Engineered probiotic Escherichia coli elicits immediate and long-term protection against influenza A virus in mice.

Influenza virus infection remains a major global health problem and requires a universal vaccine with broad protection against different subtypes as well as a rapid-response vaccine to provide immediate protection in the event of an epidemic outbreak. Here, we show that intranasal administration of probiotic Escherichia coli Nissle 1917 activates innate immunity in the respiratory tract and provides immediate protection against influenza virus infection within 1 day. Based on this vehicle, a recombinant strain is engineered to express and secret five tandem repeats of the extracellular domain of matrix protein 2 from different influenza virus subtypes. Intranasal vaccination with this strain induces durable humoral and mucosal responses in the respiratory tract, and provides broad protection against the lethal challenge of divergent influenza viruses in female BALB/c mice. Our findings highlight a promising delivery platform for developing mucosal vaccines that provide immediate and sustained protection against respiratory pathogens.

Iron-Catalyzed Multicomponent C-H Alkylation of in Situ Generated Imines via Photoinduced Ligand-to-Metal Charge Transfer.

Herein, we describe a novel photoinduced iron-catalyzed strategy for multicomponent C-H alkylation of in situ generated imines. By utilizing the alkyl radicals generated through iron-mediated photocatalytic C-H activation, the imines formed in situ are further subjected to addition reactions, resulting in the synthesis of various secondary and tertiary amine products. This method is simple to operate and does not require additional oxidants. It is applicable to inert alkane substrates such as cyclic alkanes, cyclic ethers, toluene, and ketones. The reaction is also compatible with various aromatic amines, alkyl amines, halogenated aromatic amines, as well as aromatic aldehydes, alkyl aldehydes, and cinnamaldehyde, among other different types of aldehydes.

Hyperactivation of SREBP induces pannexin-1-dependent lytic cell death.

Sterol-regulatory element binding proteins (SREBPs) are a conserved transcription factor family governing lipid metabolism. When cellular cholesterol level is low, SREBP2 is transported from the endoplasmic reticulum to the Golgi apparatus where it undergoes proteolytic activation to generate a soluble N-terminal fragment, which drives the expression of lipid biosynthetic genes. Malfunctional SREBP activation is associated with various metabolic abnormalities. In this study, we find that overexpression of the active nuclear form SREBP2 (nSREBP2) causes caspase-dependent lytic cell death in various types of cells. These cells display typical pyroptotic and necrotic signatures, including plasma membrane ballooning and release of cellular contents. However, this phenotype is independent of the gasdermin family proteins or mixed lineage kinase domain-like (MLKL). Transcriptomic analysis identifies that nSREBP2 induces expression of p73, which further activates caspases. Through whole-genome CRISPR-Cas9 screening, we find that Pannexin-1 (PANX1) acts downstream of caspases to promote membrane rupture. Caspase-3 or 7 cleaves PANX1 at the C-terminal tail and increases permeability. Inhibition of the pore-forming activity of PANX1 alleviates lytic cell death. PANX1 can mediate gasdermins and MLKL-independent cell lysis during TNF-induced or chemotherapeutic reagents (doxorubicin or cisplatin)-induced cell death. Together, this study uncovers a noncanonical function of SREBPs as a potentiator of programmed cell death and suggests that PANX1 can directly promote lytic cell death independent of gasdermins and MLKL.

Case report: Pathological complete response induced by immunochemotherapy in a case of Pulmonary Sarcomatoid Carcinoma staged IIIA-N2.

Pulmonary sarcomatoid carcinoma (PSC) represents a rare and highly aggressive variant of lung cancer, characterized by its recalcitrance to conventional therapeutic modalities and the attendant dismal prognosis it confers. Recent breakthroughs in immunotherapy have presented novel prospects for PSC patients; nevertheless, the utility of neoadjuvant/conversional immunotherapy in the context of PSC remains ambiguous. In this report, we present a middle-aged male presenting with Stage III PSC, notable for its high expression of the programmed death-ligand 1 (PD-L1), initially deemed as non-resectable for sizeable tumor mass and multiple lymph nodes metastases. The patient underwent a transformation to a resectable state after a regimen of three cycles of platinum-based chemotherapy plus immunotherapy. Following definitive surgical resection, the individual realized a pathological complete response (pCR), culminating in a significant prolongation of event-free survival (EFS). This case underscores the viability of employing immunochemotherapy as a neoadjuvant/conversional strategy for chosen cases of PSC.

Photoinduced decatungstate-catalyzed C(sp3)-H thioetherification by sulfinate salts.

Thiols and thioesters play crucial roles in pharmaceuticals, biology, and material science as essential organosulfur compounds. Leveraging readily available and cost-effective inert alkanes through direct thioetherification holds promise for yielding high-value-added products. Herein, we present a photoinduced strategy for sulfur-containing modification of inert alkanes utilizing decatungstate as hydrogen atom transfer reagent, offering a straightforward and practical approach for synthesizing thioethers and thioesters.

Difference in muscle metabolism caused by metabolism disorder of rainbow trout liver exposed to ammonia stress.

Ammonia pollution is an important environmental stress factors in water eutrophication. The intrinsic effects of ammonia stress on liver toxicity and muscle quality of rainbow trout were still unclear. In this study, we focused on investigating difference in muscle metabolism caused by metabolism disorder of rainbow trout liver at exposure times of 0, 3, 6, 9 h at 30 mg/L concentrations. Liver transcriptomic analysis revealed that short-term (3 h) ammonia stress inhibited carbohydrate metabolism and glycerophospholipid production but long-term (9 h) ammonia stress inhibited the biosynthesis and degradation of fatty acids, activated pyrimidine metabolism and mismatch repair, lead to DNA strand breakage and cell death, and ultimately caused liver damage. Metabolomic analysis of muscle revealed that ammonia stress promoted the reaction of glutamic acid and ammonia to synthesize glutamine to alleviate ammonia toxicity, and long-term (9 h) ammonia stress inhibited urea cycle, hindering the alleviation of ammonia toxicity. Moreover, it accelerated the consumption of flavor amino acids such as arginine and aspartic acid, and increased the accumulation of bitter substances (xanthine) and odorous substances (histamine). These findings provide valuable insights into the potential risks and hazards of ammonia in eutrophic water bodies subject to rainbow trout.

A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened.

The hedgehog (Hh) signaling pathway has long been a hotspot for anti-cancer drug development due to its important role in cell proliferation and tumorigenesis. However, most clinically available Hh pathway inhibitors target the seven-transmembrane region (7TM) of smoothened (SMO), and the acquired drug resistance is an urgent problem in SMO inhibitory therapy. Here, we identify a sterol analog Q29 and show that it can inhibit the Hh pathway through binding to the cysteine-rich domain (CRD) of SMO and blocking its cholesterylation. Q29 suppresses Hh signaling-dependent cell proliferation and arrests Hh-dependent medulloblastoma growth. Q29 exhibits an additive inhibitory effect on medulloblastoma with vismodegib, a clinically used SMO-7TM inhibitor for treating basal cell carcinoma (BCC). Importantly, Q29 overcomes resistance caused by SMO mutants against SMO-7TM inhibitors and inhibits the activity of SMO oncogenic variants. Our work demonstrates that the SMO-CRD inhibitor can be a new way to treat Hh pathway-driven cancers.

[Medication rules of Chinese herbal compound prescriptions for treating angina in national patent database based on multiple data mining].

This study explored the medication rules of Chinese herbal compound prescriptions for the treatment of angina based on the Chinese herbal compound patents in the patent database of the China National Intellectual Property Administration. The data of eligible Chinese herbal compound patents for the treatment of angina were collected from the patent database of the China National Intellectual Property Administration from database inception to November 10, 2022, and subjected to data modeling, analysis of main syndromes, medication frequency analysis, cluster analysis, association rule analysis, and data visualization by using Excel 2021, IBM SPSS Statistics 26.0, IBM SPSS Modeler 18.0, Cytoscape 3.9.1, and Rstudio R 4.2.2.2 to explore the medication rules for angina. The study included 636 pieces of patent data for angina that met the inclusion criteria, involving 815 drugs, with a total frequency of 6 586. The most common main syndromes were blood stasis obstructing the heart syndrome(222, 34.91%) and Qi deficiency and blood stasis syndrome(112, 17.61%). The top 10 most frequently used drugs were Salviae Miltiorrhizae Radix et Rhizoma, Chuanxiong Rhizoma, Notoginseng Radix et Rhizoma, Astragali Radix, Angelicae Sinensis Radix, Carthami Flos, Glycyrrhizae Radix et Rhizoma, Ginseng Radix et Rhizoma, Borneolum Syntheticum, and Corydalis Rhizoma. High-frequency drugs included blood-activating and stasis-resolving drugs(1 197, 18.17%) and deficiency-tonifying drugs(809, 12.28%). Cluster analysis identified eight drug combinations, including five new prescriptions suitable for clinical use and new drug development, and three drug pairs. The core drug combination of Salviae Miltiorrhizae Radix et Rhizoma-Chuanxiong Rhizoma-Carthami Flos was identified through the complex co-occurrence network analysis of Chinese medicines. Association rule analysis yielded a total of 17 rules, including 13 drug pairs and 4 tripartite combinations. Common drug pairs included Salviae Miltiorrhizae Radix et Rhizoma-Chuanxiong Rhizoma(support degree 25.79%, confidence coefficient 69.49%, lift 1.30) and Salviae Miltiorrhizae Radix et Rhizoma-Notoginseng Radix et Rhizoma(support degree 22.01%, confidence coefficient 61.95%, lift 1.16). Common tripartite combinations included Salviae Miltiorrhizae Radix et Rhizoma-Chuanxiong Rhizoma-Astragali Radix(support degree 10.85%, confidence coefficient 73.40%, lift 1.37) and Salviae Miltiorrhizae Radix et Rhizoma-Chuanxiong Rhizoma-Notoginseng Radix et Rhizoma(support degree 10.69%, confidence coefficient 79.07%, lift 1.48). The results showed that the underlying pathogenesis of angina involved blood stasis obstructing the heart and Qi deficiency and blood stasis. The overall nature of the disease was characterized as asthenia in origin and sthenia in superficiality. In the prescription formulation, blood-activating and stasis-resolving drugs, such as Salviae Miltiorrhizae Radix et Rhizoma, Chuanxiong Rhizoma, and Carthami Flos were often used to resolve the excess manifestation, which were combined with tonifying drugs such as Astragali Radix, Angelicae Sinensis Radix, Glycyrrhizae Radix et Rhizoma, and Ginseng Radix et Rhizoma to reinforce the deficiency. The syndrome, pathogenesis, disease nature, and medication were consistent with clinical practice. Additionally, the new compound prescriptions and drug combinations derived from the multiple data mining in this study could provide references and insights for the clinical diagnosis and treatment of angina and the development of new drugs.

The effects of casein kinase 2 interacting protein-1 on the growth and development of craniomaxillofacial soft and hard tissues in mice / 口腔疾病防治

Objective@# To investigate the effect of casein kinase 2 interacting protein-1 (CKIP-1) on craniofacial soft tissues and hard tissues, to provide the basis for the study and treatment of craniomaxillofacial related diseases.@*Methods@#6-month- old male CKIP-1 knockout (KO) mice were selected as the experimental group, and wild-type (WT) mice were selected as the control group. The craniomaxillofacial hard tissues (parietal bone, nasal bone, incisors and molars) were analyzed through micro- CT, and the morphological changes of maxillofacial soft tissues (nasal cartilage, lip mucosa and tongue) were analyzed through HE staining and toluidine blue staining.@* Results@#CKIP-1 negatively regulated bone mass of cancellous bone of cranial and maxillofacial bones and dentin mineralization. Compared with the WT mice, the thickness of the parietal baffle layer increased by 93% in KO mice, while cortical bone showed no significant difference between the two groups. The nasal cancellous bone thickness increased by 160% in KO-mice, while cortical bone showed no significant difference between the two groups; the enamel thickness was normal, but the pulp cavity became smaller and the dentin thickness increased by 48%. Compared with the WT mice, the HE staining and toluidine blue staining analyses of the soft tissues revealed that the thickness of the alar cartilage plate of KO mice increased by 57%, and local ossification was found within the cartilage plate. The thickness of the keratinized layer of the labial mucosa increased by 170% in KO mice and the muscle fiber diameter of the lingual muscle increased by 45%. @*Conclusion@#CKIP-1 genes have different effects on the growth and development of various soft and hard tissues in the maxillofacial region of mice.