput nanobody screening platform is critical to the rapid development of nanobodies. To date, droplet-based microfluidic systems have exhibited improved performance compared to the traditional phage display technology in terms of time and throughput. In realistic situations, however, it is difficult to directly apply the technology to the screening of nanobodies. Requirements of plasma cell enrichment and high cell viability, as well as a lack of related commercial reagents, are leading causes for impeding the development of novel methods. We overcame these obstacles by constructing a eukaryotic display system that secretes nanobodies utilizing homologous recombination and eukaryotic transformation technologies, and the significant advantages are that it is independent of primary cell viability and it does not require plasma cell enrichment in advance. Next, a signal capture system of "SA-beads + Biotin-antigen + nanobody-6 × His + fluorescence-labeled anti-6 × His (secondary antibody)" was designed for precise localization of the eukaryotic-expressed nanobodies in a droplet. Based on this innovation, we screened 293T cells expressing anti-PD-L1 nanobodies with a high positive rate of targeted cells (up to 99.8%). Then, single-cell transcriptomic profiling uncovered the intercellular heterogeneity and BCR sequence of target cells at a single-cell level. The complete complementarity determining region (CDR3) structure was obtained, which was totally consistent with the BCR reference. This study expanded the linkage between microfluidic technology and nanobody applications and also showed potential to accelerate the rapid transformation of nanobodies in the large-scale market.

Detection performance of PCR for Legionella pneumophila in environmental samples: a systematic review and meta-analysis.

BACKGROUND: Legionellosis remains a public health problem. The most common diagnostic method to detect Legionella pneumophila (L. pneumophila) is culture. Polymerase chain reaction (PCR) is a fast and accurate method for this detection in environmental samples. METHODS: Four databases were searched for studies that evaluated the detection efficiency of PCR in L. pneumophila. The quality evaluation was conducted using Review Manager 5.3. We used Meta-DiSc 1.4 software and the Stata 15.0 software to create forest plots, a meta-regression, a bivariate boxplot and a Deeks' funnel plot. RESULTS: A total of 18 four-fold tables from 16 studies were analysed. The overall pooled sensitivity and specificity of PCR was 94% and 72%, respectively. The positive likelihood ratio (RLR) and negative likelihood ratio (NLR) was 2.73 and 0.12, respectively. The result of the diagnostic odds ratio (DOR) was 22.85 and the area under the curve (AUC) was 0.7884. CONCLUSION: Establishing a laboratory diagnostic tool for L. pneumophila detection is important for epidemiological studies. In this work, PCR demonstrated a promising diagnostic accuracy for L. pneumophila.

Hydrogen abstraction/addition reactions in soot surface growth.

The hydrogen abstraction (HB) and addition reactions (HD) by H radicals are examined on a series of polycyclic aromatic hydrocarbon (PAH) monomers and models of quasi-surfaces using quasi-classical trajectory (QCT) method. QCT results reproduce the rate constants of HB reactions on PAH monomers from density functional theory (DFT) in the range of 1500-2700 K. The PAH size has a minor impact on the rates of HB reactions, especially at temperatures beyond 2100 K. In contrast, HD reactions have a clear size dependence, and a larger PAH yields a higher rate. It was also found that the preferred reaction pathway changes from HB to HD reactions at ∼1900 K. The rates of surface HB and HD reactions exceed those in the gas phase by nearly one factor of magnitude. Further analysis of the detailed trajectory of the QCT method reveals that about 50% of surface reactions can be attributed to the events of surface diffusion, which depends on the local energy transfer in gas-surface interactions. However, this phenomenon is not preferred in PAH monomers, as expected. Our finding here questions the treatment of the surface reactions of soot as the product of the first collision between the gaseous species and particle surface. The surface diffusion-induced reactions should be accounted for in the rates of the surface HB and HD reactions. The rate constants of HB and HD reactions on each reactive site (surface zig-zag, surface free-edge and pocket free-edge sites) were calculated by QCT method, and are recommended for the further development of surface chemistry models in soot formation.

Ochraceopetalin, a Mixed-Biogenetic Salt of Polyketide and Amino Acid Origins from a Marine-Derived Aspergillus ochraceopetaliformis Fungus.

Ochraceopetalin (1), a mixed-biogenetic salt compound and its component 2 were isolated from the culture broths of a marine-derived fungus, Aspergillus ochraceopetaliformis. Based on combined spectroscopic and chemical analyses, the structure of 1 was determined to be a sulfonated diphenylether-aminol-amino acid ester guanidinium salt of an unprecedented structural class, while 2 was determined to be the corresponding sulfonated diphenylether. Ochraceopetaguanidine (3), the other guanidine-bearing aminol amino acid ester component, was also prepared and structurally elucidated. Compound 1 exhibited significant cytotoxicity against K562 and A549 cells.

miR-340 Alleviates Psoriasis in Mice through Direct Targeting of IL-17A.

Th17 cell is a well-known lineage of CD4+ effector Th cells that selectively produce IL-17A and play critical roles during the pathogenesis of autoimmune disease. A microRNA (miRNA) is a small noncoding RNA molecule that functions in posttranscriptional regulation of gene expression. Recently, an increasing number of studies have demonstrated that multiple miRNAs are dysregulated in patients with various autoimmune diseases and mediate autoimmune disease pathologic condition at least in part through the regulation of Th17 response. However, among the few miRNAs identified so far that play possible roles in the differentiation of Th17 cells, they all regulate the Th17 response through targeting negative or positive regulators of Th17 differentiation. In the current study, we sought to identify new miRNAs that can directly regulate the expression of IL-17A, the most important cytokine produced by Th17 cells. Our results showed that the 3' untranslated region of mouse IL-17A can act as a negative regulatory element to downregulate gene expression. Further study revealed that miR-340 can specifically bind to the 3' untranslated region of mouse IL-17A and downregulate the expression of endogenous IL-17A. More importantly, we demonstrated that treatment with miR-340 alleviates the clinical severity of imiquimod-induced psoriasis in mice through the downregulation of IL-17A. These data indicate that miR-340 may be a useful therapeutic target for the treatment of psoriasis and other IL-17A-mediated autoimmune diseases.

Antitumor Activity of Asperphenin A, a Lipopeptidyl Benzophenone from Marine-Derived Aspergillus sp. Fungus, by Inhibiting Tubulin Polymerization in Colon Cancer Cells.

Marine-derived microorganisms are a valuable source of novel bioactive natural products. Asperphenin A is a lipopeptidyl benzophenone metabolite isolated from large-scale cultivation of marine-derived Aspergillus sp. fungus. The compound has shown potent antiproliferative activity against various cancer cells. However, the underlying mechanism of action remained to be elucidated. In this study, we demonstrated the antitumor activity and molecular mechanism of asperphenin A in human colon cancer cells for the first time. Asperphenin A inhibited the growth of colon cancer cells through G2/M cell cycle arrest followed by apoptosis. We further discovered that asperphenin A can trigger microtubule disassembly. In addition to its effect on cell cycle, asperphenin A-induced reactive oxygen species. The compound suppressed the growth of tumors in a colon cancer xenograft model without any overt toxicity and exhibited a combination effect with irinotecan, a topoisomerase I inhibitor. Moreover, we identified the aryl ketone as a key component in the molecular structure responsible for the biological activity of asperphenin A using its synthetic derivatives. Collectively, this study has revealed the antiproliferative and antitumor mechanism of asperphenin A and suggested its possibility as a chemotherapeutic agent and lead compound with a novel structure.

Discovery of Three New Phytotoxins from the Fungus Aspergillus nidulans by Pathway Inactivation.

Fungi are a source of novel phytotoxic compounds to be explored in the search for effective and environmentally safe herbicides. The genetic inactivation of the biosynthetic pathway of the new phytotoxin cichorine has led to the isolation of three novel phytotoxins from the fungus Aspergillus nidulans: 8-methoxycichorine (4), 8-epi-methoxycichorine (5), and N-(4'-carboxybutyl) cichorine (6). The structure of the new compounds was clearly determined by a combination of nuclear magnetic resonance (NMR) analysis and high-resolution electrospray ionization (HRESIMS). The phytotoxic bioassay was studied on leaves from Zea mays and Medicago polymorpha L. at the concentration of 5 × 10-3 M by using a moist chamber technique. Novel phytotoxins 8-methoxycichorine (4), 8-epi-methoxycichorine (5), and N-(4'-carboxybutyl) cichorine (6) exhibited a better phytotoxic effect than cichorine.

Alkaloidal metabolites from a marine-derived Aspergillus sp. fungus.

Fumiquinazoline S (1), a new quinazoline-containing alkaloid, and the known fumiquinazolines F (6) and L (7) of the same structural class were isolated from the solid-substrate culture of an Aspergillus sp. fungus collected from marine-submerged wood. In addition, isochaetominines A-C (2-4) and 14-epi-isochaetominine C (5), new alkaloids possessing an unusual amino acid-based tetracyclic core framework related to the fumiquinazolines, were isolated from the same fungal strain. The structures of these compounds were determined by combined spectroscopic methods, and the absolute configurations were assigned by NOESY, ROESY, and advanced Marfey's analyses along with biogenetic considerations. The new compounds exhibited weak inhibition against Na(+)/K(+)-ATPase.

Lumazine peptides from the marine-derived fungus Aspergillus terreus.

Terrelumamides A (1) and B (2), two new lumazine-containing peptides, were isolated from the culture broth of the marine-derived fungus Aspergillus terreus. From the results of combined spectroscopic and chemical analyses, the structures of these compounds were determined to be linear assemblies of 1-methyllumazine-6-carboxylic acid, an amino acid residue and anthranilic acid methyl ester connected by peptide bonds. These new compounds exhibited pharmacological activity by improving insulin sensitivity, which was evaluated in an adipogenesis model using human bone marrow mesenchymal stem cells. In addition, the compounds exhibited fluorescence changes upon binding to DNA, demonstrating their potential applications to DNA sequence recognition.

Penicillipyrones A and B, meroterpenoids from a marine-derived Penicillium sp. fungus.

Penicillipyrones A (1) and B (2), two novel meroterpenoids, were isolated from the marine-derived fungus Penicillium sp. On the basis of the results of combined spectroscopic analyses, these compounds were structurally elucidated to be sesquiterpene γ-pyrones from a new skeletal class derived from a unique linkage pattern between the drimane sesquiterpene and pyrone moieties. Compound 2 elicited significant induction of quinone reductase.

Quantification and identification of bioactive metabolites from Kalopanacis Cortex by HPLC with evaporative light scattering detection and ESI quadrupole TOF MS.

A method based on HPLC coupled with an evaporative light scattering detection and ESI quadrupole TOF MS was established for the quantification and identification of phenolics and triterpene saponins in Kalopanacis Cortex using a gradient elution of acetonitrile with 0.1% formic acid and water with 0.1% formic acid on an RP C18 column (4.6 × 250 mm, 5 µm). Diverse validation parameters, such as the linearity, LOD and LOQ, accuracy, precision, repeatability, and stability, were successfully obtained. Additionally, the efficiencies of different extraction methods were compared. The developed method was applied for the quantitative analysis of twelve representative metabolites in 61 Kalopanacis Cortex samples. The quantitation results showed that coniferin, kalopanaxsaponin C, septemlosides II, III, C, and D exhibited distinct regional patterns in Kalopanacis Cortex samples. These six compounds including one new triterpene saponin show potential as marker compounds for evaluating the quality of Kalopanacis Cortex and the geographical variation in its chemical composition.

Identification and validation of immune and cuproptosis - related genes for diabetic nephropathy by WGCNA and machine learning.

Background: As the leading cause of chronic kidney disease, diabetic kidney disease (DKD) is an enormous burden for all healthcare systems around the world. However, its early diagnosis has no effective methods. Methods: First, gene expression data in GEO database were extracted, and the differential genes of diabetic tubulopathy were obtained. Immune-related genesets were generated by WGCNA and immune cell infiltration analyses. Then, differentially expressed immune-related cuproptosis genes (DEICGs) were derived by the intersection of differential genes and genes related to cuproptosis and immune. To investigate the functions of DEICGs, volcano plots and GO term enrichment analysis was performed. Machine learning and protein-protein interaction (PPI) network analysis helped to finally screen out hub genes. The diagnostic efficacy of them was evaluated by GSEA analysis, receiver operating characteristic (ROC) curve, single-cell RNA sequencing and the Nephroseq website. The expression of hub genes at the animal level by STZ -induced and db/db DKD mouse models was further verified. Results: Finally, three hub genes, including FSTL1, CX3CR1 and AGR2 that were up-regulated in both the test set GSE30122 and the validation set GSE30529, were screened. The areas under the curve (AUCs) of ROC curves of hub genes were 0.911, 0.935 and 0.922, respectively, and 0.946 when taking as a whole. Correlation analysis showed that the expression level of three hub genes demonstrated their negative relationship with GFR, while those of FSTL1 displayed a positive correlation with the level of serum creatinine. GSEA was enriched in inflammatory and immune-related pathways. Single-nucleus RNA sequencing indicated the main distribution of FSTL1 in podocyte and mesangial cells, the high expression of CX3CR1 in leukocytes and the main localization of AGR2 in the loop of Henle. In mouse models, all three hub genes were increased in both STZ-induced and db/db DKD models. Conclusion: Machine learning was combined with WGCNA, immune cell infiltration and PPI analyses to identify three hub genes associated with cuproptosis, immunity and diabetic nephropathy, which all have great potential as diagnostic markers for DKD and even predict disease progression.

Biosafety and biosecurity: treading China's synbio tightrope.

Our second piece dissects China's intricate balancing act in synthetic biology (synbio), analyzing its adept maneuvering between fostering innovation and imposing strict regulations. The priority is enhancing biosecurity, biosafety, and public trust, crucial for sustainable gene editing advancements and preventing potential misuse of synthetic viruses.

Intellectual property and funding: fueling Chinese synbio.

As China emerges as a synthetic biology (synbio) global leader, it faces distinct science-society challenges. Our series offers a snapshot of China's synbio state, emphasizing the intersection and its policy implications. The debut piece elucidates the intellectual property rights (IPR)-funding interplay in China's expanding synbio territory, underlining its key role in driving innovation and commercialization.

Cinnamaldehyde: An effective component of Cinnamomum cassia inhibiting Helicobacter pylori.

ETHNOPHARMACOLOGICAL RELEVANCE: Cinnamomum cassia Presl (Cinnamomum cassia) is a common traditional Chinese medicine, which can promote the secretion and digestion of gastric juice, improve the function of gastrointestinal tract. Cinnamaldehyde (CA) is a synthetic food flavoring in the Chinese Pharmacopoeia. AIM OF THE STUDY: This study aimed to search for the active ingredient (CA) of inhibiting H. pylori from Cinnamomum cassia, and elucidate mechanism of action, so as to provide the experimental basis for the treatment of H. pylori infection with Cinnamomum cassia. MATERIALS AND METHODS: It's in vitro and in vivo pharmacological properties were evaluated based on minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and an acute gastric inflammation model in mice infected with H. pylori. Drug safety was evaluated using the CCK8 method and high-dose administration in mice. The advantageous characteristics of CA in inhibiting H. pylori were confirmed using acidic conditions and in combination with the antibiotics. The mechanism underlying the action of CA on H. pylori was explored using scanning electron microscopy (SEM), adhesion experiments, biofilm inhibition tests, ATP and ROS release experiments, and drug affinity responsive target stability (DARTS) screening of target proteins. The protein function and target genes were verified by molecular docking and Real-Time quantitative reverse transcription PCR (qRT-PCR). RESULTS: The results demonstrated that CA was found to be the main active ingredient against H. pylori in Cinnamomum cassia in-vitro tests, with a MIC of 8-16 µg/mL. Moreover, CA effectively inhibited both sensitive and resistant H. pylori strains. The dual therapy of PPI + CA exhibited remarkable in vivo efficacy in the acute gastritis mouse model, superior to the standard triple therapy. DARTS, molecular docking, and qRT-PCR results suggested that the target sites of action were closely associated with GyrA, GyrB, AtpA, and TopA, which made DNA replication and transcription impossible, then leading to inhibition of bacterial adhesion and colonization, suppression of biofilm formation, and inhibition ATP and enhancing ROS. CONCLUSIONS: This study demonstrated the suitability of CA as a promising lead drug against H. pylori, The main mechanisms can target GyrA ect, leading to reduce ATP and produce ROS, which induces the apoptosis of bacterial.

Cytotoxic diterpenoid pseudodimers from the Korean sponge Phorbas gukhulensis.

Four new cytotoxic diterpenoid pseudodimers (2-5), along with a previously reported one, gukulenin A (1), were isolated from the marine sponge Phorbas gukhulensis collected off the coast of Gagu-do, Korea. These novel compounds, designated gukulenins C-F (2-5), were determined by extensive spectroscopic analyses to be pseudodimers of the gagunins, like gukulenin A. The termini of the tropolone-containing side chains in gukulenins C-E (2-4) were found to have diverse modifications involving acetamides or taurine, whereas gukulenin F (5) was formed from 1 by the ring-opening of a cyclic hemiketal. The relative and absolute configurations were assigned by Murata's and modified Snatzke's methods using a HETLOC experiment and a CD measurement of a dimolybdenum complex, respectively. All of these compounds exhibited significant cytotoxicity against the K562 and A549 cell lines.

Ethics and engagement: steering China's synbio future.

In the final article of the series, we delve into the crucial role of public engagement and ethical guidelines in shaping the trajectory of synthetic biology (synbio) within China's evolving scientific landscape. We discuss the interconnectedness of enhanced public discourse, stronger ethics, and responsible, transparent advancements in the field.