Comprehending the inhibition mechanism of indole-based bis-acylhydrazone compounds on α-glucosidase: Spectral and theoretical approaches.

Indole-based bis-acylhydrazone compounds can inhibit the activity of α-glucosidase and control the concentration of blood glucose. In this paper, the characteristics of three indole-based bis-acylhydrazone compounds with different inhibitory activities of α-glucosidase as well as the interaction with α-glucosidase were studied by experiments and computational simulation techniques. Enzyme kinetic and spectral experiments showed that the indole-based bis-acylhydrazone compounds were able to inhibit enzyme activity through mixed inhibition dominated by competitive inhibition, and during the binding reaction, indole-based bis-acylhydrazone compounds can quench the intrinsic fluorescence of α-glucosidase through static quenching and an aggregation of the indole-based bis-acylhydrazone with α-glucosidase produces a stable complex with a molar ratio of 1:1, and the combination of indole-based bis-acylhydrazone compounds could lead to slight change in the conformation of α-glucosidase. The theoretical simulation demonstrated that the stability of the complex systems was positively correlated with the inhibitory activity of indole-based bis-acylhydrazone compounds, and the indole-based bis-acylhydrazone compounds occupied the active site in the multi-ligand system, resulting in a significant decrease in the binding ability of starch to active amino acids. These results suggested that indole-based bis-acylhydrazone compound was expected to be a new type of α-glucosidase inhibitor.

Dual-Mechanism Peptide SR25 has Broad Antimicrobial Activity and Potential Application for Healing Bacteria-infected Diabetic Wounds.

The rise of antibiotic resistance poses a significant public health crisis, particularly due to limited antimicrobial options for the treatment of infections with Gram-negative pathogens. Here, an antimicrobial peptide (AMP) SR25 is characterized, which effectively kills both Gram-negative and Gram-positive bacteria through a unique dual-targeting mechanism without detectable resistance. Meanwhile, an SR25-functionalized hydrogel is developed for the efficient treatment of infected diabetic wounds. SR25 is obtained through genome mining from an uncultured bovine enteric actinomycete named Nonomuraea Jilinensis sp. nov. Investigations reveal that SR25 has two independent cellular targets, disrupting bacterial membrane integrity and restraining the activity of succinate:quinone oxidoreductase (SQR). In a diabetic mice wound infection model, the SR25-incorporated hydrogel exhibits high efficacy against mixed infections of Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA), accelerating wound healing. Overall, these findings demonstrate the therapeutic potential of SR25 and highlight the value of mining drugs with multiple mechanisms from uncultured animal commensals for combating challenging bacterial pathogens.

The potential association between metabolic disorders and pulmonary tuberculosis: a Mendelian randomization study.

BACKGROUND: Metabolic disorders (MetDs) have been demonstrated to be closely linked to numerous diseases. However, the precise association between MetDs and pulmonary tuberculosis (PTB) remains poorly understood. METHOD: Summary statistics for exposure and outcomes from genome-wide association studies (GWASs) for exposures and outcomes were obtained from the BioBank Japan Project (BBJ) Gene-exposure dataset. The 14 clinical factors were categorized into three groups: metabolic laboratory markers, blood pressure, and the MetS diagnostic factors. The causal relationship between metabolic factors and PTB were analyzed using two-sample Mendelian Randomization (MR). Additionally, the direct effects on the risk of PTB were investigated through multivariable MR. The primary method employed was the inverse variance-weighted (IVW) model. The sensitivity of this MR analysis was evaluated using MR-Egger regression and the MR-PRESSO global test. RESULTS: According to the two-sample MR, HDL-C, HbA1c, TP, and DM were positively correlated with the incidence of active TB. According to the multivariable MR, HDL-C (IVW: OR 2.798, 95% CI 1.484-5.274, P = 0.001), LDL (IVW: OR 4.027, 95% CI 1.140-14.219, P = 0.03) and TG (IVW: OR 2.548, 95% CI 1.269-5.115, P = 0.009) were positively correlated with the occurrence of PTB. TC (OR 0.131, 95% CI 0.028-0.607, P = 0.009) was negatively correlated with the occurrence of PTB. We selected BMI, DM, HDL-C, SBP, and TG as the diagnostic factors for metabolic syndrome. DM (IVW, OR 1.219, 95% CI 1.040-1.429 P = 0.014) and HDL-C (IVW, OR 1.380, 95% CI 1.035-1.841, P = 0.028) were directly correlated with the occurrence of PTB. CONCLUSIONS: This MR study demonstrated that metabolic disorders, mainly hyperglycemia, and dyslipidemia, are associated with the incidence of active pulmonary tuberculosis.

Engineered endolysin of Klebsiella pneumoniae phage is a potent and broad-spectrum bactericidal agent against "ESKAPEE" pathogens.

The rise of antimicrobial resistance in ESKAPEE pathogens poses significant clinical challenges, especially in polymicrobial infections. Bacteriophage-derived endolysins offer promise in combating this crisis, but face practical hurdles. Our study focuses on engineering endolysins from a Klebsiella pneumoniae phage, fusing them with ApoE23 and COG133 peptides. We assessed the resulting chimeric proteins' bactericidal activity against ESKAPEE pathogens in vitro. ApoE23-Kp84B (CHU-1) reduced over 3 log units of CFU for A. baumannii, E. faecalis, K. pneumoniae within 1 h, while COG133-Kp84B (CHU-2) showed significant efficacy against S. aureus. COG133-L1-Kp84B, with a GS linker insertion in CHU-2, exhibited outstanding bactericidal activity against E. cloacae and P. aeruginosa. Scanning electron microscopy revealed alterations in bacterial morphology after treatment with engineered endolysins. Notably, CHU-1 demonstrated promising anti-biofilm and anti-persister cell activity against A. baumannii and E. faecalis but had limited efficacy in a bacteremia mouse model of their coinfection. Our findings advance the field of endolysin engineering, facilitating the customization of these proteins to target specific bacterial pathogens. This approach holds promise for the development of personalized therapies tailored to combat ESKAPEE infections effectively.

In-Depth Characterization of bZIP Genes in the Context of Endoplasmic Reticulum (ER) Stress in Brassica campestris ssp. chinensis.

Numerous studies have been conducted to investigate the genomic characterization of bZIP genes and their involvement in the cellular response to endoplasmic reticulum (ER) stress. These studies have provided valuable insights into the coordinated cellular response to ER stress, which is mediated by bZIP transcription factors (TFs). However, a comprehensive and systematic investigations regarding the role of bZIP genes and their involvement in ER stress response in pak choi is currently lacking in the existing literature. To address this knowledge gap, the current study was initiated to elucidate the genomic characteristics of bZIP genes, gain insight into their expression patterns during ER stress in pak choi, and investigate the protein-to-protein interaction of bZIP genes with the ER chaperone BiP. In total, 112 members of the BcbZIP genes were identified through a comprehensive genome-wide analysis. Based on an analysis of sequence similarity, gene structure, conserved domains, and responsive motifs, the identified BcbZIP genes were categorized into 10 distinct subfamilies through phylogenetic analysis. Chromosomal location and duplication events provided insight into their genomic context and evolutionary history. Divergence analysis estimated their evolutionary history with a predicted divergence time ranging from 0.73 to 80.71 million years ago (MYA). Promoter regions of the BcbZIP genes were discovered to exhibit a wide variety of cis-elements, including light, hormone, and stress-responsive elements. GO enrichment analysis further confirmed their roles in the ER unfolded protein response (UPR), while co-expression network analysis showed a strong relationship of BcbZIP genes with ER-stress-responsive genes. Moreover, gene expression profiles and protein-protein interaction with ER chaperone BiP further confirmed their roles and capacity to respond to ER stress in pak choi.

Relationships among anxiety, depression, and health-related quality of life in adult epilepsy: A network analysis.

OBJECTIVE: Comorbid depression and anxiety in patients with epilepsy (PWE) are common and frequently under-treated, thus, causing poor health-related quality of life (HRQoL). However, little is known regarding the interconnections between anxious/depressive symptoms and the dimensions of HRQoL. Therefore, we conducted a network analysis to explore these relationships in detail among Chinese adult PWE. METHODS: A cohort of adult PWE was consecutively recruited from the First Affiliated Hospital of Chongqing Medical University. HRQoL, depression, and anxiety were measured with Quality of Life in Epilepsy Inventory-31, Neurological Disorders Depression Inventory for Epilepsy, and Generalized Anxiety Disorder 7-Item Scale, respectively. A regularized partial correlation network was constructed to investigate the interconnections between symptoms of anxiety/depression and the dimensions of HRQoL. We calculated expected influence (EI) and bridge expected influence (BEI) values to identify the most influential nodes. RESULTS: A total of 396 PWE were enrolled in this study, 78.1% of whom had focal onset epilepsy. The prevalence of anxiety and depression was 30.3% and 28.8%, respectively. The symptoms "frustrated" and "uncontrollable worry" had the highest EI values, whereas "emotional well-being", "seizure worry", "difficulty finding pleasure", and "nervousness or anxiety" had the highest BEI values. CONCLUSION: This study provides new insights into the relationships among anxiety, depression, and HRQoL. Critical central symptoms and bridge symptoms identified in the network might help to quickly identify PWE comorbid anxiety and depression in busy outpatient settings, thereby enabling early intervention and enhancing quality of life.

ApoE Mimetic Peptide COG1410 Kills Mycobacterium smegmatis via Directly Interfering ClpC's ATPase Activity.

Antimicrobial peptides (AMPs) hold promise as alternatives to combat bacterial infections, addressing the urgent global threat of antibiotic resistance. COG1410, a synthetic peptide derived from apolipoprotein E, has exhibited potent antimicrobial properties against various bacterial strains, including Mycobacterium smegmatis. However, our study reveals a previously unknown resistance mechanism developed by M. smegmatis against COG1410 involving ClpC. Upon subjecting M. smegmatis to serial passages in the presence of sub-MIC COG1410, resistance emerged. The comparative genomic analysis identified a point mutation in ClpC (S437P), situated within its middle domain, which led to high resistance to COG1410 without compromising bacterial fitness. Complementation of ClpC in mutant restored bacterial sensitivity. In-depth analyses, including transcriptomic profiling and in vitro assays, uncovered that COG1410 interferes with ClpC at both transcriptional and functional levels. COG1410 not only stimulated the ATPase activity of ClpC but also enhanced the proteolytic activity of Clp protease. SPR analysis confirmed that COG1410 directly binds with ClpC. Surprisingly, the identified S437P mutation did not impact their binding affinity. This study sheds light on a unique resistance mechanism against AMPs in mycobacteria, highlighting the pivotal role of ClpC in this process. Unraveling the interplay between COG1410 and ClpC enriches our understanding of AMP-bacterial interactions, offering potential insights for developing innovative strategies to combat antibiotic resistance.

Investigating the effects of tauroursodeoxycholic acid (TUDCA) in mitigating endoplasmic reticulum stress and cellular responses in Pak choi.

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) within plant cells due to unfavourable conditions leads to ER stress. This activates interconnected pathways involving reactive oxygen species (ROS) and unfolded protein response (UPR), which play vital roles in regulating ER stress. The aim of this study is to investigate the underlying mechanisms of tunicamycin (TM) induced ER stress and explore the potential therapeutic applications of tauroursodeoxycholic acid (TUDCA) in mitigating cellular responses to ER stress in Pak choi (Brassica campestris subsp. chinensis). The study revealed that ER stress in Pak choi leads to detrimental effects on plant morphology, ROS levels, cellular membrane integrity, and the antioxidant defence system. However, treatment with TUDCA in TM-induced ER stressed Pak choi improved morphological indices, pigment contents, ROS accumulation, cellular membrane integrity, and antioxidant defence system restoration. Additionally, TUDCA also modulates the transcription levels of ER stress sensors genes, ER chaperone genes, and ER-associated degradation (ERAD) genes during ER stress in Pak choi. Furthermore, TUDCA has demonstrated its ability to alleviate ER stress, stabilize the UPR, reduce oxidative stress, prevent apoptosis, and positively influence plant growth and development. These results collectively comprehend TUDCA as a promising agent for mitigating ER stress-induced damage in Pak choi plants and provide valuable insights for further research and potential applications in crop protection and stress management.

Unraveling the impact of cancer-associated fibroblasts on hypovascular pancreatic neuroendocrine tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) with low microvessel density and fibrosis often exhibit clinical aggressiveness. Given the contribution of cancer-associated fibroblasts (CAFs) to the hypovascular fibrotic stroma in pancreatic ductal adenocarcinoma, investigating whether CAFs play a similar role in PNETs becomes imperative. In this study, we investigated the involvement of CAFs in PNETs and their effects on clinical outcomes. METHODS: We examined 79 clinical PNET specimens to evaluate the number and spatial distribution of α-smooth muscle actin (SMA)-positive cells, which are indicative of CAFs. Then, the findings were correlated with clinical outcomes. In vitro and in vivo experiments were conducted to assess the effects of CAFs (isolated from clinical specimens) on PNET metastasis and growth. Additionally, the role of the stromal-cell-derived factor 1 (SDF1)-AGR2 axis in mediating communication between CAFs and PNET cells was investigated. RESULTS: αSMA-positive and platelet-derived growth factor-α-positive CAFs were detected in the hypovascular stroma of PNET specimens. A higher abundance of α-SMA-positive CAFs within the PNET stroma was significantly associated with a higher level of clinical aggressiveness. Notably, conditioned medium from PNET cells induced an inflammatory phenotype in isolated CAFs. These CAFs promoted PNET growth and metastasis. Mechanistically, PNET cells secreted interleukin-1, which induced the secretion of SDF1 from CAFs. This cascade subsequently elevated AGR2 expression in PNETs, thereby promoting tumor growth and metastasis. The downregulation of AGR2 in PNET cells effectively suppressed the CAF-mediated promotion of PNET growth and metastasis. CONCLUSION: CAFs drive the growth and metastasis of aggressive PNETs. The CXCR4-SDF1 axis may be a target for antistromal therapy in the treatment of PNET. This study clarifies mechanisms underlying PNET aggressiveness and may guide future therapeutic interventions targeting the tumor microenvironment.

Synthesis and biological evaluation of indole derivatives containing thiazolidine-2,4-dione as α-glucosidase inhibitors with antidiabetic activity.

In order to develop potential α-glucosidase inhibitors with antidiabetic activity, twenty-six indole derivatives containing thiazolidine-2,4-dione were synthesized. All compounds presented potential α-glucosidase inhibitory activities with IC50 values ranging from 2.35 ± 0.11 to 24.36 ± 0.79 µM, respectively compared to acarbose (IC50 = 575.02 ± 10.11 µM). Especially, compound IT4 displayed the strongest α-glucosidase inhibitory activity (IC50 = 2.35 ± 0.11 µM). The inhibition mechanism of compound IT4 on α-glucosidase was clarified by the investigation of kinetics studies, fluorescence quenching, CD spectra, 3D fluorescence spectra, and molecular docking. In vivo antidiabetic experiments demonstrated that oral administration of compound IT4 would suppress fasting blood glucose level and ameliorate their glucose tolerance and dyslipidemia in diabetic mice.

Oncogenic KRAS, Mucin 4, and Activin A-Mediated Fibroblast Activation Cooperate for PanIN Initiation.

Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic-clear 3D histology is used to analyze entire pancreases of 2-week-old Pdx1-Cre; LSL-KrasG12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA+ fibroblasts in both transgenic mice and human specimens. Mechanistically, KrasG12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN-associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic KrasG12D/+ -driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches.

In Vitro and In Vivo Biological Evaluation of Indole-thiazolidine-2,4-dione Derivatives as Tyrosinase Inhibitors.

Tyrosinase is an important rate-limiting enzyme in melanin biosynthesis. To find potential tyrosinase inhibitors with anti-melanogenic activity, a series of indole-thiazolidine-2,4-dione derivatives 5a~5z were synthesized by incorporating indole with thiazolidine-2,4-dione into one compound and assayed for their biological activities. All compounds displayed tyrosinase inhibitory activities and 5w had the highest anti-tyrosinase inhibitory activity with an IC50 value of 11.2 µM. Inhibition kinetics revealed 5w as a mixed-type tyrosinase inhibitor. Fluorescence quenching results indicated that 5w quenched tyrosinase fluorescence in a static process. CD spectra and 3D fluorescence spectra results suggested that the binding of 5w with tyrosinase could change the conformation and microenvironment of tyrosinase. Molecular docking also represented the binding between 5w and tyrosinase. Moreover, 5w could inhibit tyrosinase activity and melanogenesis both in B16F10 cells and the zebrafish model. Therefore, compound 5w could serve as a tyrosinase inhibitor with anti-melanogenic activity.

Chitosan coating enriched with biosynthetic CuO NPs: Effects on postharvest decay and quality of mango fruit.

A chitosan-based nanocomposite film (CSC) was developed by mixing chitosan (CS, 2 %, v/v) and copper oxide nanoparticles (CuO NPs, 500 µg∙mL-1) synthesized using Alpinia officinarum extract for the safe storage of mango fruit. The effects of CuO NPs on the morphological, mechanical, thermal, physical and antifungal properties of the CS films and postharvest quality of mango fruit were determined. Scanning electron microscopy (SEM) analysis confirmed that CuO NPs were uniformly dispersed into the CS matrix. X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) profiles showed that intermolecular H-bondings occurred between CS and CuO NPs, accompanied by decreased crystallinity and increased amorphous structure. In comparison to the pure CS film, addition of CuO NPs obviously improved the morphological, mechanical, thermal, physical and antifungal properties of CSC film. CSC coating treatment obviously delayed the fruit decay and yellowing, as well as reduced losses of weight and firmness of mango (Mangifera indica L.) fruit during the storage, when compared with the control and CS coating treatment. Meanwhile, it significantly decreased the respiration rate and ethylene generation and maintained high level of ascorbic acid (AsA), titratable acid (TA) and soluble sugar content (SSC) of the fruit during the storage. Notably, Cu presented in the CSC film was restrained to the peel, indicating that the CSC coated mango fruit had good edible safety. Principal component analysis (PCA) confirmed that CSC coating played a positive role in mango preservation. Therefore, CSC coating can be considered a potential application for successfully controlling of postharvest disease and prolonging the shelf life for mango fruit.

Pulmonary mucosa-associated lymphoid tissue lymphoma with Sjögren's syndrome and literature review: A case report.

INTRODUCTION: A 54-year-old woman was admitted to hospital with chest tightness, shortness of breath, and chest pain on exertion. Her chest computed tomography showed a space-occupying lesion in the right lower lobe of the lung. CASE PRESENTATION: The ultrasound-guided right lung mass biopsy showed mucosa-associated lymphoid tissue (MALT), and the patient was diagnosed with Sjögren's syndrome (SS). The patient's symptoms were partially relieved with chemotherapy. CONCLUSIONS: Autoimmune diseases like SS and systemic lupus erythematosus are recognized risk factors for pulmonary MALT. It is necessary to identify predictors of malignant transformation of SS to pulmonary MALT lymphoma.

Recent advances and future perspectives of CAR-T cell therapy in head and neck cancer.

Head and neck cancer (HNC) ranks as the sixth most prevalent type of cancer globally and accounts for about 4% of all types of cancer. Among all HNC, most are head and neck squamous cell carcinoma (HNSCC) with clinical therapies that include surgery, radiation therapy, chemotherapy, immunotherapy, targeted therapy, and multimodal treatments. In recent years, chimeric antigen receptor (CAR)-T cell immunotherapy has significantly transformed the therapeutic approaches for leukemia and lymphoma and has garnered increased attention as a potential treatment for a wide range of cancers. However, CAR-T immunotherapy in solid tumors, especially HNSCCs, lags significantly behind due to the paucity of tumor-specific antigens, high levels of tumor heterogeneity, immunosuppressive tumor microenvironment, the risk of treatment-related toxicities and off-target adverse events in HNSCCs. The objective of this review is to explore the advancement of CAR-T cell therapy in the treatment of HNSCCs. We aim to outline the targeted antigens in HNSCCs, highlight the challenges and potential solutions, and discuss the relevant combination therapies. Our review presents a comprehensive overview of the recent developments in CAR-T cell therapy for HNSCCs, and provides valuable insights into future research avenues.

Nutritional status in patients with active pulmonary tuberculosis and new nutritional risk screening model for active tuberculosis: a national, multicenter, cross-sectional study in China.

Background: Tuberculosis (TB) remains a significant challenge for public health and is closely associated with malnutrition; however, few studies have attempted to screen malnutrition among TB patients. The study aimed to evaluate the nutrition status and build a new nutritional screening model for active TB. Methods: A retrospective, multicenter, large cross-sectional study was conducted in China from 1 January 2020 to 31 December 2021. All included patients diagnosed with active pulmonary TB (PTB) were evaluated both by Nutrition Risk Screening 2002 (NRS 2002) and Global Leadership Initiative on Malnutrition (GLIM) criteria. Univariate and multivariate analyses were conducted to screen the risk factors associated with malnutrition, and a new screening risk model, mainly for TB patients, was constructed. Results: A total of 14,941 cases meeting the inclusion criteria were entered into the final analysis. The malnutrition risk rate among PTB patients in China was 55.86% and 42.70%, according to the NRS 2002 and GLIM, respectively. The inconsistency rate between the two methods was 24.77%. A total of 11 clinical factors, including elderly, low body mass index (BMI), decreased lymphocyte cells, taking immunosuppressive agents, co-pleural TB, diabetes mellitus (DM), human immunodeficiency virus (HIV), severe pneumonia, decreased food intake within a week, weight loss and dialysis were identified as independent risk factors of malnutrition based on multivariate analyses. A new nutritional risk screening model was constructed for TB patients with a diagnostic sensitivity of 97.6% and specificity of 93.1%. Conclusions: Active TB patients have severe malnutrition status according to screening by the NRS 2002 and GLIM criteria. The new screening model is recommended for PTB patients as it is more closely tailored to the characteristics of TB.

Photosensitive small extracellular vesicles regulate the immune microenvironment of triple negative breast cancer.

Currently, the treatment of triple-negative breast cancer (TNBC) is limited by the special pathological characteristics of this disease. In recent years, photodynamic therapy (PDT) has created new hope for the treatment of TNBC. Moreover, PDT can induce immunogenic cell death (ICD) and improve tumor immunogenicity. However, even though PDT can improve the immunogenicity of TNBC, the inhibitory immune microenvironment of TNBC still weakens the antitumor immune response. Therefore, we used the neutral sphingomyelinase inhibitor GW4869 to inhibit the secretion of small extracellular vesicles (sEVs) by TNBC cells to improve the tumor immune microenvironment and enhance antitumor immunity. In addition, bone mesenchymal stem cell (BMSC)-derived sEVs have good biological safety and a strong drug loading capacity, which can effectively improve the efficiency of drug delivery. In this study, we first obtained primary BMSCs and sEVs, and then the photosensitizers Ce6 and GW4869 were loaded into the sEVs by electroporation to produce immunomodulatory photosensitive nanovesicles (Ce6-GW4869/sEVs). When administered to TNBC cells or orthotopic TNBC models, these photosensitive sEVs could specifically target TNBC and improve the tumor immune microenvironment. Moreover, PDT combined with GW4869-based therapy showed a potent synergistic antitumor effect mediated by direct killing of TNBC and activation of antitumor immunity. Here, we designed photosensitive sEVs that could target TNBC and regulate the tumor immune microenvironment, providing a potential approach for improving the effectiveness of TNBC treatment. STATEMENT OF SIGNIFICANCE: We designed an immunomodulatory photosensitive nanovesicle (Ce6-GW4869/sEVs) with the photosensitizer Ce6 to achieve photodynamic therapy and the neutral sphingomyelinase inhibitor GW4869 to inhibit the secretion of small extracellular vesicles (sEVs) by triple-negative breast cancer (TNBC) cells to improve the tumor immune microenvironment and enhance antitumor immunity. In this study, the immunomodulatory photosensitive nanovesicle could target TNBC cells and regulate the tumor immune microenvironment, thus providing a potential approach for improving the treatment effect in TNBC. We found that the reduction in tumor sEVs secretion induced by GW4869 improved the tumor-suppressive immune microenvironment. Moreover, similar therapeutic strategies can also be applied in other kinds of tumors, especially immunosuppressive tumors, which is of great value for the clinical translation of tumor immunotherapy.

Bicyclic Amidine-Triggered Cyclization of o-Alkynylisocyanobenzenes: Synthesis of Lactam-Derived Quinolines.

Efficient access to the synthesis of lactam-derived quinoline through a bicyclic amidine-triggered cyclization reaction from readily prepared o-alkynylisocyanobenzenes has been developed. The reaction was initiated by nucleophilic attack of the bicyclic amidines to o-alkynylisocyanobenzenes, subsequently with intramolecular cyclization to produce a DBU-quinoline-based amidinium salt, followed by hydrolysis to afford the lactam-derived quinoline in moderate to good yields.

Resolution of an insidious and migratory Mycobacterium tuberculosis-associated secondary organizing pneumonia: a case report and literature review.

BACKGROUND: Organizing pneumonia (OP) is a rare interstitial lung disease. Secondary organizing pneumonia (SOP) caused by Mycobacterium tuberculosis (MTB) is extremely rare. Migratory MTB-associated SOP is more deceptive and dangerous. When insidious tuberculosis (TB) is not recognized, SOP would be misdiagnosed as cryptogenic organizing pneumonia (COP). Use of steroid hormone alone leads to the progression of TB foci or even death. Clues of distinguishing atypical TB at the background of OP is urgently needed. CASE PRESENTATION: A 56-year-old female patient was hospitalized into the local hospital because of cough and expectoration for more than half a month. Her medical history and family history showed no relation to TB or other lung diseases. Community-acquired pneumonia was diagnosed and anti-infection therapy was initialized but invalid. The patient suffered from continuous weigh loss. More puzzling, the lesions were migratory based on the chest computed tomography (CT) images. The patient was then transferred to our hospital. The immunological indexes of infection in blood and pathogenic tests in sputum and the bronchoalveolar lavage fluid were negative. The percutaneous lung puncture biopsy and pathological observation confirmed OP, but without granulomatous lesions. Additionally, pathogen detection of the punctured lung tissues by metagenomics next generation sequencing test (mNGS) were all negative. COP was highly suspected. Fortunately, the targeted next-generation sequencing (tNGS) detected MTB in the punctured lung tissues and MTB-associated SOP was definitely diagnosed. The combined therapy of anti-TB and prednisone was administrated. After treatment for 10 days, the partial lesions were significantly resorbed and the patient was discharged. In the follow-up of half a year, the patient was healthy. CONCLUSIONS: It is difficult to distinguish SOP from COP in clinical practice. Diagnosis of COP must be very cautious. Transient small nodules and cavities in the early lung image are a clue to consider TB, even though all pathogen tests are negative. tNGS is also a powerful tool to detect pathogen, ensuring prompt diagnosis of TB-related SOP. For clinicians in TB high burden countries, we encourage them to keep TB in mind before making a final diagnosis of COP.

Pancreatic cancer-derived small extracellular vesical ezrin activates fibroblasts to exacerbate cancer metastasis through STAT3 and YAP-1 signaling pathways.

Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC), play an important role in tumorigenesis, metastasis, and chemoresistance. Tumor-derived small extracellular vesicles (sEVs), which mediate cell-to-cell communication between cancer cells and fibroblasts, are also critical for cancer progression and metastasis. However, it remains unclear how PDAC cell-derived sEVs activate fibroblasts, which contributes to tumor progression. Here, we report that ezrin (EZR) expression in PDAC cell-derived sEVs (sEV-EZR) can activate fibroblasts, resulting in increased migration ability and high expression of α-SMA, PDGFRB, and high production of extracellular matrix in fibroblasts. Reciprocally, sEV-EZR-activated fibroblasts enhanced PDAC cell proliferation, invasion, and metastasis to the liver in animal models. Conversely, fibroblasts treated with PDAC cell-derived sEVs with EZR knockdown resulted in the reduced metastatic ability of PDAC. Mechanistically, we demonstrated that PDAC cell-derived sEV-EZR increases the STAT3 and YAP-1 signaling pathways to induce fibroblast activation, and the activated fibroblasts promote PDAC cell proliferation, invasion, and liver metastasis. Inhibition of the STAT3 and YAP-1 signaling pathways by gene knockdown can abrogate sEV-EZR-induced effects. These findings suggest that targeting the interaction between PDAC cell-derived sEV-EZR and fibroblasts is a potential therapeutic strategy for PDAC.