Inhibiting apoptosis and GSDME-mediated pyroptosis attenuates hepatic injury in septic mice.

BACKGROUND: Sepsis is characterized by severe inflammation and organ dysfunction resulting from a dysregulated organismal response to infection. Although pyroptosis has been presumably shown to be a major cause of multiple organ failure and septic death, whether gasdermin E (GSDME)-mediated pyroptosis occurs in septic liver injury and whether inhibiting apoptosis and GSDME-mediated pyroptosis can attenuate septic liver injury remain unclear. This study investigated the role of apoptosis and GSDME-mediated pyroptosis in septic liver injury. METHODS: Adult male C57BL/6 mice were randomly divided into four groups: sham, cecal ligation puncture (CLP), CLP + Z-DEVD-FMK (a caspase-3 inhibitor, 5 mg/kg), and CLP + Ac-DMLD-CMK (a GSDME inhibitor, 5 mg/kg). Sepsis severity was assessed using the murine sepsis score (MSS). Hepatic tissue damage was observed by the hematoxylin-eosin staining method, the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the levels of malondialdehyde (MDA), the concentrations of interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) were measured according to the related kits, and the changes in the hepatic tissue reactive oxygen species (ROS) levels were detected by immunofluorescence (IF). The protein expression levels of cleaved caspase-3, GSDME-N, IL-1ß, B-cell lymphoma-2 (Bcl-2), cytochrome C (Cyt-c), and acetaldehyde dehydrogenase 2 (ALDH2) were detected using western blotting. GSDME expression was detected by immunohistochemistry. RESULTS: Compared with the Sham group, CLP mice showed high sepsis scores and obvious liver damage. However, in the CLP + Z-DEVD-FMK and CLP + Ac-DMLD-CMK groups, the sepsis scores were reduced and liver injury was alleviated. Compared with the Sham group, the serum ALT and AST activities, MDA and ROS levels, and IL-1ß and TNF-α concentrations were increased in the CLP group, as well as the protein expression of cleaved caspase-3, GSDME-N, IL-1ß, Cyt-c, and GSDME positive cells (P < 0.05). However, the expression levels of Bcl-2 and ALDH2 protein were decreased (P < 0.05). Compared with the CLP group, the CLP + Z-DEVD-FMK and CLP + Ac-DMLD-CMK groups showed low sepsis scores, ALT and AST activities, MDA and ROS levels, decreased IL-1ß and TNF-α concentrations, and decreased expression of cleaved caspase-3, GSDME-N, IL-1ß protein expression, and GSDME positive cells (P < 0.05). The expression levels of Bcl-2 and ALDH2 protein were increased (P < 0.05). CONCLUSION: Apoptosis and GSDME-mediated pyroptosis are involved in the development of sepsis-induced hepatic injury. Inhibition of apoptosis and GSDME-mediated pyroptosis attenuates injury. ALDH2 plays a protective role by inhibiting apoptosis and pyroptosis.

An evaluation of the effectiveness of four chemical additives on the fermentation characteristics, in vitro digestibility and aerobic stability of total mixed ration silage based on soy sauce residue.

The study aimed to compare the impact of four chemical additives on fermentation characteristics, aerobic stability and in vitro digestibility of total mixed ration (TMR) silage based on soy sauce residue. The TMR (35% soy sauce residue + 45% Napier grass + 20% concentrate) was placed into silos (10 L). The experiment followed the completely random design, treated with different chemical additives: (1) distilled water (control); (2) 0.1% potassium sorbate (SP); (3) 0.1% sodium benzoate (SS); (4) 0.5% calcium propionate (SC); (5) 0.5% sodium diacetate (SD). Total of 100 silos (5 treatments × 4 aerobic exposure days × 5 replicates) were ensiled for 60 days. After exposure to the air, the samples were analyzed for the dynamic change of fermentation parameters at 4, 9 and 15 days, and the data was analyzed as repeated measures. The content of butyric acid and ammonia nitrogen was maintained at a low level. The highest (p < 0.05) lactic acid (LA) content and the lowest (p < 0.05) pH value were measured in SP. At the first 4 days of aerobic exposure, TMR silages treated with four chemical additives were more stable relative to the control, as indicated by the low pH value and yeast counts. Furthermore, the highest (p < 0.05) LA content and the lowest (p < 0.05) pH value indicated that SP performed superior aerobic stability compared with other chemical additives. The SP shows higher (p < 0.05) 72 h cumulative gas production (GP72) and in vitro neutral detergent fiber digestibility (IVNDFD) relative to the control. In conclusion, the SP performed superior in improving fermentation characteristics, aerobic stability and in vitro digestibility of TMR silages based on soy sauce residue.

Effect of citric acid residue and short-chain fatty acids on fermentation quality and aerobic stability of lucerne ensiled with lactic acid bacteria inoculants.

The experiment aimed to compare the effects of citric acid residue (CAR) to that of three commonly used short-chain fatty acids on the fermentation quality, aerobic stability and structural carbohydrate degradation of lucerne ensiled with lactic acid bacteria (LAB) inoculants. Fresh lucerne was ensiled with distilled water (control), LAB inoculant (L), CAR + LAB inoculant (CL), formic acid + LAB inoculant (FL), acetic acid + LAB inoculant (AL) and propanoic acid + LAB inoculant (PL) for 50 days. Chemical composition and microbial populations were determined after ensiling. The residual silages ensiled for 50 days were evaluated for aerobic stability. Compared with control, CL, FL, AL and PL treatments significantly (p < 0.05) decreased pH, ammonia nitrogen (NH3 -N) and butyric acid contents and increased lactic acid, acetic acid and propionic acid contents. Among them, CL silages had the lowest pH, dry matter and water-soluble carbohydrate (WSC) content, whereas the population of LAB and the lactic acid contents were highest. Besides, CL outperformed in enhancing fibre degradation, CL silages significantly decreased (p < 0.05) neutral detergent fibre, acid detergent fibre, hemicellulose and cellulose contents compared with control and had the highest Flieg's point. All treated-silages improved the aerobic stability compared with control, of which L improved 32 h, whereas CL, FL, AL and PL improved 46, 20, 46, >64 h, respectively. Applying a combination of CAR and LAB inoculant improved the fermentation quality and structural carbohydrate degradation of lucerne silage and had a similar effect on aerobic stability compared with other three short-chain fatty acids. The CAR had a comparable effect on enhancing the fermentation quality compared with three short-chain fatty acids. Thus, the combination of CAR and LAB inoculant might be used as an ideal additive for lucerne silage making with low WSC and high moisture content.

Pharmacokinetic study of deufruquintinibs in rats by HPLC-MS/MS after oral administration.

A sensitive and specific high-performance liquid chromatography-tandem mass spectrometry method was established to quantitatively determine the pharmacokinetics of fruquintinib (HMPL-013) and its derivatives [deufruquintinib-3D (HMPL-013-3D), deufruquintinib-6D (HMPL-013-6D) and deufruquintinib-9D (HMPL-013-9D)] in rats. Detection was performed on a triple quadrupole mass spectrometer in multiple reaction monitoring mode. The method established in this assay was successfully applied to a pharmacokinetic study of HMPL-013 and HMPL-013-Ds after oral administration. These results showed that HMPL-013-Ds had longer half-life and larger area under the plasma concentration-time curve than HMPL-013, especially HMPL-013-6D, which provides a significant basis for innovative ideas for drug structure transformation to reduce drug administration frequency and dosage.

Bruceine D ameliorates the balance of Th1/Th2 in a mouse model of ovalbumin-induced allergic asthma via inhibiting the NOTCH pathway.

Allergic asthma is a heterogeneous inflammatory disorder triggered by inhaled allergens, leading to airflow obstruction, bronchial inflammation, and airway hyperresponsiveness (AHR). T helper (Th) 2 cell-mediated immune response and airway inflammation are the key features of allergic asthma. Bruceine D (BD) is a bioactive compound extracted from the seeds of Brucea javanica. The present study aimed to investigate the effects of increased doses of BD on AHR, secretion of Th1-/Th2-associated cytokines, and inflammatory cell infiltration in ovalbumin (OVA)-induced allergic asthma mice. The results showed that BD reduced OVA-induced inflammatory cell infiltration and bronchial hyperresponsiveness into the peribronchial tissues and perivascular areas. Mice treated with BD also showed significantly decreased expressions of Th2-associated cytokines (i.e., interleukin (IL)-4, IL-5, and IL-13) and elevated production of Th1-associated cytokines (i.e., interferon gamma and IL-2) following OVA stimulation. BD treatment dose-dependently inhibited OVA-induced accumulation of inflammatory cells in asthmatic mice. Further analysis revealed that OVA exposure upregulated pulmonary expressions of NOTCH signaling receptors, a group of transmembrane proteins that communicate signals upon binding to transmembrane ligands expressed on adjacent cells, while BD treatment significantly abolished OVA-induced activation of the NOTCH pathway. In conclusion, BD protected mice against OVA-induced allergic asthma by reducing AHR and restoring the Th1/Th2 balance through the NOTCH signaling pathway. Our findings highlighted the potential of BD as a therapeutic agent for allergic asthma.

Mal-Prec: computational prediction of protein Malonylation sites via machine learning based feature integration : Malonylation site prediction.

BACKGROUND: Malonylation is a recently discovered post-translational modification that is associated with a variety of diseases such as Type 2 Diabetes Mellitus and different types of cancers. Compared with experimental identification of malonylation sites, computational method is a time-effective process with comparatively low costs. RESULTS: In this study, we proposed a novel computational model called Mal-Prec (Malonylation Prediction) for malonylation site prediction through the combination of Principal Component Analysis and Support Vector Machine. One-hot encoding, physio-chemical properties, and composition of k-spaced acid pairs were initially performed to extract sequence features. PCA was then applied to select optimal feature subsets while SVM was adopted to predict malonylation sites. Five-fold cross-validation results showed that Mal-Prec can achieve better prediction performance compared with other approaches. AUC (area under the receiver operating characteristic curves) analysis achieved 96.47 and 90.72% on 5-fold cross-validation of independent data sets, respectively. CONCLUSION: Mal-Prec is a computationally reliable method for identifying malonylation sites in protein sequences. It outperforms existing prediction tools and can serve as a useful tool for identifying and discovering novel malonylation sites in human proteins. Mal-Prec is coded in MATLAB and is publicly available at https://github.com/flyinsky6/Mal-Prec , together with the data sets used in this study.

[Effects of activation of mitochondrial aldehyde dehydrogenase 2 on inflammasome production in high glucose induced A549 cells].

OBJECTIVE: To investigate the effects of activation of mitochondrial aldehyde dehydrogenase 2(ALDH2) on high glucose-induced inflammasome production in alveolar epithelial A549 cells. METHODS: The alveolar epithelial A549 cells were cultured with 25 mmol/L high glucose complete medium and divided into 4 groups: Control group, ALDH2 agonist 20 µmol/L Alda-1 group, ALDH2 antagonist 60 µmol/L Daidzin group, 20 µmol/L Alda-1 + 60 µmol/L Daidzin group. After the cells treated for 24 h, the cell proliferation activity was measured by thiazolyl blue tetrazolium bromide(MTT) colorimetric assaymethod, and the cellular reactive oxygen species(ROS) level were detected by dihydroethidium(DHE) fluorescent staining method, the cell migration ability was performed by cell scratching experiments, the protein expressions of ALDH2 and the core components of inflammasome, nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3), apoptosis-associated speck-like protein containing CARD(ASC) and cysteinyl aspartate specific protease-1(caspase-1) were detected by western blot. RESULTS: Compared with the control group, after Alda-1 activated ALDH2 specifically, the cell proliferation activity did not change significantly, but the oxidative stress level and cell migration rate were significantly decreased(P<0.05). ALDH2 protein expression was significantly increased(P<0.05), the protein expressions of NLRP3, ASC and caspase-1 were significantly decreased(P<0.05). After Daidzin blocked ALDH2 specifically, there were no significant changes in cell proliferation, oxidative stress, cell migration rate, ALDH2 and ASC protein expressions, while NLRP3 protein expression was significantly increased(P<0.05), and caspase-1 protein expression was significantly decreased(P<0.05). Compared with Alda-1 group, there was no significant changes in cell proliferation and oxidative stress in Alda-1+Daidzin group, cell migration rate was significantly increased(P<0.05), ALDH2 protein expression was decreased(P<0.05), and the protein expressions of NLRP3, ASC and caspase-1 were significantly increased(P<0.05). CONCLUSION: Increasing ALDH2 expression in alveolar epithelial A549 cells may attenuate high glucose-induced cellular inflammatory reaction, possibly through reducing cellular ROS level and reducing inflammasome expression.

Genetic signatures of plant resistance genes with known function within and between species.

Plant disease resistance (R) genes have undergone significant evolutionary divergence to cope with rapid changes in pathogens. These highly variable evolutionary patterns may have contributed to diversity in R gene protein families or structures. Here, the evolutionary patterns of 76 identified R genes and their homologs were investigated within and between plant species. Results demonstrated that nucleotide binding sites and leucine-rich-repeat genes located in loci with complex evolutionary histories tended to evolve rapidly, have high variation in copy numbers, exhibit high levels of nucleotide variation and frequent gene conversion events, and also exhibit high non-synonymous to synonymous substitution ratios in LRR regions. However, non-NBS-LRR R genes are relatively well conserved with constrained variation and are more likely to participate in the basic defense system of hosts. In addition, both conserved and highly divergent evolutionary patterns were observed for the same R genes and were consistent with inter- and intra-specific distributions of some R genes. These results thus indicate either continuous or altered evolutionary patterns between and within species. The present investigation is the first attempt to investigate evolutionary patterns among all clearly functional R genes. The results reported here thus provide a foundation for future plant disease studies.

Comparative genomic analysis of the Lipase3 gene family in five plant species reveals distinct evolutionary origins.

Lipases are physiologically important and ubiquitous enzymes that share a conserved domain and are classified into eight different families based on their amino acid sequences and fundamental biological properties. The Lipase3 family of lipases was reported to possess a canonical fold typical of α/ß hydrolases and a typical catalytic triad, suggesting a distinct evolutionary origin for this family. Genes in the Lipase3 family do not have the same functions, but maintain the conserved Lipase3 domain. There have been extensive studies of Lipase3 structures and functions, but little is known about their evolutionary histories. In this study, all lipases within five plant species were identified, and their phylogenetic relationships and genetic properties were analyzed and used to group them into distinct evolutionary families. Each identified lipase family contained at least one dicot and monocot Lipase3 protein, indicating that the gene family was established before the split of dicots and monocots. Similar intron/exon numbers and predicted protein sequence lengths were found within individual groups. Twenty-four tandem Lipase3 gene duplications were identified, implying that the distinctive function of Lipase3 genes appears to be a consequence of translocation and neofunctionalization after gene duplication. The functional genes EDS1, PAD4, and SAG101 that are reportedly involved in pathogen response were all located in the same group. The nucleotide diversity (Dxy) and the ratio of nonsynonymous to synonymous nucleotide substitutions rates (Ka/Ks) of the three genes were significantly greater than the average across the genomes. We further observed evidence for selection maintaining diversity on three genes in the Toll-Interleukin-1 receptor type of nucleotide binding/leucine-rich repeat immune receptor (TIR-NBS LRR) immunity-response signaling pathway, indicating that they could be vulnerable to pathogen effectors.

Aspirin attenuates monocrotaline-induced pulmonary arterial hypertension in rats by suppressing the ERK/MAPK pathway.

This study aimed to investigate the therapeutic effects of aspirin (ASA) and its potential mechanisms of action in monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in rats. PAH was induced in a rat model by a single intraperitoneal (IP) injection of MCT. Saline was injected in a control group. Two weeks following MCT injection, right ventricular systolic pressure (RVSP) and systolic blood pressure (SBP) were measured in six rats from each group to confirm establishment of a PAH model. The remaining MCT-treated rats were randomly allocated to receive IP injection of saline, ASA, or ERK1/2 inhibitor PD98059. Four weeks following treatment, RVSP was measured and all rats were sacrificed for histological study. There was no significant difference in SBP in any group two weeks following MCT administration. Nonetheless RVSP was significantly increased in the MCT group compared with the control group. At 6 weeks, ASA treatment remarkably attenuated MCT-induced increased RVSP, RV hypertrophy, and pulmonary artery remodeling compared with the MCT group. The density of pulmonary capillaries in ASA-treated rats was also dramatically increased. Treatment with ASA significantly inhibited the increased p-ERK1/2 and restored the impaired endothelial nitric oxide synthase (eNOS) in MCT-treated rats. This study demonstrated that ASA distinctively attenuates MCT-induced PAH by inhibition of the ERK1/2 signaling pathway.

Synthesis and Antitumor Activities of Chiral Dipeptide Thioureas Containing an Alpha-Aminophosphonate Moiety.

Thiourea derivatives demonstrate potent cytotoxic activity against various leukemias and many tumor cell lines. In our previous study, the combination of thiourea and phosphonate has been proven as an effective strategy for developing antitumor agents. Herein, we synthesized and evaluated a series of novel chiral dipeptide thioureas containing an α-aminophosphonate moiety as antitumor agents. Finally, we developed novel dipeptide thioureas 11d and 11f that showed comparable inhibition with that of Cisplatin against BGC-823 and A-549 cells, respectively.

[Application of pylorus-vagus-preserving gastrectomy in early gastric cancer in middle third of stomach].

OBJECTIVE: To evaluate the long-term outcomes of pylorus-vagus-preserving partial gastrectomy for early gastric cancer in middle third of stomach. METHODS: Between January 2004 and June 2009, 46 patients with early gastric cancer in middle third of stomach underwent pylorus-vagus-preserving partial gastrectomy (PPG) while another 85 patients had conventional distal gastrectomy (DG). Clinicopathologic data and follow-up results of two groups were analyzed retrospectively, including the results of subjective nutritional assessments, laboratory blood biochemical data, endoscopic findings of remnant stomach and total 5-year survival rates. RESULTS: Postprandial dumping syndrome occurred in 7 patients (8.2%) in DG group while no syndrome occurred in PPG group. The incidence of gallbladder stones at 18 months after operation in DG group was higher than that in PPG group. Significant difference existed between two groups (P<0.05). Even though no significant difference existed in laboratory blood biochemical data and endoscopic findings, PPG group recovered better and regurgitation was frequently found in DG group. Food residue in gastric remnant was frequently observed in PPG (31.1%) than in DG (10.8%, P<0.05) by endoscopic findings. At 2 years post-operation, the postoperative 5-year recurrence rate was 6.5% (2/46) in PPG group versus 8.2% (7/85) in DG group. However no significant difference existed between 2 groups (P=0.724). No significant difference existed between PPG group (91.3%) and DG group (90.6%) in overall 5-year survival rate. CONCLUSION: For early gastric cancer in middle third of stomach, pylorus-vagus-preserving partial gastrectomy is effective in maintaining postoperative function. And it has the same postoperative survival rate as conventional distal gastrectomy.

[Efficacies of neoadjuvant chemotherapy plus nutritional support in advanced gastric cancer complicated with pylori obstruction].

OBJECTIVE: To explore the efficacies of neoadjuvant chemotherapy plus nutritional supports for gastric cancer complicated with pyloric obstruction. METHODS: Retrospective analyses were performed for a total of 116 patients of gastric cancer complicated with pyloric obstruction undergoing exploratory laparotomy from January 2004 to June 2013. RESULTS: Sixty-two patients (group A) received neoadjuvant chemotherapy (regimen of FOLFOX) plus preoperative nutritional support. And parenteral (PN, n = 30) and enteral (EN, n = 32) nutritional supports were provided. Another 54 patients (group B) underwent exploratory laparotomy alone. The serum level of albumin and score of quality of life in group A at the last preoperative day improved significantly. And EN was better than PN. The rate of excision/radical excision of group A (85.5%, 45.2%) was much higher than group B (64.8%, 18.5%) (both P < 0.05). CONCLUSION: Nutritional support, especially EN, can improve the nutritional status and quality of life in patients with gastric cancer complicated with pyloric obstruction. And nutritional support plus neoadjuvant chemotherapy increase the rate of tumor excision.

[Causal association between immune cells and sepsis: a based on Mendelian randomization method study].

OBJECTIVE: To investigate the causal association between immune cell and different types of sepsis by using Mendelian randomization (MR) method, and to find the immune cell phenotypes causally associated with sepsis. METHODS: Summary data for various circulating immune cell phenotypes were obtained from the GWAS catalog (GCST90001391-GCST90002121). Sepsis data were sourced from the UK Biobank database. Single nucleotide polymorphisms (SNP) were used as instrumental variables. The correlation threshold of P < 5×10-6 was used to identify the strongly correlated instrumental variables, and the code was used to remove the linkage disequilibrium and the instrumental variables with F-value < 10. Inverse variance weighting (IVW) was used as the main research method to evaluate the stability and reliability of the results, including Cochran's Q test, MR-Egger regression and Leave one out. Reverse MR analysis was performed based on the immunophenotypic results of the removal of horizontal pleiotropy, and the immune cell phenotype with one-way causal association was obtained. Odds ratio (OR) and 95% confidence interval (95%CI) were used to represent the effect value of the results. RESULTS: CD16 on CD14-CD16+; monocyte had horizontal pleiotropy in sepsis (OR = 0.965 4, 95%CI was 0.933 5-0.998 3, P = 0.039 6). There were five immunophenotypes that had reverse causal associations with the types associated with sepsis. After excluding immune cell phenotypes with horizontal pleiotropy and reverse causation, a total of 42 immune cell phenotypes with sepsis, 36 immune cell phenotypes with sepsis (28-day death in critical care), 32 immune cell phenotypes with sepsis (critical care), 44 immune cell phenotypes with sepsis (28-day death), and 30 immune cell phenotypes had potential causal associations with sepsis (under 75 years old). After false discovery rate (FDR) correction, the correlations between BAFF-R on IgD- CD38br and sepsis (28-day death) were negative and strong (OR = 0.737 8, 95%CI was 0.635 9-0.856 0, P = 6.05×10-5, PFDR = 0.044 2). CONCLUSIONS: A variety of immune cell phenotypes may have a protective effect on sepsis, especially BAFF-R on IgD- CD38br expression is negatively correlated with sepsis (28-day death), which provides a new idea for immune modulation therapy in sepsis.

Structural Health Monitoring of Glass Fiber-Reinforced Polymer Laminates with Carbon Nanotube-Coated Glass Fiber Sensing Layer after Low-Velocity Impact Using Electrical Resistance Tomography.

Structural health monitoring (SHM) of composite materials is of great significance in various practical applications. However, it is a challenge to accurately monitor the damage of composites without affecting their mechanical properties. In this paper, an embedded sensing layer based on carbon nanotube-coated glass fiber is designed, combined with electrical resistance tomography (ERT) for in situ damage monitoring. Multi-wall carbon nanotube-coated glass fiber (MWCNT-GF) is prepared and embedded into laminates as an in situ sensing layer. Low-velocity impact experiments demonstrate that the embedded sensing layer has high compatibility with the composite laminates and has no adverse effect on its impact response; although, the energy absorption behavior of glass fiber-reinforced polymer (GFRP) laminates containing MWCNT-GF occurs about 10% earlier than that of GFRP laminates overall. ERT technology is used to analyze the laminates after a low-velocity impact test. The results show that the in situ monitoring method with the embedded MWCNT-GF sensing layer can achieve high precision in imaging localization of impact damage, and the error of the detected damage area is only 4.5%.

Damage Monitoring of Regularly Arrayed Short-Fiber-Reinforced Composite Laminates under Tensile Load Based on Acoustic Emission Technology.

Carbon-fiber-reinforced polymer (CFRP) composites are widely used in lightweight structures because of their high specific strength, specific modulus, and low coefficient of thermal expansion. Additionally, the unidirectionally arrayed chopped strand (UACS) laminates have excellent mechanical properties and flowability, making them suitable for fabricating structures with complex geometry. In this paper, the damage process of UACS quasi-isotropic laminates under tensile load was tested using acoustic emission detection technology. The mechanical properties and damage failure mechanism of UACS laminates were studied combined with finite element calculation. By comparing and analyzing the characteristic parameters of acoustic emission signals such as amplitude, relative energy, and impact event, it is found that acoustic emission behavior can accurately describe the damage evolution of specimens during loading. The results show that the high-amplitude signals representing fiber fracture in continuous fiber laminates are concentrated in the last 41%, while in UACS laminates they are concentrated in the last 30%. In UACS laminates, more of the damage is caused by matrix cracks and delamination with medium- and low-amplitude signals, which indicates that UACS laminates have a good suppression effect on damage propagation. The stress-strain curves obtained from finite element analysis agree well with the experiment results, showing the same damage sequence, which confirms that the model described in this research is reliable.

Neighboring Effect-Initiated Supramolecular Nanocomplex with Sequential Infiltration as Irreversible Apoptosis Inducer for Synergetic Chemo-Immunotherapy.

Chemotherapy-based combination regimens are recommended as first-line treatment for colorectal cancer. However, multidrug resistance (MDR) and limited drug infiltration in tumor microenvironment remain critical challenges. Herein, a pH/redox dual activated supramolecular DAS@CD-OxPt (IV) nanoparticles (NPs) via host-guest molecular recognition to achieve relay drugs delivery of active oxaliplatin (OxPt (IV)) and Src inhibitor dasatinib (DAS) between tumor cells is developed. DAS@CD-OxPt (IV) NPs exhibit prolonged circulation in the blood and intra-tumoral retention. Triggered by the endo/lysosome (pH 5.0), flexible DAS@CD-OxPt (IV) NPs exhibited proton-driven in situ assembly to form nanofiber in tumor cells. Dual chemotherapeutic agents released from DAS@CD-OxPt (IV) NPs synergistically cause irreversible DNA damage by blocking p53-mediated DNA repair. Supramolecular nanofibers can further serve as the "ammunition depot" to continuously release drugs from dying cells and transport them into neighboring tumor cells, leading to domino-like cell death and enhanced immunogenicity. Furthermore, DAS@CD-OxPt (IV) NPs combined with immune checkpoint blockade (ICB) therapy strikingly suppress CT26 tumor growth and pulmonary metastasis.

Galectin-1 Promotes Gastric Carcinoma Progression and Cisplatin Resistance Through the NRP-1/c-JUN/Wee1 Pathway.

PURPOSE: Gastric cancer (GC) is among the deadliest malignancies and the third leading cause of cancer-related deaths worldwide. Galectin-1 (Gal-1) is a primary protein secreted by cancer-associated fibroblasts (CAFs); however, its role and mechanisms of action of Gal-1 in GC remain unclear. In this study, we stimulated GC cells with exogenous human recombinant galectin-1 protein (rhGal-1) to investigate its effects on the proliferation, migration, and resistance to cisplatin. MATERIALS AND METHODS: We used simulated rhGal-1 protein as a paracrine factor produced by CAFs to induce GC cells and investigated its promotional effects and mechanisms in GC progression and cisplatin resistance. Immunohistochemical (IHC) assay confirmed that Gal-1 expression was associated with clinicopathological parameters and correlated with the expression of neuropilin-1 (NRP-1), c-JUN, and Wee1. RESULTS: Our study reveals Gal-1 expression was significantly associated with poor outcomes. Gal-1 boosts the proliferation and metastasis of GC cells by activating the NRP-1/C-JUN/Wee1 pathway. Gal-1 notably increases GC cell resistance to cisplatin The NRP-1 inhibitor, EG00229, effectively counteracts these effects. CONCLUSIONS: These findings revealed a potential mechanism by which Gal-1 promotes GC growth and contributes to chemoresistance, offering new therapeutic targets for the treatment of GC.

Inhibiting caspase-3/GSDME-mediated pyroptosis ameliorates septic lung injury in mice model.

Acute lung injury is one of the most serious complications of sepsis, which is a common critical illness in clinic. This study aims to investigate the role of caspase-3/ gasdermin-E (GSDME)-mediated pyroptosis in sepsis-induced lung injury in mice model. Cecal ligation (CLP) operation was used to establish mice sepsis-induced lung injury model. Lung coefficient, hematoxylin and eosin staining and transmission electron microscopy were used to observe the lung injury degree. In addition, caspase-3-specific inhibitor Z-DEVD-FMK and GSDME-derived inhibitor AC-DMLD-CMK were used in CLP model, caspase-3 activity, GSDME immunofluorescence, serum lactate dehydrogenase (LDH) and interleukin-6 (IL-6) levels, TUNEL staining, and the expression levels of GSDME related proteins were detected. The mice in CLP group showed the increased expressions of cleaved-caspase-3 and GSDME-N terminal, destruction of lung structure, and the increases of LDH, IL-6, IL-18 and IL-1ß levels, which were improved in mice treated with Z-DEVD-FMK or AC-DMLD-CMK. In conclusion, caspase-3/GSDME mediated pyroptosis is involved in the occurrence of sepsis-induced lung injury in mice model, inhibiting caspase-3 or GSDME can both alleviate lung injury.