Gastric Cancer Assembloids Derived from Patient-Derived Xenografts: A Preclinical Model for Therapeutic Drug Screening.

The construction of reliable preclinical models is crucial for understanding the molecular mechanisms involved in gastric cancer and for advancing precision medicine. Currently, existing in vitro tumor models often do not accurately replicate the human gastric cancer environment and are unsuitable for high-throughput therapeutic drug screening. In this study, droplet microfluidic technology is employed to create novel gastric cancer assembloids by encapsulating patient-derived xenograft gastric cancer cells and patient stromal cells in Gelatin methacryloyl (GelMA)-Gelatin-Matrigel microgels. The usage of GelMA-Gelatin-Matrigel composite hydrogel effectively alleviated cell aggregation and sedimentation during the assembly process, allowing for the handling of large volumes of cell-laden hydrogel and the uniform generation of assembloids in a high-throughput manner. Notably, the patient-derived xenograft assembloids exhibited high consistency with primary tumors at both transcriptomic and histological levels, and can be efficiently scaled up for preclinical drug screening efforts. Furthermore, the drug screening results clearly demonstrated that the in vitro assembloid model closely mirrored in vivo drug responses. Thus, these findings suggest that gastric cancer assembloids, which effectively replicate the in vivo tumor microenvironment, show promise for enabling more precise high-throughput drug screening and predicting the clinical outcomes of various drugs.

Numerical Simulation and ANN Prediction of Crack Problems within Corrosion Defects.

Buried pipelines are widely used, so it is necessary to analyze and study their fracture characteristics. The locations of corrosion defects on the pipe are more susceptible to fracture under the influence of internal pressure generated during material transportation. In the open literature, a large number of studies have been conducted on the failure pressure or residual strength of corroded pipelines. On this basis, this study conducts a fracture analysis on buried pipelines with corrosion areas under seismic loads. The extended finite element method was used to model and analyze the buried pipeline under seismic load, and it was found that the stress value at the crack tip was maximum when the circumferential angle of the crack was near 5° in the corrosion area. The changes in the stress field at the crack tip in the corrosion zone of the pipeline under different loads were compared. Based on the BP algorithm, a neural network model that can predict the stress field at the pipe crack tip is established. The neural network is trained using numerical model data, and a prediction model with a prediction error of less than 10% is constructed. The crack tip characteristics were further studied using the BP neural network model, and it was determined that the tip stress fluctuation range is between 450 MPa and 500 MPa. The neural network model is optimized based on the GA algorithm, which solves the problem of convergence difficulties and improves the prediction accuracy. According to the prediction results, it is found that when the internal pressure increases, the corrosion depth will significantly affect the crack tip stress field. The maximum error of the optimized neural network is 5.32%. The calculation data of the optimized neural network model were compared with the calculation data of other models, and it was determined that GA-BPNN has better adaptability in this research problem.

Evolutionary and immune-activating character analyses of NLR genes in algae suggest the ancient origin of plant intracellular immune receptors.

Nucleotide-binding leucine-rich repeat (NLR) proteins are crucial intracellular immune receptors in plants, responsible for detecting invading pathogens and initiating defense responses. While previous studies on the evolution and function of NLR genes were mainly limited to land plants, the evolutionary trajectory and immune-activating character of NLR genes in algae remain less explored. In this study, genome-wide NLR gene analysis was conducted on 44 chlorophyte species across seven classes and seven charophyte species across five classes. A few but variable number of NLR genes, ranging from one to 20, were identified in five chlorophytes and three charophytes, whereas no NLR gene was identified from the remaining algal genomes. Compared with land plants, algal genomes possess fewer or usually no NLR genes, implying that the expansion of NLR genes in land plants can be attributed to their adaptation to the more complex terrestrial pathogen environments. Through phylogenetic analysis, domain composition analysis, and conserved motifs profiling of the NBS domain, we detected shared and lineage-specific features between NLR genes in algae and land plants, supporting the common origin and continuous evolution of green plant NLR genes. Immune-activation assays revealed that both TNL and RNL proteins from green algae can elicit hypersensitive responses in Nicotiana benthamiana, indicating the molecular basis for immune activation has emerged in the early evolutionary stage of different types of NLR proteins. In summary, the results from this study suggest that NLR proteins may have taken a role as intracellular immune receptors in the common ancestor of green plants.

Acetyl-CoA Synthetase Mutations S868G and V949I Do Not Confer Resistance to Antimalarial Drugs in vitro in Plasmodium falciparum.

Plasmodium falciparum acetyl-CoA synthetase (PfACAS) protein is an important source of acetyl-CoA. We detected the mutations S868G and V949I in PfACAS by whole-genome sequencing analysis in some recrudescent parasites after antimalarial treatment with artesunate and dihydroartemisinin-piperaquine, suggesting that they may confer drug resistance. Using CRISPR/Cas9 technology, we engineered parasite lines carrying the PfACAS S868G and V949I mutations in two genetic backgrounds and evaluated their susceptibility to antimalarial drugs in vitro. The results demonstrated that PfACAS S868G and V949I mutations alone or in combination were not enough to provide resistance to antimalarial drugs.

Synthesis of acylated derivatives of alginate oligosaccharides and evaluation of their potential antibacterial activities against Staphylococcus aureus.

Alginate oligosaccharides (AOS) are crucial carbohydrate-based biomaterial used in the synthesis of potential drugs and biological agents, but their antibacterial activities are not significant. In this study, AOS acylated derivatives were synthesized by grafting maleic anhydride (MA) onto AOS at varying ratios. Additionally, their inhibitory effects against Staphylococcus aureus were thoroughly investigated. Characterization of the AOS acylated derivatives (AOS-MA-x, where x = 1, 5, 10, and 20) was conducted using Fourier-transformed infrared spectroscopy, 1H nuclear magnetic resonance spectroscopy, and X-ray diffraction, which confirmed the successful synthesis of these derivatives. The bacteriostatic activity of the AOS-MA derivatives was assessed using growth curves and plate coating method, demonstrating significant antibacterial effects against S. aureus, as compared with AOS. Among these derivatives, AOS-MA-20 exhibited the most potent bacteriostatic activity and was selected for further investigation of its inhibitory mechanism. Scanning electron microscopy analysis revealed that treatment with AOS-MA-20 led to the lysis and rupture of S. aureus cells, expelling their intracellular contents. Moreover, AOS-MA-20 disrupted the integrity of cell wall and cell membrane, impacted ATPase activity, and inhibited the formation of biofilm to some extent, ultimately resulting in bacterial death. These findings lay a foundational framework for the development of environmentally friendly antimicrobial agents.

[3D tumor spheroids promote activation, expansion, and anti-tumor effects of tumor-infiltrating lymphocytes in vitro].

The adoptive immunotherapy mediated by tumor-infiltrating lymphocytes (TILs) has shown definite efficacy against various solid tumors. However, the inefficiency of the conventional method based on in vitro expansion of TILs fails to achieve the cell count and high tumor-killing activity required for therapeutic purposes. This study investigated the effect of 3D tumor spheroids on the activation and expansion of TILs in vitro, aiming to provide a novel approach for the expansion of TILs. We procured TILs and primary tumor cells from surgical samples of lung cancer patients and then compared the impacts of lung cancer cell line NCI-H1975 and primary lung cancer cells cultured under 2D and 3D conditions on the activation, expansion, and anti-tumor activity of TILs. Furthermore, we added the programmed cell death protein 1 (PD-1) antibody into the co-culture of primary tumor cells and TILs within a 3D environment to assess the effects of the antibody on TILs. The results showed that compared with 2D cultured tumor cells, the 3D cultured H1975 cells significantly enhanced the expansion of TILs, increasing the proportion of CD3+/CD8+ cells in TILs to 61.6%. The 3D primary tumor model also enhanced the proportion of CD3+/CD8+ cells in TILs (45.5%, 54.4%), induced apoptosis of tumor epithelial cells and decreased the overall tumor cells survival rate (16.7%) after co-culture. PD-1 antibodies further improved the in vitro expansion capacity of TILs mediated by 3D tumor spheroids, resulting in the proportions of 50.9% and 57.0% for CD3+/CD8+ cells and enhancing the antitumor activity significantly (reducing the overall tumor survival rate to 9.36%). In summary, the use of 3D tumor spheroids significantly promoted the expansion and improved the anti-tumor effect of TILs, and the use of the PD-1 antibody further promoted the expansion and tumor-killing effect of TILs.

How can governments and fishermen collaborate to participate in a fishing ban for ecological restoration?

To safeguard aquatic ecosystems and fishery resources while facilitating cooperative engagement between local governments and fishermen, an evolutionary game model featuring both stakeholders has been constructed in this study. The model examines the degree of compliance with ecological restoration policies linked to fishing bans, as well as the adaptive strategies of different types of fishermen with varied incentives while simulating the ecological restoration policy under diverse scenarios. The findings suggest that: (1) Compliance with the fishing ban policy among fishermen is determined by their economic interests, environmental preferences, and government regulations, while its enforcement by local authorities is influenced by regulatory costs, political performance, and reputation. (2) Variations in the ecological restoration policy of fishing bans result from several factors, including punitive measures and compensation. The higher the penalty, the greater the chance of compliance among fishermen, and the higher the restoration degree of the watershed ecosystem. Conversely, the higher the compensation, the more satisfied the fishermen are with the fishing ban policy, and the smoother the transformation of their livelihoods. (3) To enhance the effectiveness and sustainability of fishing bans, it is essential to consider the interests of multiple stakeholders and adopt a coordination mechanism that facilitates the design of a reasonable and effective incentive-compatible system, thereby increasing the fairness and acceptability of the policy. This study provides a new theoretical framework and methodology applicable to ecological restoration policies for fishery closures on a global scale, accompanied by robust data support and theoretical guidance for developing and implementing fishery closure policies.

A Lateral Flow-Recombinase Polymerase Amplification Method for Colletotrichum gloeosporioides Detection.

The greater yam (Dioscorea alata), a widely cultivated and nutritious food crop, suffers from widespread yield reduction due to anthracnose caused by Colletotrichum gloeosporioides. Latent infection often occurs before anthracnose phenotypes can be detected, making early prevention difficult and causing significant harm to agricultural production. Through comparative genomic analysis of 60 genomes of 38 species from the Colletotrichum genus, this study identified 17 orthologous gene groups (orthogroups) that were shared by all investigated C. gloeosporioides strains but absent from all other Colletotrichum species. Four of the 17 C. gloeosporioides-specific orthogroups were used as molecular markers for PCR primer designation and C. gloeosporioides detection. All of them can specifically detect C. gloeosporioides out of microbes within and beyond the Colletotrichum genus with different sensitivities. To establish a rapid, portable, and operable anthracnose diagnostic method suitable for field use, specific recombinase polymerase amplification (RPA) primer probe combinations were designed, and a lateral flow (LF)-RPA detection kit for C. gloeosporioides was developed, with the sensitivity reaching the picogram (pg) level. In conclusion, this study identified C. gloeosporioides-specific molecular markers and developed an efficient method for C. gloeosporioides detection, which can be applied to the prevention and control of yam anthracnose as well as anthracnose caused by C. gloeosporioides in other crops. The strategy adopted by this study also serves as a reference for the identification of molecular markers and diagnosis of other plant pathogens.

Genome-Wide Identification and Evolutionary Analysis of Receptor-like Kinase Family Genes Provides Insights into Anthracnose Resistance of Dioscorea alata.

Dioscorea alata, commonly known as "greater yam", is a vital crop in tropical and subtropical regions of the world, yet it faces significant threats from anthracnose disease, mainly caused by Colletotrichum gloeosporioides. However, exploring disease resistance genes in this species has been challenging due to the difficulty of genetic mapping resulting from the loss of the flowering trait in many varieties. The receptor-like kinase (RLK) gene family represents essential immune receptors in plants. In this study, genomic analysis revealed 467 RLK genes in D. alata. The identified RLKs were distributed unevenly across chromosomes, likely due to tandem duplication events. However, a considerable number of ancient whole-genome or segmental duplications dating back over 100 million years contributed to the diversity of RLK genes. Phylogenetic analysis unveiled at least 356 ancient RLK lineages in the common ancestor of Dioscoreaceae, which differentially inherited and expanded to form the current RLK profiles of D. alata and its relatives. The analysis of cis-regulatory elements indicated the involvement of RLK genes in diverse stress responses. Transcriptome analysis identified RLKs that were up-regulated in response to C. gloeosporioides infection, suggesting their potential role in resisting anthracnose disease. These findings provide novel insights into the evolution of RLK genes in D. alata and their potential contribution to disease resistance.

Construction of a Tumor-Targeting Nanobubble with Multiple Scattering Interfaces and its Enhancement of Ultrasound Imaging.

Introduction: Recently, nanobubbles (NBs) have gained significant traction in the field of tumor diagnosis and treatment owing to their distinctive advantages. However, the application of NBs is limited due to their restricted size and singular reflection section, resulting in low ultrasonic reflection. Methods: We synthesized a nano-scale ultrasound contrast agent (IR783-SiO2NPs@NB) by encapsulating SiO2 nanoparticles in an IR783-labeled lipid shell using an improved film hydration method. We characterized its physicochemical properties, examined its microscopic morphology, evaluated its stability and cytotoxicity, and assessed its contrast-enhanced ultrasound imaging capability both in vitro and in vivo. Results: The results show that IR783-SiO2NPs@NB had a "donut-type" composite microstructure, exhibited uniform particle size distribution (637.2 ± 86.4 nm), demonstrated excellent stability (30 min), high biocompatibility, remarkable tumor specific binding efficiency (99.78%), and an exceptional contrast-enhanced ultrasound imaging capability. Conclusion: Our newly developed multiple scattering NBs with tumor targeting capacity have excellent contrast-enhanced imaging capability, and they show relatively long contrast enhancement duration in solid tumors, thus providing a new approach to the structural design of NBs.

A patient-specific lung cancer assembloid model with heterogeneous tumor microenvironments.

Cancer models play critical roles in basic cancer research and precision medicine. However, current in vitro cancer models are limited by their inability to mimic the three-dimensional architecture and heterogeneous tumor microenvironments (TME) of in vivo tumors. Here, we develop an innovative patient-specific lung cancer assembloid (LCA) model by using droplet microfluidic technology based on a microinjection strategy. This method enables precise manipulation of clinical microsamples and rapid generation of LCAs with good intra-batch consistency in size and cell composition by evenly encapsulating patient tumor-derived TME cells and lung cancer organoids inside microgels. LCAs recapitulate the inter- and intratumoral heterogeneity, TME cellular diversity, and genomic and transcriptomic landscape of their parental tumors. LCA model could reconstruct the functional heterogeneity of cancer-associated fibroblasts and reflect the influence of TME on drug responses compared to cancer organoids. Notably, LCAs accurately replicate the clinical outcomes of patients, suggesting the potential of the LCA model to predict personalized treatments. Collectively, our studies provide a valuable method for precisely fabricating cancer assembloids and a promising LCA model for cancer research and personalized medicine.

N -N-Butyl Haloperidol Iodide Mitigates Myocardial Ischemia/Reperfusion Injury Through Activation of SIRT1-Nrf2 Signaling Loop.

ABSTRACT: N -n-butyl haloperidol iodide (F 2 ), a derivative of haloperidol developed by our group, exhibits potent antioxidative properties and confers protection against cardiac ischemia/reperfusion (I/R) injury. The protective mechanisms by which F 2 ameliorates I/R injury remain obscure. The activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor transactivating many antioxidative genes, also attenuates I/R-induced myocardial damage. The present study investigated whether the cardioprotective effect of F 2 depends on Nrf2 using a mouse heart I/R model. F 2 (0.1, 0.2 or 0.4 mg/kg) or vehicle was intravenously injected to mice 5 minutes before reperfusion. Systemic administration of 0.4 mg/kg F 2 led to a significant reduction in I/R injury, which was accompanied by enhanced activation of Nrf2 signaling. The cardioprotection conferred by F 2 was largely abrogated in Nrf2-deficient mice. Importantly, we found F 2 -induced activation of Nrf2 is silent information regulator of transcription 1 (SIRT1)-dependent, as pharmacologically inhibiting SIRT1 by the specific inhibitor EX527 blocked Nrf2 activation. Moreover, F 2 -upregulated expression of SIRT1 was also Nrf2-dependent, as Nrf2 deficiency inhibited SIRT1 upregulation. These results indicate that SIRT1-Nrf2 signaling loop activation is indispensable for the protective effect of F 2 against myocardial I/R injury and may provide new insights for the treatment of ischemic heart disease.

Clinical diagnosis of pheochromocytoma and paraganglioma-induced secondary hypertension through UPLC-MS/MS analysis of plasma catecholamines and their metabolites.

This study aimed to elucidate the clinical diagnostic value of plasma catecholamines and their metabolites for pheochromocytoma and paraganglioma (PPGL)-induced secondary hypertension using ultraperformance liquid chromatography-mass spectrometry (UPLC-MS/MS). The study population included 155 patients with PPGL that were divided into the PPGL with hypertension (n = 79) and a PPGL without hypertension (n = 76) groups, and 90 healthy volunteers and 90 patients with primary hypertension as the control groups. UPLC-MS/MS was performed to detect plasma levels of catecholamines and their metabolites, including dopamine, vanillylmandelic acid (VMA), norepinephrine, metanephrine, and normetanephrine. Receiver operating characteristic curves were generated to analyze the diagnostic value of the plasma levels of catecholamines and their metabolites in PPGL-induced secondary hypertension. Patients in the primary hypertension and PPGL without hypertension groups had higher levels of dopamine, VMA, norepinephrine, metanephrine, and normetanephrine than patients in the normal group (all p < .05). On the other hand, patients in the PPGL with hypertension group had higher levels of dopamine, VMA, norepinephrine, metanephrine, and normetanephrine than patients in the normal, primary hypertension, and PPGL without hypertension groups (all p < .05). Collectively, our findings showed that dopamine, VMA, norepinephrine, metanephrine, and normetanephrine are all effective biomarkers for the diagnosis of PPGL and PPGL-induced secondary hypertension.

Efficacy of different doses of corticosteroids in treating severe COVID-19 pneumonia.

BACKGROUND: To investigate the efficacy of different doses of corticosteroids in treating severe coronavirus disease 2019 (COVID-19) pneumonia. METHODS: Between May 01, 2023, and June 20, 2023, 48 patients with severe COVID-19 pneumonia were treated at the Department of Respiratory and Critical Care Medicine of Jinan Fourth People's Hospital. The observation group (21 patients) received standard care and high-dose corticosteroids, (high-dose group). The control group (27 patients) received standard care and low-dose corticosteroids (low-dose group). We collected baseline data and recorded inflammatory marker levels after 3 days of treatment, body temperature recovery time, length of stay, and 28-day all-cause mortality. The results of outpatient follow-up were recorded after 1 month. RESULTS: There were no significant differences in 28-day mortality and length of stay. The number of days it took for body temperature to return to normal in the high-dose group was less than in the low-dose group. The high-dose group had significantly more reduced inflammatory factors (C-reactive protein (CRP), interleukin-6 (IL-6). A total of 20 discharged patients were given 8-16 mg of methylprednisolone, depending on chest computed tomography (CT) and clinical symptoms after 1 month; in all discharged patients using oral corticosteroids, CT features improved. CONCLUSION: High-dose corticosteroids had a significantly positive effect on the reduction of inflammatory factors and shortening body temperature recovery time. In the treatment of severe COVID-19 pneumonia, early administration of high-dose, short-course corticosteroids should be implemented.

Absence of association between Pfnfs1 mutation and in vitro susceptibility to lumefantrine in Plasmodium falciparum.

Artemether-lumefantrine (AL) is the most widely used antimalarial drug for treating uncomplicated falciparum malaria. This study evaluated whether the K65Q mutation in the Plasmodium falciparum cysteine desulfurase IscS (Pfnfs1) gene was associated with alternated susceptibility to lumefantrine using clinical parasite samples from Ghana and the China-Myanmar border area. Parasite isolates from the China-Myanmar border had significantly higher IC50 values to lumefantrine than parasites from Ghana. In addition, the K65 allele was significantly more prevalent in the Ghanaian parasites (34.5%) than in the China-Myanmar border samples (6.8%). However, no difference was observed in the lumefantrine IC50 value between the Pfnfs1 reference K65 allele and the non reference 65Q allele in parasites from the two regions. These data suggest that the Pfnfs1 K65Q mutation may not be a reliable marker for reduced susceptibility to lumefantrine.

[Cloning and functional analysis of flavanone synthase â ¡ from Dendrobium huoshanense].

Flavonoid C-glycosides are a class of natural products that are widely involved in plant defense responses and have diverse pharmacological activities. They are also important active ingredients of Dendrobium huoshanense. Flavanone synthase Ⅱ has been proven to be a key enzyme in the synthesis pathway of flavonoid C-glycosides in plants, and their catalytic product 2-hydroxyflavanone is the precursor compound for the synthesis of various reported flavonoid C-glycosides. In this study, based on the reported amino acid sequence of flavanone synthase Ⅱ, a flavanone synthase Ⅱ gene(DhuFNSⅡ) was screened and verified from the constructed D. huoshanense genome localization database. Functional validation of the enzyme showed that it could in vitro catalyze naringenin and pinocembrin to produce apigenin and chrysin, respectively. The open reading frame(ORF) of DhuFNSⅡ was 1 644 bp in length, encoding 547 amino acids. Subcellular localization showed that the protein was localized on the endoplasmic reticulum. RT-qPCR results showed that DhuFNSⅡ had the highest expression in stems, followed by leaves and roots. The expression levels of DhuFNSⅡ and other target genes in various tissues of D. huoshanense were significantly up-regulated after four kinds of abiotic stresses commonly encountered in the growth process, but the extent of up-regulation varied among treatment groups, with drought and cold stress having more significant effects on gene expression levels. Through the identification and functional analysis of DhuFNSⅡ, this study is expected to contribute to the elucidation of the molecular mechanism of the formation of quality metabolites of D. huoshanense, flavonoid C-glycosides, and provide a reference for its quality formation and scientific cultivation.

Unraveling the Molecular Basis of Color Variation in Dioscorea alata Tubers: Integrated Transcriptome and Metabolomics Analysis.

Dioscorea alata L. (Dioscoreaceae) is a widely cultivated tuber crop with variations in tuber color, offering potential value as health-promoting foods. This study focused on the comparison of D. alata tubers possessing two distinct colors, white and purple, to explore the underlying mechanisms of color variation. Flavonoids, a group of polyphenols known to influence plant color and exhibit antioxidant properties, were of particular interest. The total phenol and total flavonoid analyses revealed that purple tubers (PTs) have a significantly higher content of these metabolites than white tubers (WTs) and a higher antioxidant activity than WTs, suggesting potential health benefits of PT D. alata. The transcriptome analysis identified 108 differentially expressed genes associated with the flavonoid synthesis pathway, with 57 genes up-regulated in PTs, including CHS, CHI, DFR, FLS, F3H, F3'5'H, LAR, ANS, and ANR. The metabolomics analysis demonstrated that 424 metabolites, including 104 flavonoids and 8 tannins, accumulated differentially in PTs and WTs. Notably, five of the top ten up-regulated metabolites were flavonoids, including 6-hydroxykaempferol-7-O-glucoside, pinocembrin-7-O-(6″-O-malonyl)glucoside, 6-hydroxykaempferol-3,7,6-O-triglycoside, 6-hydroxykaempferol-7-O-triglycoside, and cyanidin-3-O-(6″-O-feruloyl)sophoroside-5-O-glucoside, with the latter being a precursor to anthocyanin synthesis. Integrating transcriptome and metabolomics data revealed that the 57 genes regulated 20 metabolites within the flavonoid synthesis pathway, potentially influencing the tubers' color variation. The high polyphenol content and antioxidant activity of PTs indicate their suitability as nutritious and health-promoting food sources. Taken together, the findings of this study provide insights into the molecular basis of tuber color variation in D. alata and underscore the potential applications of purple tubers in the food industry and human health promotion. The findings contribute to the understanding of flavonoid biosynthesis and pigment accumulation in D. alata tubers, opening avenues for future research on enhancing the nutritional quality of D. alata cultivars.

The mechanism of gut-lung axis in pulmonary fibrosis.

Pulmonary fibrosis (PF) is a terminal change of a lung disease that is marked by damage to alveolar epithelial cells, abnormal proliferative transformation of fibroblasts, excessive deposition of extracellular matrix (ECM), and concomitant inflammatory damage. Its characteristics include short median survival, high mortality rate, and limited treatment effectiveness. More in-depth studies on the mechanisms of PF are needed to provide better treatment options. The idea of the gut-lung axis has emerged as a result of comprehensive investigations into the microbiome, metabolome, and immune system. This theory is based on the material basis of microorganisms and their metabolites, while the gut-lung circulatory system and the shared mucosal immune system act as the connectors that facilitate the interplay between the gastrointestinal and respiratory systems. The emergence of a new view of the gut-lung axis is complementary and cross-cutting to the study of the mechanisms involved in PF and provides new ideas for its treatment. This article reviews the mechanisms involved in PF, the gut-lung axis theory, and the correlation between the two. Exploring the gut-lung axis mechanism and treatments related to PF from the perspectives of microorganisms, microbial metabolites, and the immune system. The study of the gut-lung axis and PF is still in its early stages. This review systematically summarizes the mechanisms of PF related to the gut-lung axis, providing ideas for subsequent research and treatment of related mechanisms.

Interaction between Wnt/ß-catenin signaling pathway and EMT pathway mediates the mechanism of sunitinib resistance in renal cell carcinoma.

BACKGROUND: Targeted drugs are the main methods of RCC treatment. However, drug resistance is common in RCC patients, in-depth study of the drug-resistant mechanism is essential. METHODS: We constructed sunitinib resistant and Twist overexpressed A498 cells, and studied its mechanisms in vitro and in vivo. RESULTS: In cell research, we found that either sunitinib resistance or Twist overexpression can activate Wnt/ß-catenin and EMT signaling pathway, and the sunitinib resistance may work through ß-catenin/TWIST/TCF4 trimer. In zebrafish research, we confirmed the similarity of Twist overexpression and sunitinib resistance, and the promoting effect of Twist overexpression on drug resistance. CONCLUSIONS: Sunitinib resistance and Twist overexpression can activate Wnt/ß-catenin signaling pathway and EMT to promote the growth and metastasis of RCC cells.

H2S-Releasing Versatile Montmorillonite Nanoformulation Trilogically Renovates the Gut Microenvironment for Inflammatory Bowel Disease Modulation.

Abnormal activation of the intestinal mucosal immune system, resulting from damage to the intestinal mucosal barrier and extensive invasion by pathogens, contributes to the pathogenesis of inflammatory bowel disease (IBD). Current first-line treatments for IBD have limited efficacy and significant side effects. An innovative H2S-releasing montmorillonite nanoformulation (DPs@MMT) capable of remodeling intestinal mucosal immune homeostasis, repairing the mucosal barrier, and modulating gut microbiota is developed by electrostatically adsorbing diallyl trisulfide-loaded peptide dendrimer nanogels (DATS@PDNs, abbreviated as DPs) onto the montmorillonite (MMT) surface. Upon rectal administration, DPs@MMT specifically binds to and covers the damaged mucosa, promoting the accumulation and subsequent internalization of DPs by activated immune cells in the IBD site. DPs release H2S intracellularly in response to glutathione, initiating multiple therapeutic effects. In vitro and in vivo studies have shown that DPs@MMT effectively alleviates colitis by eliminating reactive oxygen species (ROS), inhibiting inflammation, repairing the mucosal barrier, and eradicating pathogens. RNA sequencing revealed that DPs@MMT exerts significant immunoregulatory and mucosal barrier repair effects, by activating pathways such as Nrf2/HO-1, PI3K-AKT, and RAS/MAPK/AP-1, and inhibiting the p38/ERK MAPK, p65 NF-κB, and JAK-STAT3 pathways, as well as glycolysis. 16S rRNA sequencing demonstrated that DPs@MMT remodels the gut microbiota by eliminating pathogens and increasing probiotics. This study develops a promising nanoformulation for IBD management.