Up-bottom assessments of nutrient supply and gaseous pollutant from Chinese wheat straw field management.

To achieve resource efficiency, and carbon neutrality, it is vital to evaluate nutrient supply and gaseous pollutant emissions associated with field management of bio-straw resources. Previous straw yield estimates have typically relied on a constant grain-to-straw yield ratio without accounting for grain yield levels in a given region. Addressing this high-resolution data gap, our study introduces a novel empirical model for quantifying grain-to-straw yield, which has been used to gauge wheat straw field management practices at the city level during 2011-2015. Utilizing both statistical review and GIS-based methods, average nitrogen (N), phosphorus (P), and potassium (K) supplies from straw field management stood at 1510, 1229, and 61700 tons, respectively. Average emissions of PM2.5, SO2, NOx, NH3, CH4, and CO2 due to straw burning were 367, 41, 160, 18, 165, and 70,644 tons, respectively. We also reported uncertainty from Monte Carlo model as the 5th-95th percentiles of estimated nutrient supply and gaseous pollutant. These insights will provide foundational support for the sustainable and environmentally friendly management of wheat straw in China.

Desmoglein-2 Affects Vascular Function in Moyamoya Disease by Interacting with MMP-9 and Influencing PI3K Signaling.

The pathogenesis and development of Moyamoya disease are still unclear. This study aimed to investigate the effect of desmoglein-2 (DSG2) on Moyamoya disease and determine the inhibitory effect of DSG2 in vascular remodeling in Moyamoya disease.RNA sequencing, immunohistochemistry (IHC), and western blotting were used to detect the expression of DSG2 in the superficial temporal artery (STA) tissues of Moyamoya disease. The association between DSG2 and endothelial cells' biological activities was investigated by cell counting kit-8 (CCK-8), migration assay, tube formation assay, flow cytometry with Annexin V-FITC/PI staining, and TUNEL apoptotic cell detection kit. Pathways affected by overexpression or knockdown of DSG2 were identified in endothelial cells.The expression of DSG2 in the STA tissues of Moyamoya disease was lower than that in normal controls. Overexpression of DSG2 inhibits the proliferation and migration but promotes apoptosis in endothelial cells, and low DSG2 levels result in impaired angiogenesis. In addition, there was an interaction between DSG2 and MMP-9, and DSG2 acted through the PI3K signaling in endothelial cells.Our results indicate that DSG2 affects PI3K signaling in vascular endothelial cells, and MMP-9 is involved in DSG2-mediated vascular changes in Moyamoya disease.

Plant polysaccharides extracted by high pressure: A review on yields, physicochemical, structure properties, and bioactivities.

Polysaccharides are biologically essential macromolecules, widely exist in plants, which are used in food, medicine, bioactives' encapsulation, targeted delivery and other fields. Suitable extraction technology can not only improve the yield, but also regulate the physicochemical, improve the functional property, and is the basis for the research and application of polysaccharide. High pressure (HP) extraction (HPE) induces the breakage of raw material cells and tissues through rapid changes in pressure, increases extraction yield, reduces extraction time, and modifies structure of polysaccharides. However, thus far, literature review on the mechanism of extraction, improved yield and modified structure of HPE polysaccharide is lacking. Therefore, the present work reviews the mechanism of HPE polysaccharide, increasing extraction yield, regulating physicochemical and functional properties, modifying structure and improving activity. This review contributes to a full understanding of the HPE or development of polysaccharide production and modification methods and promotes the application of HP technology in polysaccharide production.

A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity.

Apart from the canonical serotonin (5-hydroxytryptamine [5-HT])-receptor signaling transduction pattern, 5-HT-involved post-translational serotonylation has recently been noted. Here, we report a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serotonylation system that promotes the glycolytic metabolism and antitumor immune activity of CD8+ T cells. Tissue transglutaminase 2 (TGM2) transfers 5-HT to GAPDH glutamine 262 and catalyzes the serotonylation reaction. Serotonylation supports the cytoplasmic localization of GAPDH, which induces a glycolytic metabolic shift in CD8+ T cells and contributes to antitumor immunity. CD8+ T cells accumulate intracellular 5-HT for serotonylation through both synthesis by tryptophan hydroxylase 1 (TPH1) and uptake from the extracellular compartment via serotonin transporter (SERT). Monoamine oxidase A (MAOA) degrades 5-HT and acts as an intrinsic negative regulator of CD8+ T cells. The adoptive transfer of 5-HT-producing TPH1-overexpressing chimeric antigen receptor T (CAR-T) cells induced a robust antitumor response. Our findings expand the known range of neuroimmune interaction patterns by providing evidence of receptor-independent serotonylation post-translational modification.

Stabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells.

The peptidyl-prolyl cis-trans isomerase Pin1 is a pivotal therapeutic target in cancers, but the regulation of Pin1 protein stability is largely unknown. High Pin1 expression is associated with SUMO1-modified protein hypersumoylation in glioma stem cells (GSCs), but the underlying mechanisms remain elusive. Here we demonstrate that Pin1 is deubiquitinated and stabilized by USP34, which promotes isomerization of the sole SUMO E2 enzyme Ubc9, leading to SUMO1-modified hypersumoylation to support GSC maintenance. Pin1 interacts with USP34, a deubiquitinase with preferential expression and oncogenic function in GSCs. Such interaction is facilitated by Plk1-mediated phosphorylation of Pin1. Disruption of USP34 or inhibition of Plk1 promotes poly-ubiquitination and degradation of Pin1. Furthermore, Pin1 isomerizes Ubc9 to upregulate Ubc9 thioester formation with SUMO1, which requires CDK1-mediated phosphorylation of Ubc9. Combined inhibition of Pin1 and CDK1 with sulfopin and RO3306 most effectively suppresses orthotopic tumor growth. Our findings provide multiple molecular targets to induce Pin1 degradation and suppress hypersumoylation for cancer treatment.

Targeting PUF60 prevents tumor progression by retarding mRNA decay of oxidative phosphorylation in ovarian cancer.

PURPOSE: Ovarian cancer (OC) is the leading cause of death from gynecological malignancies, and its etiology and pathogenesis are currently unclear. Recent studies have found that PUF60 overexpressed in various cancers. However, the exact function of PUF60 in global RNA processing and its role in OC has been unclear. METHODS: The expression of PUF60 and its relationship with clinical characteristics were analyzed by multiple database analysis and immunohistochemistry. Phenotypic effects of PUF60 on ovarian cancer cell proliferation and metastasis were examined by in vitro cell proliferation assay, migration assay, and in vivo xenograft models and lung metastasis models. RNA immunoprecipitation, seahorse analyses, RNA stability assay were used to study the effect of PUF60 on the stability of oxidative phosphorylation (OXPHOS)-related genes in OC. RESULTS: We report PUF60 is highly expressed in OC with frequent amplification of up to 33.9% and its upregulation predicts a poor prognosis. PUF60 promotes the proliferation and migration of OC cells both in vitro and in vivo. Mechanistically, we demonstrated that silencing of PUF60 enhanced the stability of mRNA transcripts involved in OXPHOS and decreased the formation of processing bodies (P-bodies), ultimately elevating the OXPHOS level. CONCLUSION: Our study unveils a novel function of PUF60 in OC energy metabolism. Thus, PUF60 may serve as a novel target for the treatment of patients with OC.

Tidal channel meanders serve as stepping-stones to facilitate cordgrass landward spread by creating invasion windows.

Understanding the mechanisms by which the geomorphic structures affect habitat invasibility by mediating various abiotic and biotic factors is essential for predicting whether these geomorphic structures may provide spatial windows of opportunity to facilitate range-expansion of invasive species in salt marshes. Many studies have linked geomorphic landscape features such as tidal channels to invasion by exotic plants, but the role of tidal channel meanders (i.e., convex and concave sides) in regulating the Spartina alterniflora invasion remains unclear. Here, we examined the combined effects of tidal channel meander-mediated hydrodynamic variables, soil abiotic stresses, and propagule pressure on the colonization of Spartina in the Yellow River Delta, China, by conducting field observations and experiments. The results showed that lower hydrodynamic disturbance, bed shear stress, and higher propagule pressure triggered by eddies due to the convex structure of channel meanders facilitated Spartina seedling establishment and growth, whereas the concave side considerably inhibited the Spartina invasion. Lower soil abiotic stresses also significantly promoted the invasibility of the channel meanders by Spartina. Based on these findings, we propose a conceptual framework to illustrate the effects of the meandering geomorphology of tidal channels on the mechanisms that might allow the landward spread of Spartina and related processes. Our results demonstrate that the meandering geomorphic structures of tidal channels could act as stepping-stones to significantly facilitate the landward invasion of Spartina along tidal channels. This implies that geomorphic characteristics of tidal channels should be integrated into invasive species control and salt marsh management strategies.

Prediction of Mild Cognitive Impairment Progression to Alzheimer's Disease Based on Diffusion Tensor Imaging-Derived Diffusion Parameters: Construction and Validation of a Nomogram.

INTRODUCTION: The aim of the study was to construct and validate a nomogram that combines diffusion tensor imaging (DTI) parameters and clinically relevant features for predicting the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD). METHOD: A retrospective analysis was conducted on the MRI and clinical data of 121 MCI patients, of whom 32 progressed to AD during a 4-year follow-up period. The MCI patients were divided into training and validation sets at a ratio of 7:3. DTI features were extracted from MCI patient data in the training set, and their dimensionality was reduced to construct a radiomics signature (RS). Then, combining the RS with independent predictors of MCI disease progression, a joint model was constructed, and a nomogram was generated. Finally, the area under the receiver operating characteristic curve (AUC) and decision curve analysis (DCA) were used to evaluate the diagnostic and clinical efficacy of the nomogram based on the data from the validation set. RESULT: The AUCs of the RS in the training and validation sets were 0.81 and 0.84, with sensitivities of 0.87 and 0.78 and specificities of 0.71 and 0.81, respectively. Multiple logistic regression analysis showed that the RS, clinical dementia rating scale score, and Alzheimer's disease assessment scale score were the independent predictors of progression and were thus used to construct the nomogram. The AUCs of the nomogram in the training and validation sets were 0.89 and 0.91, respectively, with sensitivities of 0.78 and 0.89 and specificities of 0.90 and 0.88, respectively. DCA showed that the nomogram was the most valuable model for predicting the progression of MCI to AD and that it provided greater net benefits than other analysed models. CONCLUSION: Changes in white matter fibre bundles can serve as predictive imaging markers for MCI disease progression, and the combination of white matter DTI features and relevant clinical features can be used to construct a nomogram with important predictive value for MCI disease progression.

TXNIP aggravates cardiac fibrosis and dysfunction after myocardial infarction in mice by enhancing the TGFB1/Smad3 pathway and promoting NLRP3 inflammasome activation.

Myocardial infarction (MI) results in high mortality. The size of fibrotic scar tissue following MI is an independent predictor of MI outcomes. Thioredoxin-interacting protein (TXNIP) is involved in various fibrotic diseases. Its role in post-MI cardiac fibrosis, however, remains poorly understood. In the present study, we investigate the biological role of TXNIP in post-MI cardiac fibrosis and the underlying mechanism using mouse MI models of the wild-type (WT), Txnip-knockout ( Txnip-KO) type and Txnip-knock-in ( Txnip-KI) type. After MI, the animals present with significantly upregulated TXNIP levels, and their fibrotic areas are remarkably expanded with noticeably impaired cardiac function. These changes are further aggravated under Txnip-KI conditions but are ameliorated in Txnip-KO animals. MI also leads to increased protein levels of the fibrosis indices Collagen I, Collagen III, actin alpha 2 (ACTA2), and connective tissue growth factor (CTGF). The Txnip-KI group exhibits the highest levels of these proteins, while the lowest levels are observed in the Txnip-KO mice. Furthermore, Txnip-KI significantly upregulates the levels of transforming growth factor (TGF)B1, p-Smad3, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), Cleaved Caspase-1, and interleukin (IL)1B after MI, but these effects are markedly offset by Txnip-KO. In addition, after MI, the Smad7 level significantly decreases, particularly in the Txnip-KI mice. TXNIP may aggravate the progression of post-MI fibrosis and cardiac dysfunction by activating the NLRP3 inflammasome, followed by IL1B generation and then the enhancement of the TGFB1/Smad3 pathway. As such, TXNIP might serve as a novel potential therapeutic target for the treatment of post-MI cardiac fibrosis.

Prediction of p53 mutation status in rectal cancer patients based on magnetic resonance imaging-based nomogram: a study of machine learning.

BACKGROUND: The current study aimed to construct and validate a magnetic resonance imaging (MRI)-based radiomics nomogram to predict tumor protein p53 gene status in rectal cancer patients using machine learning. METHODS: Clinical and imaging data from 300 rectal cancer patients who underwent radical resections were included in this study, and a total of 166 patients with p53 mutations according to pathology reports were included in these patients. These patients were allocated to the training (n = 210) or validation (n = 90) cohorts (7:3 ratio) according to the examination time. Using the training data set, the radiomic features of primary tumor lesions from T2-weighted images (T2WI) of each patient were analyzed by dimensionality reduction. Multivariate logistic regression was used to screen predictive features, which were combined with a radiomics model to construct a nomogram to predict p53 gene status. The accuracy and reliability of the nomograms were assessed in both training and validation data sets using receiver operating characteristic (ROC) curves. RESULTS: Using the radiomics model with the training and validation cohorts, the diagnostic efficacies were 0.828 and 0.795, the sensitivities were 0.825 and 0.891, and the specificities were 0.722 and 0.659, respectively. Using the nomogram with the training and validation data sets, the diagnostic efficacies were 0.86 and 0.847, the sensitivities were 0.758 and 0.869, and the specificities were 0.833 and 0.75, respectively. CONCLUSIONS: The radiomics nomogram based on machine learning was able to predict p53 gene status and facilitate preoperative molecular-based pathological diagnoses.

Dihydroartemisinin attenuates ischemia/reperfusion-induced renal tubular senescence by activating autophagy.

Acute kidney injury (AKI) is an important factor for the occurrence and development of CKD. The protective effect of dihydroartemisinin on AKI and and reported mechanism have not been reported. In this study, we used two animal models including ischemia-reperfusion and UUO, as well as a high-glucose-stimulated HK-2 cell model, to evaluate the protective effect of dihydroartemisinin on premature senescence of renal tubular epithelial cells in vitro and in vivo. We demonstrated that dihydroartemisinin improved renal aging and renal injury by activating autophagy. In addition, we found that co-treatment with chloroquine, an autophagy inhibitor, abolished the anti-renal aging effect of dihydroartemisinin in vitro. These findings suggested that activation of autophagy/elimination of senescent cell might be a useful strategy to prevent AKI/UUO induced renal tubular senescence and fibrosis.

Angiotensin II type 1a receptor knockout ameliorates high-fat diet-induced cardiac dysfunction by regulating glucose and lipid metabolism.

Obesity-related cardiovascular diseases are associated with overactivation of the renin-angiotensin system (RAS). However, the underlying mechanisms remain elusive. In this study, we investigate the role of angiotensin II (Ang II) in high-fat diet (HFD)-induced cardiac dysfunction by focusing on cardiac glucose and lipid metabolism and energy supply. Ang II plays a role in cardiovascular regulation mainly by stimulating angiotensin II type 1 receptor (AT1R), among which AT1aR is the most important subtype in regulating the function of the cardiovascular system. AT1aR gene knockout (AT1aR ‒/‒) rats and wild-type (WT) rats are randomly divided into four groups and fed with either a normal diet (ND) or a HFD for 12 weeks. The myocardial lipid content, Ang II level and cardiac function are then evaluated. The expressions of a number of genes involved in glucose and fatty acid oxidation and mitochondrial dynamics are measured by quantitative polymerase chain reaction and western blot analysis. Our results demonstrate that AT1aR knockout improves HFD-induced insulin resistance and dyslipidemia as well as lipid deposition and left ventricular dysfunction compared with WT rats fed a HFD. In addition, after feeding with HFD, AT1aR ‒/‒ rats not only show further improvement in glucose and fatty acid oxidation but also have a reverse effect on increased mitochondrial fission proteins. In conclusion, AT1aR deficiency ameliorates HFD-induced cardiac dysfunction by enhancing glucose and fatty acid oxidation, regulating mitochondrial dynamics-related protein changes, and further promoting cardiac energy supply.

Comparison in structural, physicochemical and functional properties of sweet potato stems and leaves polysaccharide conjugates from different technologies.

In order to better understand the influences of extraction techniques on the yield, characteristics, and bioactivities of polysaccharide conjugates, hot reflux extraction (HRE), ultrasonic-assisted extraction (UAE), microwave-assisted extraction (MAE), complex enzymolysis extraction (CEE), ultra-high pressure extraction (UPE), ultrasonic complex enzymes extraction (UEE) were used to extract sweet potato stems leaves polysaccharide conjugates (SPSPCs), and their physicochemical characteristics, functional properties, antioxidant and hypoglycemic activities were compared. Results showed that compared with HRE conjugate (HR-SPSPC), the yield, content of uronic acid (UAC), total phenol (TPC), total flavonoid (TFC) and sulfate group (SGC), water solubility (WS), percentage of glucuronic acid (GlcA), galacuronic acid (GalA) and galactose (Gal), antioxidant and hypoglycemia activities of UEE polysaccharide conjugates (UE-SPSPC) significant increased, while its molecular weight (Mw), degree of esterification (DE), content of protein (PC) and percentage of glucose (Glc) declined, but monosaccharides and amino acid types, and glycosyl linkages were not much different. Indeed, UE-SPSPC possessed the highest antioxidant activities and hypolipidemic activities among six SPSPCs, which might be due to the high UAC, TPC, TFC, SGC, GlcA, GalA and WS, low Mw, DE and Glc of UE-SPSPC. The results reveal that UEE is an effective extraction and modification technology of polysaccharide conjugates.

Retractorless Surgery for Tuberculum Sellae Meningiomas via the Frontolateral Approach: A Single Institution's Experience.

OBJECTIVE: Although technologic advances have improved the surgical outcomes of tuberculum sellae meningiomas (TSMs), the treatment of these tumors remains challenging given important neurovascular structures involvement. In this article, the authors retrospectively reviewed the effectiveness of retractorless surgery for TSMs via the frontolateral approach (FLA). METHODS: Between 2015 and 2022, 36 patients with TSMs underwent retractorless surgery via the FLA. The gross total resection (GTR) rates, visual outcomes, and complications were evaluated as the main outcome parameters. RESULTS: GTR was achieved in 34 patients (94.4%). Visual acuity improved in 93.9% (n = 31) of the 33 patients with visual deficits and remained unchanged in 6.1% (n = 2). No patients suffered from visual deterioration, brain retraction injury, mortality, and tumor recurrence in the mean follow-up duration of 33 months. CONCLUSIONS: Retractorless surgery via the FLA is a reliable transcranial option for the treatment of TSMs. High rates of GTR, excellent visual outcomes, and the low incidence of complications could be achieved if the surgical strategy mentioned in the article is adopted.

The importance of structural and functional characteristics of tidal channels to smooth cordgrass invasion in the Yellow River Delta, China: Implications for coastal wetland management.

Understanding the spatiotemporal landscape dynamics and spread pathways of invasive plants, as well as their interactions with geomorphic landscape features, are of great importance for predicting and managing their future range-expansion in non-native habitats. Although previous studies have linked geomorphic landscape features such as tidal channels to plant invasions, the potential mechanisms and critical characteristics of tidal channels that affect the landward invasion by Spartina alterniflora, an aggressive plant in global coastal wetlands, remain unclear. Here, using high-resolution remote-sensing images of the Yellow River Delta from 2013 to 2020, we first quantified the evolution of tidal channel networks by analyzing the spatiotemporal dynamics of their structural and functional characteristics. The invasion patterns and pathways of S. alterniflora were then identified. Based on the above-mentioned quantification and identification, we finally quantified the influences of tidal channel characteristics on S. alterniflora invasion. The results showed that tidal channel networks presented increasing growth and development over time, and their spatial structure evolved from simple to complex. The external isolated expansion of S. alterniflora played a dominant role during the initial invasion stage, and then they connected the discrete patches into the meadow through marginal expansion. Afterwards, tidal channel-driven expansion gradually increased and became the primary way during the late invasion stage, accounting for about 47.3%. Notably, tidal channel networks with higher drainage efficiency (shorter OPL, higher D and E) attained larger invasion areas. The longer the tidal channels and the more sinuous the channel structure, the greater the invasion potential by S. alterniflora. These findings highlight the importance of structural and functional properties of tidal channel networks in driving plant invasion landward, which should be incorporated into future control and management of invasive plants in coastal wetlands.

Nucleolar HEAT Repeat Containing 1 Up-regulated by the Mechanistic Target of Rapamycin Complex 1 Signaling Promotes Hepatocellular Carcinoma Growth by Dominating Ribosome Biogenesis and Proteome Homeostasis.

BACKGROUND & AIMS: Hyperactivation of ribosome biogenesis leads to hepatocyte transformation and plays pivotal roles in hepatocellular carcinoma (HCC) development. We aimed to identify critical ribosome biogenesis proteins that are overexpressed and crucial in HCC progression. METHODS: HEAT repeat containing 1 (HEATR1) expression and clinical correlations were analyzed using The Cancer Genome Atlas and Gene Expression Omnibus databases and further evaluated by immunohistochemical analysis of an HCC tissue microarray. Gene expression was knocked down by small interfering RNA. HEATR1-knockdown cells were subjected to viability, cell cycle, and apoptosis assays and used to establish subcutaneous and orthotopic tumor models. Chromatin immunoprecipitation and quantitative polymerase chain reaction were performed to detect the association of candidate proteins with specific DNA sequences. Endogenous coimmunoprecipitation combined with mass spectrometry was used to identify protein interactions. We performed immunoblot and immunofluorescence assays to detect and localize proteins in cells. The nucleolus ultrastructure was detected by transmission electron microscopy. Click-iT (Thermo Fisher Scientific) RNA imaging and puromycin incorporation assays were used to measure nascent ribosomal RNA and protein synthesis, respectively. Proteasome activity, 20S proteasome foci formation, and protein stability were evaluated in HEATR1-knockdown HCC cells. RESULTS: HEATR1 was the most up-regulated gene in a set of ribosome biogenesis mediators in HCC samples. High expression of HEATR1 was associated with poor survival and malignant clinicopathologic features in patients with HCC and contributed to HCC growth in vitro and in vivo. HEATR1 expression was regulated by the transcription factor specificity protein 1, which can be activated by insulin-like growth factor 1-mammalian target of rapamycin complex 1 signaling in HCC cells. HEATR1 localized predominantly in the nucleolus, bound to ribosomal DNA, and was associated with RNA polymerase I transcription/processing factors. Knockdown of HEATR1 disrupted ribosomal RNA biogenesis and impaired nascent protein synthesis, leading to reduced cytoplasmic proteasome activity and inhibitory-κB/nuclear factor-κB signaling. Moreover, HEATR1 knockdown induced nucleolar stress with increased nuclear proteasome activity and inactivation of the nucleophosmin 1-MYC axis. CONCLUSIONS: Our study revealed that HEATR1 is up-regulated by insulin-like growth factor 1-mammalian target of rapamycin complex 1-specificity protein 1 signaling in HCC and functions as a crucial regulator of ribosome biogenesis and proteome homeostasis to promote HCC development.

Dipyridamole enhances the anti-cancer ability of aspirin against colorectal cancer by inducing apoptosis in an unfolded protein response-dependent manner.

PURPOSE: Available evidence indicates that dipyridamole enhances the anti-thrombotic effects of aspirin for the prevention of secondary strokes. Aspirin is a well-known non-steroid anti-inflammatory drug. This anti-inflammatory property has turned aspirin into a potential drug for inflammation-related cancers such as colorectal cancer (CRC). Here, we aimed to explore whether the anti-cancer effect of aspirin against CRC could be improved by combined administration with dipyridamole. METHODS: Population-based clinical data analysis was conducted to assess a possible therapeutic effect of combined dipyridamole and aspirin treatment in inhibiting CRC compared with either monotherapy. This therapeutic effect was further verified in different CRC mouse models, i.e. an orthotopic xenograft mouse model, an AOM/DSS mouse model, an Apcmin/+ mouse model and a patient derived xenograft (PDX) mouse model. The in vitro effects of the drugs on CRC cells were tested using CCK8 and flow cytometry assays. RNA-Seq, Western blotting, qRT-PCR and flow cytometry were used to identify the underlying molecular mechanisms. RESULTS: We found that dipyridamole combined with aspirin had a better inhibitory effect on CRC than either monotherapy alone. The enhanced anti-cancer effect of the combined use of dipyridamole with aspirin was found to rely on the induction of an overwhelmed endoplasmic reticulum (ER) stress and subsequent pro-apoptotic unfolded protein response (UPR), which was different from the anti-platelet effect. CONCLUSIONS: Our data indicate that the anti-cancer effect of aspirin against CRC may be enhanced by combined administration with dipyridamole. In case further clinical studies confirm our findings, these may be repurposed as adjuvant agents.

Systematic evaluation of membrane-camouflaged nanoparticles in neutralizing Clostridium perfringens ε-toxin.

Clostridium perfringens ε-toxin (ETX) is the main toxin leading to enterotoxemia of sheep and goats and is classified as a potential biological weapon. In addition, no effective treatment drug is currently available in clinical practice for this toxin. We developed membrane-camouflaged nanoparticles (MNPs) with different membrane origins to neutralize ETX and protect the host from fatal ETX intoxication. We evaluated the safety and therapeutic efficacy of these MNPs in vitro and in vivo. Compared with membranes from karyocytes, such as Madin-Darby canine kidney (MDCK) cells and mouse neuroblastoma N2a cells (N2a cells), membrane from erythrocytes, which do not induce any immune response, are superior in safety. The protective ability of MNPs was evaluated by intravenous injection and lung delivery. We demonstrate that nebulized inhalation is as safe as intravenous injection and that both modalities can effectively protect mice against ETX. In particular, pulmonary delivery of nanoparticles more effectively treated the challenge of inhaled toxins than intravenously injected nanoparticles. Moreover, MNPs can alter the biological distribution of ETX among different organs in the body, and ETX was captured, neutralized and slowly delivered to the liver and spleen, where nanoparticles with ETX could be phagocytized and metabolized. This demonstrates how MNPs treat toxin infections in vivo. Finally, we injected the MNPs into mice in advance to find out whether MNPs can provide preventive protection, and the results showed that the long-cycle MNPs could provide at least a 3-day protection in mice. These findings demonstrate that MNPs provide safe and effective protection against ETX intoxication, provide new insights into membrane choices and delivery routes of nanoparticles, and new evidence of the ability of nanoparticles to provide preventive protection against infections.

Coadaptation fostered by the SLIT2-ROBO1 axis facilitates liver metastasis of pancreatic ductal adenocarcinoma.

To explore the mechanism of coadaptation and the potential drivers of pancreatic ductal adenocarcinoma (PDAC) metastasis to the liver, we study key molecules involved in this process and their translational value. Premetastatic niche (PMN) and macrometastatic niche (MMN) formation in a mouse model is observed via CT combined with 3D organ reconstruction bioluminescence imaging, and then we screen slit guidance ligand 2 (SLIT2) and its receptor roundabout guidance receptor 1 (ROBO1) as important factors. After we confirm the expression and distribution of SLIT2 and ROBO1 in samples from PDAC patients and several mouse models, we discover that SLIT2-ROBO1-mediated coadaptation facilitated the implantation and outgrowth of PDAC disseminated tumour cells (DTCs) in the liver. We also demonstrate the dependence receptor (DR) characteristics of ROBO1 in a follow-up mechanistic study. A neutralizing antibody targeting ROBO1 significantly attenuate liver metastasis of PDAC by preventing the coadaptation effect. Thus, we demonstrate that coadaptation is supported by the DR characteristics in the PMN and MMN.