Naoxintong capsule for treating cardiovascular and cerebrovascular diseases: from bench to bedside.

Naoxintong Capsule (NXT), a renowned traditional Chinese medicine (TCM) formulation, has been broadly applied in China for more than 30 years. Over decades, accumulating evidences have proven satisfactory efficacy and safety of NXT in treating cardiovascular and cerebrovascular diseases (CCVD). Studies have been conducted unceasingly, while this growing latest knowledge of NXT has not yet been interpreted properly and summarized comprehensively. Hence, we systematically review the advancements in NXT research, from its chemical constituents, quality control, pharmacokinetics, to its profound pharmacological activities as well as its clinical applications in CCVD. Moreover, we further propose specific challenges for its future perspectives: 1) to precisely clarify bioactivities of single compound in complicated mixtures; 2) to evaluate the pharmacokinetic behaviors of NXT feature components in clinical studies, especially drug-drug interactions in CCVD patients; 3) to explore and validate its multi-target mechanisms by integrating multi-omics technologies; 4) to re-evaluate the safety and efficacy of NXT by carrying out large-scale, multicenter randomized controlled trials. In brief, this review aims to straighten out a paradigm for TCM modernization, which help to contribute NXT as a piece of Chinese Wisdom into the advanced intervention strategy for CCVD therapy.

Global emergence of double and multi-carbapenemase producing organisms: epidemiology, clinical significance, and evolutionary benefits on antimicrobial resistance and virulence.

Redundant carbapenemase-producing (RCP) bacteria, which carry double or multiple carbapenemases, represent a new and concerning phenomenon. The objective of this study is to conduct a comprehensive analysis of the epidemiology and genetic mechanisms of RCP strains to support targeted surveillance and control measures. A retrospective analysis was conducted using surveillance data from 277 articles. Statistical analysis was performed to determine and evaluate species prevalence, proportions of carbapenemases, antibiotic susceptibility profiles, sample information, and patient outcomes. Complete plasmid sequencing data were utilized to investigate potential antimicrobial resistance or virulence advantages that strains may gain from acquiring redundant carbapenemases. RCP bacteria are widely distributed globally, and their prevalence is increasing over time. Several countries, including China, India, Iran, Turkey, and South Korea, have reported more than 100 RCP strains. The most commonly reported RCP species are Klebsiella pneumoniae and Acinetobacter baumannii, which exhibit varying proportions of carbapenemase combinations. Certain species-carbapenemase combinations, such as K. pneumoniae carrying New Delhi metallo-ß-lactamase (NDM) + oxacillinase (OXA) (56.76%) and K. pneumoniae carbapenemase (KPC) + Verona integron-encoded metallo-ß-lactamase (VIM) (50.00%) carbapenemases, are associated with high mortality rates. In patients with RCP strains isolated from the bloodstream and respiratory system, the mortality rates are 58.70% and 69.23%, respectively. Analysis of plasmids from RCP strains suggests that they may acquire additional antibiotic resistance phenotypes and virulence factors. Carbapenem-resistant bacteria carrying redundant carbapenemases pose a significant global health threat. This study provides valuable insights into the epidemiology and genetic mechanisms of these bacteria, supporting the development of effective control and prevention strategies to mitigate their transmission.IMPORTANCEThis study examined the global distribution patterns of 1,780 bacteria with double or multiple carbapenemases from 277 articles and assessed their clinical impact. The presence of multiple carbapenemases increases the chances of co-resistance to other classes of antibiotics and more virulence factors, further complicating the clinical management of infections.

Involvement of S100A6/S100A11 in T-Cell Immune Regulatory in HCC Revealed by Single Cell RNA-seq.

Background: Immunotherapy plays a significant role in the treatment of hepatocellular carcinoma (HCC). Members of the S100 protein family (S100s) have been widely implicated in the pathogenesis and progression of tumors. However, the exact mechanism by which S100s contribute to tumor immunity remains unclear. Methods: To explore the role of S100s in HCC immune cells, we collected and comparatively analyzed single-cell RNA sequencing (scRNA-seq) data of HCC and hepatitis B virus-associated HCC. By mapping cell classification and searching for S100s binding targets and downstream targets. Results: S100A6/S100A11 was differentially expressed in tumor T cells and involved in the nuclear factor (NF) κB pathway. Further investigation of the TCGA dataset revealed that patients with low S100A6/S100A11 expression had a better prognosis. Temporal cell trajectory analysis showed that the activation of the NF-κB pathway is at a critical stage and has an important impact on the tumor microenvironment. Conclusion: Our study revealed that S100A6/S100A11 could be involved in regulating the differentiation and cellular activity of T-cell subpopulations in HCC, and its low expression was positively correlated with prognosis. It may provide a new direction for immunotherapy of HCC and a theoretical basis for future clinical applications.

Bifidobacterium modulation of tumor immunotherapy and its mechanism.

The advent of tumor immunotherapy in patients has revolutionized the treatment of tumors and significantly improved survival rates for a wide range of tumors. However, the full therapeutic potential of immune checkpoint inhibitors (ICIs) has yet to be realized, as not all patients have a lasting survival benefit from them, and a significant proportion of patients show primary or acquired resistance to immunotherapy. Bifidobacterium is one of the most common probiotics, and its antitumor and immunomodulatory effects have been demonstrated in recent years, but its immunomodulatory effects in tumors, especially on ICIs and in combination, have not been extensively studied in clinical practice, and its effects on the immune system and the mechanisms that modulate immunotherapy are largely unknown. Therefore, this review will focus on the immunomodulatory effects of Bifidobacteria in malignancies and the possible mechanisms of action of Bifidobacteria on immunotherapy in the hope of providing a basis for further research and better application of Bifidobacteria in clinical practice.

Metagenomic analysis of individual mosquito viromes reveals the geographical patterns and drivers of viral diversity.

Mosquito transmitted viruses are responsible for an increasing burden of human disease. Despite this, little is known about the diversity and ecology of viruses within individual mosquito hosts. Here, using a meta-transcriptomic approach, we determined the viromes of 2,438 individual mosquitoes (81 species), spanning ~4,000 km along latitudes and longitudes in China. From these data we identified 393 viral species associated with mosquitoes, including 7 (putative) species of arthropod-borne viruses (that is, arboviruses). We identified potential mosquito species and geographic hotspots of viral diversity and arbovirus occurrence, and demonstrated that the composition of individual mosquito viromes was strongly associated with host phylogeny. Our data revealed a large number of viruses shared among mosquito species or genera, enhancing our understanding of the host specificity of insect-associated viruses. We also detected multiple virus species that were widespread throughout the country, perhaps reflecting long-distance mosquito dispersal. Together, these results greatly expand the known mosquito virome, linked viral diversity at the scale of individual insects to that at a country-wide scale, and offered unique insights into the biogeography and diversity of viruses in insect vectors.

A Germinal Center Checkpoint of AIRE in B Cells Limits Antibody Diversification.

In response to antigens, B cells undergo affinity maturation and class switching mediated by activation-induced cytidine deaminase (AID) in germinal centers (GCs) of secondary lymphoid organs, but uncontrolled AID activity can precipitate autoimmunity and cancer. The regulation of GC antibody diversification is of fundamental importance but not well understood. We found that autoimmune regulator (AIRE), the molecule essential for T cell tolerance, is expressed in GC B cells in a CD40-dependent manner, interacts with AID and negatively regulates antibody affinity maturation and class switching by inhibiting AID function. AIRE deficiency in B cells caused altered antibody repertoire, increased somatic hypermutations, elevated autoantibodies to T helper 17 effector cytokines and defective control of skin Candida albicans. These results define a GC B cell checkpoint of humoral immunity and illuminate new approaches of generating high-affinity neutralizing antibodies for immunotherapy.

Regulation of Mycobacterium biofilm development and novel measures against antibiotics resistance.

Currently, there are over 170 recognized species of Mycobacterium, the only genus in the family Mycobacteriaceae. Organisms belonging to this genus are quite diverse with respect to their ability to cause disease in humans. The Mycobacterium genus includes human pathogens (Mycobacterium tuberculosis complex and Mycobacterium leprae) and environmental microorganisms known as non-tuberculosis mycobacteria (NTM). A common pathogenic factor of Mycobacterium is the formation of biofilms. Bacterial biofilms are usually defined as bacterial communities attached to the surface, and are also considered as shared spaces of encapsulated microbial cells, including various extracellular polymeric substrates (EPS), such as polysaccharides, proteins, amyloid proteins, lipids, and extracellular DNA (EDNA), as well as membrane vesicles and humic like microorganisms derived refractory substances. The assembly and dynamics of the matrix are mainly coordinated by second messengers, signaling molecules, or small RNAs. Fully deciphering how bacteria provide structure for the matrix, thereby promoting extracellular reactions and benefiting from them, remains a challenge for future biofilm research. This review introduces a five step development model for biofilms and a new model for biofilm formation, analyses the pathogenicity of biofilms, their interactions with bacteriophages and host immune cells, and the key genes and regulatory networks of mycobacterial biofilms, as well as mycobacterial biofilms and drug resistance, in order to provide a basis for clinical treatment of diseases caused by biofilms.

Metagenomic analysis of individual mosquitos reveals the ecology of insect viruses.

Mosquito transmitted viruses are responsible for an increasing burden of human disease. Despite this, little is known about the diversity and ecology of viruses within individual mosquito hosts. Using a meta-transcriptomic approach, we analysed the virome of 2,438 individual mosquitos (79 species), spanning ~4000 km along latitudes and longitudes in China. From these data we identified 393 core viral species associated with mosquitos, including seven (putative) arbovirus species. We identified potential species and geographic hotspots of viral richness and arbovirus occurrence, and demonstrated that host phylogeny had a strong impact on the composition of individual mosquito viromes. Our data revealed a large number of viruses shared among mosquito species or genera, expanding our knowledge of host specificity of insect-associated viruses. We also detected multiple virus species that were widespread throughout the country, possibly facilitated by long-distance mosquito migrations. Together, our results greatly expand the known mosquito virome, linked the viral diversity at the scale of individual insects to that at a country-wide scale, and offered unique insights into the ecology of viruses of insect vectors.

Efficient in-situ conversion of low-concentration carbon dioxide in exhaust gas using silver nanoparticles in N-heterocyclic carbene polymer.

Efficient utilizing CO2 is crucial approaches in achieving carbon neutralization. One of the challenges lies in the in-situ conversion of low concentration CO2 found in waste gases. This study introduces a novel heterogeneous catalyst known as silver nanoparticles in porous N-heterocyclic carbene polymer (Ag@POP-NL-3). The catalyst is synthesized via a streamlined pre-coordination method. Ag@POP-NL-3 exhibits uniform distribution of silver nanoparticles, a porous structure and nitrogen activation groups. It demonstrates high efficiency and selectivity in absorbing and activating CO2 and enabling the conversion of low concentration CO2 (30 vol%) from lime kiln waste gas into cyclic carbonate under mild conditions. This catalytic system achieves both CO2 capture and resource utilization of CO2 simultaneously, effectively fixing low-concentration CO2 from waste gases into C2+ valuable chemicals. This approach elegantly addresses two goals in one solution.

The clinicopathological significance and potential function of ULK1 in colon cancer.

Uncoordinated 51-like kinase 1 (ULK1) is an essential part involved in autophagy to maintain cell viability and homeostasis. Herein, the expression levels of ULK1 in colon cancer (CC) were investigated, and its clinicopathological features and potential function were analyzed. Data of ULK1 were obtained from a public database. UCSC XENA RNAseq data were uniformly processed by using the Toil process. STRING was employed for identification of co-expression genes and development of PPI networks whose interaction scores exceeded 0.4. The level of immune cells for tumor infiltration was calculated by means of single-sample GSEA (ssGSEA) on the basis of mRNA data of CC. The ULK1 expression was upregulated compared with both paired and unpaired normal tissues. The mRNA expression of ULK1 was upregulated in CC patients with lymph node metastasis, lymphatic invasion, and pathological stages of 3 and 4. The disease-specific survival (DSS), progression-free interval (PFI), and the overall survival (OS) of patients with upregulated mRNA expression of ULK1 were drastically reduced. Functionally, any changes related to the biological process of ULK1 may be related to macroautophagy, autophagosome organization and autophagosome assembly. As a co-expressed gene (CEG), ATG101 was up-regulated in CC tissues and indicated poor survival. ULK1 is closely related to immune cells. ULK1 expression is upregulated in CC cells and upregulation of ULK1 may serve as an accurate prognostic factor, thereby providing novel intervention targets for therapy.

Embelin protects against apoptosis and inflammation by regulating PI3K/Akt signaling in IL-1ß-stimulated human nucleus pulposus cells.

Embelin is a natural benzoquinone compound that displays a beneficial effect in various inflammatory-related diseases. However, the effect of embelin on degeneration of intervertebral disc (IDD), a chronic inflammatory disorder, has not been reported. This study was attempted to explore the therapeutic action of embelin on IDD in vitro. Network pharmacology analysis was performed for evaluating the link between embelin and IDD. The human nucleus pulposus cells (NPCs) were stimulated with IL-1ß to induce inflammation. Cell viability of NPCs was assessed by CCK-8 assay. Western blotting was conducted to detect the expression levels of PI3K, p-PI3K, Akt, p-Akt, cleaved caspase-3, caspase-3, Bax, Bcl-2, p65 and p-p65. Apoptotic deaths of NPCs were examined by TUNEL assay. The production of COX-2, IL-6, IL-8, and TNF-α was examined by ELISA. It can be seen that 16 overlapping genes were selected from 109 possible targets of embelin and 342 possible targets of IDD. KEGG pathway enrichment analysis showed that the PI3K/Akt signaling pathway was a close link between embelin and IDD. We found that embelin dose-dependently improved the cell viability in IL-1ß-stimulated NPCs. Embelin elevated the relative levels of p-PI3K/PI3K and p-Akt/Akt in IL-1ß-stimulated NPCs. IL-1ß induced a significant increase in apoptotic deaths of NPCs, which was attenuated by embelin treatment. IL-1ß-induced alternations in expression levels of apoptotic-related proteins including cleaved caspase-3, Bax and Bcl-2 were prevented by embelin treatment. Pretreatment with LY294002 (an inhibitor of PI3K) reversed the inhibitory effect of embelin on IL-1ß-induced apoptosis in NPCs. Embelin treatment caused inhibitory effects on the IL-1ß-stimulated production of COX-2, IL-6, IL-8, and TNF-α, which were abolished by LY294002 treatment. Furthermore, embelin treatment prevented IL-1ß-induced phosphorylation of p65 in NPCs, while LY294002 elevated the embelin-caused decrease in p-p65/p65 level. Overall, embelin protected human NPCs against IL-1ß-stimulated apoptosis and inflammation by regulating the PI3K/Akt signaling pathway. These findings provided new ideas for the clinical usage of embelin in the prevention and treatment of IDD.

Effects of selenium supplementation on concurrent chemoradiotherapy in patients with cervical cancer: A randomized, double-blind, placebo-parallel controlled phase II clinical trial.

Objective: Selenium (Se) is an essential trace element and may affect cervical cancer occurrence and progression. The association between selenium supplementation and acute toxic reactions and clinical outcomes in patients with locally advanced cervical cancer treated with concurrent chemoradiotherapy remains unclear. The aim of this study was to determine the safety profile of add-on Se yeast and assess the potential of Se to ameliorate the hematologic toxicity of concurrent chemoradiotherapy in patients with cervical cancer. Methods: Patients with Federation International of Gynecology and Obstetrics (FIGO) stage IIB cervical cancer who met all inclusion criteria were randomly assigned to either the experimental group or the control group. The experimental group received Se yeast tablets (100 µg Se, twice daily), while the control group received placebos (twice daily) for 5 weeks in total. All patients in both groups received standard treatment, including pelvic external irradiation, concurrent five cycles of chemotherapy, and brachytherapy. Measures included the incidence of myelosuppression, impairment of liver and kidney function, objective response rate (ORR), and blood Se concentrations before, during and after the treatment of the two groups. Results: A total of 104 eligible patients were enrolled in the experimental group (n = 50) or the control group (n = 54). The ORR in the experimental group and control group were 96 and 94%, respectively (p = 0.47). The baseline levels of blood Se before treatment in the experimental and control groups were similar (58.34 ± 17.63 µg/L and 60.21 ± 18.42 µg/L, p = 0.60), but the concentrations became significantly different after course completion between the two groups (76.16 ± 24.47 µg/L and 57.48 ± 14.92 µg/L, respectively, p < 0.01). Se dramatically decreased the incidence of grade 3 myelosuppression (48% vs. 63%, p = 0.034) compared to the control group. In the subgroup of patients with moderately well-differentiated cervical cancer, the incidence of thrombocytopenia induced by concurrent chemoradiotherapy was lower in the experimental group than in the control group (53.8% vs. 78.9%, p < 0.01). However, no difference was observed in liver and kidney injuries between the two groups. Conclusion: Supplementation with Se effectively increased blood Se levels in Se-inadequate cervical cancer patients. As an add-on to standard treatment, Se-yeast significantly decreased the hematologic toxicity of concurrent chemoradiotherapy.

Direct Conversion of CO2 in Lime Kiln Waste Gas Catalyzed by a Copper-Based N-heterocyclic Carbene Porous Polymer.

Industrial waste gas is one of the major sources of atmospheric CO2 , yet the direct conversion of the low concentrations of CO2 in waste gases into high value-added chemicals have been a great challenge. Herein, a copper-based N-heterocyclic carbene porous polymer catalyst (Cu@NHC-1) for the direct conversion of low concentration CO2 into oxazolidinones was successfully fabricated via a facile copolymerization process followed by the complexation with Cu(OAc)2 . A continuous flow device was designed to deliver a continuous and stable carbon source for the reaction. Due to the triple synergistic effect of its porous structure, nitrogen activation sites and catalytic Cu center, Cu@NHC-1 shows highly efficient and selective adsorption, activation, and conversion of the low concentration CO2 (30 vol%). Its practical application potential is demonstrated by the ability to successfully convert the CO2 in lime kiln waste gas into oxazolidinones in satisfactory yields under mild conditions.

USP18-mediated protein deISGylation and its role in tuberculosis and other infectious diseases.

The transcription of interferon-stimulated gene 15 (isg15) is induced by type I interferons. ISG15 can covalently modify target proteins through the sequential action of enzymesE1, E2, and E3, a process known as ISGylation. The ISGylation of host proteins is widely involved in immune responses, such as host antiviral defence. Ubiquitin-specific protease 18 (USP18), as a deubiquitinase (DUB), can remove ISG15 conjugated to target proteins and inhibit host immune responses by suppressing the type I interferon signaling. The dynamic balance between ISGylation and deISGylation mediated by ISG15 or USP18 respectively plays a significant role in the tuberculosis. Furthermore, similar to ISG15, USP18 is extensively involved in virus-host interaction. In this review, we summarize the roles of ISGylation and deISGylation in tuberculosis and other important diseases mediated by ISG15 and USP18 respectively, underlying regulator network. Further studies in this aspect will inspire new host-targeted strategies to control important diseases such as tuberculosis.

Proteomics profiling of ertapenem challenged major porin deficient carbapenem-resistant Klebsiella pneumoniae.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an urgent threat to human health. Major outer membrane proteins (OMPs) porin mutation is one important resistance mechanism of CRKP, and may also affect the inhibition activity of ß-lactam and ß-lactamase inhibitor combinations. The ertapenem-resistant K. pneumoniae strain 2018B120 with major porin mutations was isolated from a clinical patient. Genomic and time-series proteomic analyses were conducted to retrieve the ertapenem-challenged response of 2018B120. The abundance changing of proteins from PTS systems,  ABC transporters, the autoinducer 2 (AI-2) quorum sensing system, and antioxidant systems can be observed. Overexpression of alternative porins was also noticed to balance major porins' defection. These findings added a detailed regulation network in bacterial resistance mechanisms and gave new insights into bypass adaptation mechanisms the porin deficient bacteria adopted under carbapenem antibiotics pressure. SIGNIFICANCE: Outer membrane porins deficiency is an important mechanism of carbapenem resistance in K. pneumoniae. Comprehensive genomic and proteomic profiling of an ertapenem-resistant K. pneumoniae strain 2018B120 gives a detailed systematic regulation network in bacterial resistance mechanisms. Overexpression of alternative porins to balance major porins' defection was noticed, giving new insights into bypass adaptation mechanisms of porin deficient bacteria.

Pan-Genome Analysis of Laribacter hongkongensis: Virulence Gene Profiles, Carbohydrate-Active Enzyme Prediction, and Antimicrobial Resistance Characterization.

Laribacter hongkongensis is a new emerging foodborne pathogen that causes community-acquired gastroenteritis and traveler's diarrhea. However, the genetic features of L. hongkongensis have not yet been properly understood. A total of 45 aquatic animal-associated L. hongkongensis strains isolated from intestinal specimens of frogs and grass carps were subjected to whole-genome sequencing (WGS), along with the genome data of 4 reported human clinical strains, the analysis of virulence genes, carbohydrate-active enzymes, and antimicrobial resistance (AMR) determinants were carried out for comprehensively understanding of this new foodborne pathogen. Human clinical strains were genetically more related to some strains from frogs inferred from phylogenetic trees. The distribution of virulence genes and carbohydrate-active enzymes exhibited different patterns among strains of different sources, reflecting their adaption to different host environments and indicating different potentials to infect humans. Thirty-two AMR genes were detected, susceptibility to 18 clinical used antibiotics including aminoglycoside, chloramphenicol, trimethoprim, and sulfa was checked to evaluate the availability of clinical medicines. Resistance to Rifampicin, Cefazolin, ceftazidime, Ampicillin, and ceftriaxone is prevalent in most strains, resistance to tetracycline, trimethoprim-sulfamethoxazole, ciprofloxacin, and levofloxacin are aggregated in nearly half of frog-derived strains, suggesting that drug resistance of frog-derived strains is more serious, and clinical treatment for L. hongkongensis infection should be more cautious.