Isolation of two peptaibols with potent antimicrobial and cytotoxic activities from the mangrove endophytic fungus Trichoderma lentiforme ML-P8-2.

Trichorzin PA is a family of 18-residue peptaibols with linear and flexible peptide chains. The three-dimensional structures and biological activities of trichorzin PA peptaibols are largely uncharacterised. In this work, two previously identified peptaibols, trichorzin PA VI (1) and II (2), were isolated from Trichoderma lentiforme ML-P8-2. While for the first time, we report here the X-ray crystallographic structure of 1, antimicrobial activities against a panel of common pathogenic bacteria and fungi, and cytotoxicities of 1 and 2. In bioassays, 1 and 2 exhibited strong antimicrobial activities against the seven tested microbes, with MIC values in the range of 0.19-6.25 µM. Additionally, 1 and 2 displayed potent cytotoxicities against five human cancer cell lines, with IC50 values in the range of 0.01 ± 0.02-2.75 ± 0.17 µM. The bioassay results were generally better than those reported for other 18-residue peptaibols, including other trichorzin PA members.

Optimization of tight gas reservoir fracturing parameters via gradient boosting regression modeling.

In China, the exploitation of most unconventional oil and gas reservoirs is dependent on hydraulic fracturing, which is a key method employed when developing tight gas formations. Numerous scholars and field engineers, both domestically and internationally, have conducted extensive numerical simulations and physical experiments to study crack propagation and predict post-fracturing productivity in hydraulic fracturing. Although some progress has been reported in this regard, it is difficult to accurately predict the well productivity using mechanistic models owing to the vertical multilayered development of tight gas reservoirs. In this study, vertical fractured wells in a block of Sulige gas field were examined. The block relied on hydraulic fracturing to produce tight gases. However, as development progressed, the available reservoir environment deteriorated, large differences emerged between wells after fracturing, and the fracturing results did not meet the expectations. In this study, geological, construction, and generation data for this block that had been collected since 2007 were analyzed. After applying multiple machine-learning methods to filter outliers and fill in missing values, k-means clustering, classification enhancement, extreme gradient enhancement, and LightGBM algorithms were used to establish a regression model. The analysis results revealed that the regression accuracy of the cluster test set was as high as 70% and that the LightGBM model had the best regression effect among the 227 stripper wells in the block. After optimizing the fracturing construction parameters (fracturing fluid volume, proppant volume, liquid-nitrogen volume, and pumping rate), the average fracturing fluid and liquid-nitrogen volumes per well decreased, whereas the unit reservoir proppant and liquid-nitrogen volumes increased. The results also revealed that 182 wells showed an improved initial production capacity during fracturing. The average gas production index per meter increased by 22.04%. This approach enabled rapid and efficient production forecasting and construction optimization. Moreover, this represents a novel fracture design method that is applicable to onsite engineers in tight gas production fields in the Ordos region.

Spontaneous regression of a giant uterine leiomyoma after delivery: a case report and literature review.

BACKGROUND: Uterine leiomyomas are hormone-dependent benign tumors and often begin to shrink after menopause due to the reduction in ovarian steroids. The influence of pregnancy on uterine leiomyomas size remains unclear. Here, we present a case of spontaneous regression of a giant uterine leiomyoma after delivery. CASE PRESENTATION: A 40-year-old woman presented with multiple uterine leiomyomas, one of which is a giant uterine leiomyomas (approximately 8 cm in diameter) that gradually shrinked after delivery. At over two months postpartum, the large myometrial leiomyoma had transformed into a submucosal leiomyoma, and over 3 years postpartum, both the submucosal leiomyoma and multiple intramural leiomyomas completely regressed. CONCLUSION: Spontaneous regression of a giant uterine leiomyom is rare after delivery. Considering uterine leiomyoma regression until over 3 year postpartum,we need to observe the regression of uterine fibroid for a longer time postpartum in the absence of fibroid related complications. In addition, it will provide new insights for treatment options of uterine leiomyomas in the future.

Ascomylactam C Induces an Immunogenic Cell Death Signature via Mitochondria-Associated ER Stress in Lung Cancer and Melanoma.

Ascomylactam C (AsC) is a new 13-membered-ring macrocyclic alkaloid, which was first isolated and identified in 2019 from the secondary metabolites of the mangrove endophytic fungus Didymella sp. CYSK-4 in the South China Sea. AsC has been found to have a broad-spectrum cytotoxic activity. However, the antitumor effects in vivo and mechanisms of AsC remain unclear. The aim of this study was to describe the effects of AsC on lung cancer and melanoma cells and to explore the antitumor molecular mechanism of AsC. In vitro, we used plate colony formation experiments and demonstrated the ability of AsC to inhibit low-density tumor growth. An Annexin V/PI cell apoptosis detection experiment revealed that AsC induced tumor cell apoptosis. In vivo, AsC suppressed the tumor growth of LLC and B16F10 allograft significantly in mice, and promoted the infiltration of CD4+ T and CD8+ T cells in tumor tissues. Mechanistically, by analyses of Western blotting, immunofluorescence and ELISA analysis, we found that AsC increased ROS formation, induced endoplasmic reticulum (ER) stress, activated the protein kinase RNA-like ER kinase (PERK)/eukaryotic translation initiation factor (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP homologous protein (CHOP) signaling pathway, and induced immunogenic cell death (ICD) of tumor cells. Our results suggest that AsC may be a potentially promising antitumor drug candidate.

Comprehensive comparative analysis of the prognostic impact of systemic inflammation biomarkers for patients underwent cardiac surgery.

Background: Inflammation plays an integral role in the development of cardiovascular disease, and few studies have identified different biomarkers to predict the prognosis of cardiac surgery. But there is a lack of reliable and valid evidence to determine the optimal systemic inflammatory biomarkers to predict prognosis. Methods: From December 2015 and March 2021, we collected 10 systemic inflammation biomarkers among 820 patients who underwent cardiac surgery. Time-dependent receiver operating characteristic curves (ROC) curve at different time points and C-index was compared at different time points. Kaplan-Meier method was performed to analyze overall survival (OS). Cox proportional hazard regression analyses were used to assess independent risk factors for OS. A random internal validation was conducted to confirm the effectiveness of the biomarkers. Results: The area under the ROC of lymphocyte-to-C-reactive protein ratio (LCR) was 0.655, 0.620 and 0.613 at 1-, 2- and 3-year respectively, and C-index of LCR for OS after cardiac surgery was 0.611, suggesting that LCR may serve as a favorable indicator for predicting the prognosis of cardiac surgery. Patients with low LCR had a higher risk of postoperative complications. Besides, Cox proportional hazard regression analyses indicated that LCR was considered as an independent risk factor of OS after cardiac surgery. Conclusion: LCR shows promise as a noteworthy representative among the systemic inflammation biomarkers in predicting the prognosis of cardiac surgery. Screening for low LCR levels may help surgeons identify high-risk patients and guide perioperative management strategies.

Peptidase inhibitor (PI16) impairs bladder cancer metastasis by inhibiting NF-κB activation via disrupting multiple-site ubiquitination of NEMO.

BACKGROUND: Bladder cancer (BLCA) is a malignancy that frequently metastasizes and leads to poor patient prognosis. It is essential to understand the molecular mechanisms underlying the progression and metastasis of BLCA and identify potential biomarkers. METHODS: The expression of peptidase inhibitor 16 (PI16) was analysed using quantitative PCR, immunoblotting and immunohistochemistry assays. The functional roles of PI16 were evaluated using wound healing, transwell, and human umbilical vein endothelial cell tube formation assays, as well as in vivo tumour models. The effects of PI16 on nuclear factor κB (NF-κB) signalling activation were examined using luciferase reporter gene systems, immunoblotting and immunofluorescence assays. Co-immunoprecipitation was used to investigate the interaction of PI16 with annexin-A1 (ANXA1) and NEMO. RESULTS: PI16 expression was downregulated in bladder cancer tissues, and lower PI16 levels correlated with disease progression and poor survival in patients with BLCA. Overexpressing PI16 inhibited BLCA cell growth, motility, invasion and angiogenesis in vitro and in vivo, while silencing PI16 had the opposite effects. Mechanistically, PI16 inhibited the activation of the NF-κB pathway by interacting with ANXA1, which inhibited K63 and M1 ubiquitination of NEMO. CONCLUSIONS: These results indicate that PI16 functions as a tumour suppressor in BLCA by inhibiting tumour growth and metastasis. Additionally, PI16 may serve as a potential biomarker for metastatic BLCA.

Core Needle Biopsy Guidance Based on Tissue Morphology Assessment with AI-OCT Imaging.

This paper presents a combined optical imaging/artificial intelligence (OI/AI) technique for the real-time analysis of tissue morphology at the tip of the biopsy needle, prior to collecting a biopsy specimen. This is an important clinical problem as up to 40% of collected biopsy cores provide low diagnostic value due to high adipose or necrotic content. Micron-scale-resolution optical coherence tomography (OCT) images can be collected with a minimally invasive needle probe and automatically analyzed using a computer neural network (CNN)-based AI software. The results can be conveyed to the clinician in real time and used to select the biopsy location more adequately. This technology was evaluated on a rabbit model of cancer. OCT images were collected with a hand-held custom-made OCT probe. Annotated OCT images were used as ground truth for AI algorithm training. The overall performance of the AI model was very close to that of the humans performing the same classification tasks. Specifically, tissue segmentation was excellent (~99% accuracy) and provided segmentation that closely mimicked the ground truth provided by the human annotations, while over 84% correlation accuracy was obtained for tumor and non-tumor classification.

Barnacle-Inspired Wet Tissue Adhesive Hydrogels with Inherent Antibacterial Properties for Infected Wound Treatment.

Currently, antibiotics are the most common treatment for bacterial infections in clinical practice. However, with the abuse of antibiotics and the emergence of drug-resistant bacteria, the use of antibiotics has faced an unprecedented challenge. It is imminent to develop nonantibiotic antimicrobial agents. Based on the cation-π structure of barnacle cement protein, a polyphosphazene-based polymer poly[(N,N-dimethylethylenediamine)-g-(N,N,N,N-dimethylaminoethyl p-ammonium bromide (ammonium bromide)-g-(N,N,N,N-dimethylaminoethyl acetate ethylammonium bromide)] (PZBA) with potential adhesion and inherent antibacterial properties was synthesized, and a series of injectable antibacterial adhesive hydrogels (PZBA-PVA) were prepared by cross-linking with poly(vinyl alcohol) (PVA). PZBA-PVA hydrogels showed good biocompatibility, and the antibacterial rate of the best-performed hydrogel reached 99.81 ± 0.04% and 98.80 ± 2.16% against Staphylococcus aureus and Escherichia coli within 0.5 h in vitro, respectively. In the infected wound model, the healing rate of the PZBA-PVA-treated group was significantly higher than that of the Tegaderm film group due to the fact that the hydrogel suppressed inflammatory responses and modulated the infiltration of immune cells. Moreover, the wound healing mechanism of the PZBA-PVA hydrogel was further evaluated by real-time polymerase chain reaction and total RNA sequencing. The results indicated that the process of hemostasis and tissue development was prompted and the inflammatory and immune responses were suppressed to accelerate wound healing. Overall, the PZBA-PVA hydrogel is shown to have the potential for infected wound healing application.

Maleimide as the PEG end-group promotes macrophage-targeted drug delivery of PEGylated nanoparticles in vivo by enhancing interaction with circulating erythrocytes.

Radiotherapy (IR) is capable of enhancing antitumor immune responses. However, IR treatment also aggravates the infiltration of peripheral macrophages into the tumor, resulting in reversing the therapeutic effects of antitumor immunity. Thus, a strategy to effectively prevent tumor infiltration by macrophages may further improved the therapeutic efficacy of radiotherapy. Herein, we found that PEGylated solid lipid nanoparticles with maleimide as PEG end-group (SLN-PEG-Mal) show significantly enhanced adsorption onto RBCs through reacting with reactive sulfhydryl groups on RBCs' surface both in vitro and in vivo, and caused significant changes in the surface properties and morphology of RBCs. These RBCs adsorbed by SLN-PEG-Mal were rapidly removed from circulation due to efficient engulfment by reticuloendothelial macrophages, supporting the usefulness of SLN-PEG-Mal for macrophage-targeted drug delivery. While lacking the use of radioisotope tracing (considered the gold standard for PK/BD studies), our data align with the expected pathway of host defense activation through surface-loaded RBCs. Importantly, injection of paclitaxel-loaded SLN-PEG-Mal effectively inhibited the tumor-infiltration by macrophages, and significantly improved the antitumor immune responses in tumor-bearing mice treated with low-dose irradiation. This study provides insights into the effects of maleimide as PEG end-group on enhancing the interaction between PEGylated nanoparticles and RBCs and offers an effective strategy to inhibit tumor infiltration by circulating macrophages.

Association of Neutrophil-to-Lymphocyte Ratio with Nutrition in Patients with Various Types of Malignant Tumors: A Multicenter Cross-Sectional Study.

Aim: Neutrophil-to-lymphocyte ratio (NLR) is an index of systemic inflammation. This study is to clarify the role of NLR in body functional status, nutritional risk and nutritional status in the course of tumor. Methods: A multi-center cross-sectional study of patients with various types of malignant tumors was accrued from the whole country. There were 21,457 patients with completed clinical data, biochemical indicators, physical examination, the Patient-Generated Subjective Global Assessment (PG-SGA) and Nutrition Risk Screening 2002 (NRS2002) survey. Logistic regression analysis was used to figure out the influencing factors of NLR, and four models were established to evaluate the influence of NLR on body functions, nutritional risks and nutritional status. Results: Male patients, TNM stage IV, total bilirubin, hypertension and coronary atherosclerotic heart disease (CAHD) were independent predictors of NLR >2.5. BMI, digestive systemic tumors and triglyceride negatively affect NLR in multivariable logistic regression. NLR was an independent predictor of Karnofsky Performance Scale (KPS), fat store deficit in all degrees, moderate and severe muscle deficit, mild fluid retention and PG-SGA grade. Conclusion: Male patients and those with hypertension and CAHD are prone to systemic inflammation. Systemic inflammation significantly degrades body function status and nutritional status, increases nutritional risk and influences fat and muscle metabolism in patients with malignant tumor. Improving the intervenable indicators such as elevating albumin and pre-albumin, decreasing total bilirubin and enhancing nutrition support are imperative. Obesity and triglyceride behave like anti-systemic inflammation, which is misleading due to reverse causation in the course of malignancy.

Biosafety risk assessment of gold and aluminum nanoparticles in tumor-bearing mice.

To improve the biosafety of the nanodelivery system, this study developed novel monodisperse spherical aluminum nanoparticles (Al NPs) and evaluated their cytotoxicity in vitro and distribution and biotoxicity in vivo. Compared with gold nanoparticles of the same size, Al NPs not only had low cytotoxicity in vitro but also did not cause accumulation in major organs in vivo after intravenous injections. No significant abnormalities were observed in the serum biochemical indices of mice injected with Al NPs. Additionally, no substantial changes occurred in the histopathology of major organs, and no apparent biological toxicity was measured after consecutive injections of Al NPs. These results indicate that Al NPs have a good biological safety and provide a new method for developing low-toxicity nanomedicine.

A Meroterpenoid from Tibetan Medicine Induces Lung Cancer Cells Apoptosis through ROS-Mediated Inactivation of the AKT Pathway.

As a traditional Tibetan medicine in China, Meconopsis grandis Prain has been used to treat a variety of illnesses by local people for thousands of years. However, the active ingredients contained in Meconopsis grandis Prain and its pharmacodynamic mechanisms have scarcely been reported. We isolated a meroterpenoid named D1399 from Meconopsis grandis Prain endophytic fungi with strong antitumor activity. The structure analysis showed that D1399 is an alkaloid containing a 13-membered macrocyclic structure. The IC50 of D1399 for human lung cancer cells' viability ranged from 0.88 to 2.45 µM. Furthermore, we utilized TUNEL assay and western blotting to investigate the antitumor effectiveness of D1399. The results have shown that D1399 induced the apoptosis of lung cancer cells on the extrinsic and intrinsic pathways by boosting ROS generation and repressing AKT activity. In the mouse xenograft model, the average tumor weight with 30 mg·kg-1 D1399 treatment exhibited 73.19% inhibition compared with the untreated control, without affecting body weight loss. Above all, for the first time, our study provides a possible mechanism for the antitumor activity of D1399 in vitro and in vivo as a natural product from Tibetan medicine with Meconopsis grandis Prain, which may be a potentially promising antitumor drug candidate.

Size effect of cellulose nanocrystals in cellular internalization and exosome-packaging exocytosis.

With the purpose of investigating the bio-interaction between CNC and cells, the end-fluorescence CNC (FCNC) and surface-adsorbed glucosamine [(g)FCNC] were prepared by the region-selective modification and electrostatic adsorption strategy in this study. The cell growth was arrested in a time dependent manner when incubated with CNC in the low glucose environment. The small-size FCNC was preferred by the cells with the observation of higher affinity. Specifically, the affinity of (g)FCNC to the phagocytic cell RAW264.7 cell and kidney derived cell 293 t was generally increased in response to the "Warburg effect", which on the contrary was observed with the weak effect in the tumor cells. We confirmed the exocytosis of internalized rod-like nanocrystal was achieved by the packaging effect of exosomes. Our results revealed the underappreciated bio-interaction between CNC and different cells, which contributed the evidence of an inspiration for this natural nanomaterial in the cell-level application.

Only transesophageal echocardiography guided patent foramen ovale closure: A single-center experience.

Background: An increasing number of studies have proved that patent foramen ovale (PFO) occlusion could reduce the incidence of recurrent stroke more than drug therapy alone under certain conditions. Which is the "best" guidance technique still remains to be discussed. Methods: A single center retrospective study enrolled 120 patients (mean age 52.51 ± 14.29 years) who underwent PFO closure between April 2019 and March 2021. 87 patients (72.5%) had suffered cryptogenic stroke (CS) at least one time, and 24 patients (20%) had repetitive episodes of hemicrania unsourced. 65 patients were in the transesophageal echocardiography (TEE) guidance group (T-group), and the other 55 patients were in the angiographic guidance group (A-group). Results: There were no significant differences in crucial clinical characteristics between the two groups. In T-group, the procedural success rate was higher (100% vs. 92.7%, P = 0.028), and the procedural time was shorter (23.15 ± 13.87 vs. 25.75 ± 7.19, P = 0.001). No difference was detected in the procedural complication rate. Follow-up were performed at least 12 months. At 12 months, new atrial fibrillation occurred in 1 patient (1.5%) in the T-group and in 1 patient (1.8%) in the A-group (P = 0.905). Residual shunt occurred in 1 patient (1.5%) in the T-group and in 3 patients (5.5%) in the A-group (P = 0.236). Recurrent cerebral ischemia occurred in 2 patient (3.1%) in the T-group and in 2 patients (3.6%) in the A-group (P = 0.865). Conclusion: The use of only intra-procedural TEE guidance for PFO closure is safe and effective. The whole procedure can be performed without fluoroscopy and contrast medium. The short and medium follow-up results are satisfactory, especially in the residual shunt.

Prognostic Effect of Thoracic Sarcopaenia on Short- and Long-Term Clinical Outcomes in Patients Who Underwent Cardiac Valve Surgery.

BACKGROUND: As the proportion of elderly patients increases, higher incidence of malnutrition is found among patients with valvular heart disease. Sarcopaenia is one of the main manifestations of malnutrition. Studies have shown the certain predictive effect of sarcopaenia on the clinical outcome in different cases. This study aims to clarify the impact of computed tomography (CT)-derived thoracic sarcopaenia on clinical outcomes of patients who underwent cardiac valve surgery. METHODS: The clinical data of 216 patients who underwent cardiac valve surgery from December 2015 to June 2020 were retrospectively collected. Skeletal muscle mass at 12th thoracic vertebra level was measured to diagnose thoracic sarcopaenia. Postoperative complications and follow-up data were collected. Medium follow-up was 3.2 years. RESULTS: The prevalence of thoracic sarcopaenia was 16.7% in this study. The incidence of total complications and in-hospital mortality were higher in thoracic sarcopaenia group (p=0.024 and p=0.014, respectively). Multivariate analysis revealed that thoracic sarcopaenia is a significant predictor for postoperative complications (OR 2.319; 95% CI 1.003-5.366; p=0.049). Decreased long-term survival was observed in patients with thoracic sarcopaenia. Thoracic sarcopaenia (HR 4.178; 95% CI 2.062-8.465; p<0.001) was determined to be an independent risk factor for late mortality. CONCLUSION: Thoracic sarcopaenia defined by chest CT was independently associated with higher incidence of postoperative complications and long-term mortality. Routine preoperative evaluation of thoracic sarcopaenia deserves further consideration to enhance the predictive performance for operation risk.

[Effects of early life PM2.5 exposure on prefrontal cortex of offspring male rats].

Objective: To investigate the effects of PM2.5 exposure at different stages of early life on the prefrontal cortex of offspring rats. Methods: Twelve pregnant SD rats were randomly divided into four groups: Control group (CG), Maternal pregnancy exposure group (MG), Early postnatal exposure group (EP) and Perinatal period exposure group (PP), 3 rats in each group. The pregnant and offspring rats were exposed to clean air or 8-fold concentrated PM2.5. MG was exposed from gestational day (GD) 1 to GD21. EP was exposed from postnatal day (PND) 1 to PND21, and PP was exposed from GD1 to PND21. After exposure, the prefrontal cortex of 6 offspring rats in each group was analyzed. HE staining was used to observe the pathological damage in the prefrontal cortex. ELISA was employed to detect neuroinflammatory factors, and HPLC/MSC was applied to determine neurotransmitter content. Western blot and colorimetry were applied for detecting astrocyte markers and oxidative stress markers, respectively. Results: Compared with MG and CG, the pathological changes of prefrontal cortex in PP and EP were more obvious. Compared with MG and CG, the neuroinflammatory factors (IL-1, IL-6, TNF-α) in PP and EP were increased significantly (P＜0.01), the level of MT were decreased significantly (P＜0.05), and the level of oxytocin (OT) showed a downward trend; the level of neurotransmitter ACh was also increased significantly (P＜0.01). Compared with MG and CG, the GFAP level of PP and EP showed an upward trend, the level of oxidative stress index SOD in PP and EP was decreased significantly (P＜0.01), and the level of ROS was increased significantly (P＜0.01). Compared with the offspring rats of CG and MG, the CAT level of PP was decreased significantly (P＜0.01, P＜0.05). Compared with the offspring rats of CG, the CAT level of EP was decreased significantly (P＜0.05). There was no significant difference in IL-1, IL-6, TNF-α, MT, OT, ACh, GFAP, SOD, ROS and CAT levels between PP and EP, or MG and CG. Conclusion: PM2.5 exposure in early life has adverse effects on the prefrontal cortex of offspring male rats, and early birth exposure may be more sensitive.

Evaluation of JUN, FN1 and LAMB1 polymorphisms in pterygium in a Chinese Han population.

PURPOSE: To explore the underlying molecular mechanism of pterygium and identify the key genes regulating the development of pterygium. METHODS: Differentially expressed mRNAs were obtained from the Gene Expression Omnibus (GEO) database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the DAVID (http://david.abcc.ncifcrf.gov/). The differential expressions of hub genes were verified using the reverse transcription-real-time fluorescent quantitative PCR (RT-qPCR). The function of the hub genes was further confirmed based on associations between the single nucleotide polymorphisms (SNPs) in hub genes and pterygium. The genotyping results were analyzed using SNPStats online software in five gene models, including codominant, dominant, recessive, overdominant, and log-additive. Five gene models were analyzed using SNPStats. RESULTS: We found that 240 genes were significantly differentially expressed. Functional enrichment analysis showed that focal adhesion pathway is extremely meaningful, among which JUN, FN1, and LAMB1 were verified to significantly differentially express in pterygium (P = 0.0011, P = 0.0018, and P = 0.0050, respectively). However, the all nine candidate SNPs (rs11688, rs3748814 in JUN; rs1263, rs1132741, rs1250259 in FN1; rs20556, rs35710474, rs25659, rs4320486 in LAMB1), were not statistically associated with pterygium. CONCLUSION: Our results demonstrated that JUN, FN1, and LAMB1 polymorphisms were not associated with susceptibility to pterygium in Chinese Han population. Considering the fact that these three genes are differentially expressed in pterygium, further research is needed to explain its involvement in pterygium.

A Tumor Microenvironments-Adapted Polypeptide Hydrogel/Nanogel Composite Boosts Antitumor Molecularly Targeted Inhibition and Immunoactivation.

Various macro/microscopic biomaterials have been developed for controlled drug delivery in the combination therapy of malignancies. However, uncertain loading ratio, release sequence, and spatiotemporal distribution of drugs hinder their synergistic therapeutic effects and clinical applications. In this work, a tumor microenvironments-adapted composite consisting of a thermosensitive hydrogel and a reactive oxygen species (ROS)-responsive nanogel is developed for precisely sequential drug release to enhance molecularly targeted therapy and amplify immune activation. LY3200882 (LY), a selective transforming growth factor-ß (TGF-ß) inhibitor, is encapsulated in the ROS-responsive nanogel and dispersed uniformly with regorafenib (REG) in a thermosensitive hydrogel (Gel/(REG+NG/LY)). After in situ administration, REG is preferentially released from the hydrogel to inhibit tumor growth and promote ROS generation, which triggers the subsequent on-demand release of LY from the nanogel. LY contributes to preventing the epithelial-mesenchymal transition and immune escape of tumor cells induced by elevated TGF-ß. In subcutaneous and orthotopic colorectal tumor bearing mouse models, Gel/(REG+NG/LY) effectively inhibits tumor growth and liver metastases by increasing the tumor infiltration of CD8+ T cells, reducing the recruitment of tumor-associated macrophages and myeloid-derived suppressor cells, and promoting the polarization of macrophages from M2 to M1 type, indicating the significant potential in improving the prognosis of advanced cancer patients.

Iron carriers promote biofilm formation and p-nitrophenol degradation.

Vertical baffled biofilm reactors (VBBR) equipped with Plastic-carriers and Fe-carriers were employed to explore the effect of biofilm carriers on biofilm formation and p-nitrophenol (PNP) degradation. The results showed that Fe-carriers enhanced biofilm formation and PNP degradation. The maximum thickness of biofilm grown on the Fe-carriers was 1.5-fold higher than that on the Plastic-carriers. The Fe-VBBR reached a maximum rate of PNP removal at 13.02 µM L-1 h-1 with less sodium acetate addition (3 mM), while the maximum rate of PNP removal was 11.53 µM L-1 h-1 with more sodium acetate addition (6 mM) in the Plastic-based VBBR. High-throughput sequencing suggested that the Fe-VBBR had a higher biodiversity of the bacterial community in evenness, and the Achromobacter genus and Xanthobacteraceae family were as main PNP degraders. Kyoto Encyclopedia of Genes and Genomes (KEGG) Orthology analysis suggested more abundances of iron uptake genes were expressed to transport iron into the cytoplasm under an iron-limited condition in two VBBRs, and the metabolic pathway of PNP degradation went through 4-nitrocatechol and 1,2,4-benzenetriol. Our results provide a new insight for iron enhancing biofilm formation and PNP degradation.

[Effect of epithelial-mesenchymal transition on cardiac fibrosis induced by oil mist particulate matter].

Objective: To investigate the effects of oil-mist particulate matter (OMPM) on cardiac tissue structure fibrosis in rats and the role of epithelial-mesenchymal transition (EMT). Methods: Six-week-old Wistar rats (half male and half female) were randomly divided into 3 groups: control group (without OMPM exposure), low-dose exposure group (50 mg/m3) and high-dose exposure group (100 mg/m3), 18 rats in each group, with 6.5 hours per day of dynamic inhalation exposure. After 42 days of continuous exposure, cardiac tissues were collected for morphological observation; Western blot was used to detect fibrosis markers collagen I and collagen III levels, epithelial marker E-cadherin levels, interstitial markers N-cadherin, fibronectin, vimentin, alpha-smooth muscle actin (α-SMA) levels, and EMT transcription factor Twist protein levels; Real-time polymerase chain reaction (RT-qPCR) was used to detect collagen I and collagen III mRNA levels. Results: After OMPM exposure, myocardial cell edema and collagen fiber deposition were increased gradually with increasing exposure dose. Western blot results showed that compared with the control group, the expression levels of collagen I, collagen III, N-Cadherin, fibronectin, vimentin, α-SMA, and Twist protein were increased significantly in the low-dose exposure group and the high-dose exposure group (P＜0.01), and protein expression levels were higher in the high-dose exposure group than those in the low-dose exposure group (P＜0.01). In contrast, E-Cadherin protein expression levels were decreased significantly, and lower in the high-dose exposure group (P＜0.01). RT-qPCR results showed that compared with the control group, collagen I and collagen III mRNA levels were increased significantly in the low-dose exposure group and the high-dose exposure group (P＜0.01), and were increased with increasing exposure dose. (P＜0.01). Conclusion: OMPM may induce cardiac fibrosis in rats by promoting EMT process.