Early administration of Wumei Wan inhibit myeloid-derived suppressor cells via PI3K/Akt pathway and amino acids metabolism to prevent Colitis-associated Colorectal Cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Wumei Wan (WMW), a traditional Chinese medicine prescription, has been proved to be effective in treating Colitis-associated colorectal cancer (CAC), but it has not been proven to be effective in different stages of CAC. AIM OF THE STUDY: The purpose of our study is to investigate the therapeutic effect and mechanism of WMW on the progression of CAC. MATERIALS AND METHODS: Azioximethane (AOM) and dextran sulfate sodium (DSS) were used to treat mice for the purpose of establishing CAC models. WMW was administered in different stages of CAC. The presentative chemical components in WMW were confirmed by UHPLCQTOF/MS under the optimized conditions. The detection of inflammatory cytokines in the serum and colon of mice were estimated by qRT-PCR and ELISA. The changes of T cells and myeloid-derived suppressor cells (MDSCs) in each group were detected by flow cytometry. The metabolic components in serum of mice were detected by UPLC-MS/MS. Expression of genes and proteins were detected by eukaryotic transcriptomics and western blot to explore the key pathway of WMW in preventing CAC. RESULTS: WMW had significant effect on inhibiting inflammatory responses and tumors during the early development stage of CAC when compared to other times. WMW increased the length of mice's colons, reduced the level of IL-1ß, IL-6, TNF-α in colon tissues, and effectively alleviated colonic inflammation, and improved the pathological damage of colon tissues. WMW could significantly reduce the infiltration of MDSCs in the spleen, increase CD4+ T cells and CD8+ T cells in the spleen of CAC mice, and effectively reform the immune microenvironment in CAC mice. Transcriptomics analysis revealed that 2204 genes had different patterns of overlap in the colon tissues of mice between control group, AOM+DSS group, and early administration of WMW group. And KEGG enrichment analysis showed that PI3K/Akt signaling pathway, ECM-receptor interaction, IL-17 signaling pathway, MAPK signaling pathway, pancreatic secretion, thermogenesis, and Rap1 signaling pathway were all involved. The serum metabolomics results of WMW showed that the metabolic compositions of the control group, AOM+DSS group and the early stage of WMW were different, and 42 differential metabolites with the opposite trends of changes were screened. The metabolic pathways mainly included pyrimidine metabolism, glycine, serine and threonine metabolism, tryptophan metabolism, and purine metabolism. And amino acids and related metabolites may play an important role in WMW prevention of CAC. CONCLUSION: WMW can effectively prevent the occurrence and development of CAC, especially in the initial stage. WMW can reduce the immune infiltration of MDSCs in the early stage. Early intervention of WMW can improve the metabolic disorder caused by AOM+DSS, especially correct the amino acid metabolism. PI3K/Akt signaling pathway was inhabited in early administration of WMW, which can regulate the amplification and function of MDSCs.

Tumor-derived exosomal ADAM17 promotes pre-metastatic niche formation by enhancing vascular permeability in colorectal cancer.

BACKGROUND: Hematological metastasis has been recognized as a crucial factor contributing to the high rates of metastasis and mortality observed in colorectal cancer (CRC). Notably, exosomes derived from cancer cells participate in the formation of CRC pre-metastatic niches; however, the mechanisms underlying their effects are largely unknown. While our preliminary research revealed the role of exosome-derived disintegrin and metalloproteinase 17 (ADAM17) in the early stages of CRC metastasis, the role of exosomal ADAM17 in CRC hematogenous metastasis remains unclear. METHODS: In the present study, we isolated and purified exosomes using ultracentrifugation and identified exosomal proteins through quantitative mass spectrometry. In vitro, co-culture assays were conducted to evaluate the impact of exosomal ADAM17 on the permeability of the blood vessel endothelium. Vascular endothelial cell resistance, the cell index, membrane protein separation, flow cytometry, and immunofluorescence were employed to investigate the mechanisms underlying exosomal ADAM17-induced vascular permeability. Additionally, a mouse model was established to elucidate the role of exosomal ADAM17 in the modulation of blood vessel permeability and pre-metastatic niche formation in vivo. RESULTS: Our clinical data indicated that ADAM17 derived from the circulating exosomes of patients with CRC could serve as a blood-based biomarker for predicting metastasis. The CRC-derived exosomal ADAM17 targeted vascular endothelial cells, thus enhancing vascular permeability by influencing vascular endothelial cadherin cell membrane localization. Moreover, exosomal ADAM17 mediated the formation of a pre-metastatic niche in nude mice by inducing vascular leakage, thereby promoting CRC metastasis. Nonetheless, ADAM17 selective inhibitors effectively reduced CRC metastasis in vivo. CONCLUSIONS: Our results suggest that exosomal ADAM17 plays a pivotal role in the hematogenous metastasis of CRC. Thus, this protein may serve as a valuable blood-based biomarker and potential drug target for CRC metastasis intervention.

Reversing Zincophobic/Hydrophilic Nature of Metal-N-C via Metal-Coordination Interaction for Dendrite-Free Zn Anode with High Depth-of-Discharge.

Dendrite-free Zn metal anodes with high depth-of-discharge (DoD) and robust cycle performances are highly desired for the practical application of aqueous Zn-ion batteries. Herein, the zincophobic/hydrophilic nature of Metal-N-C through manipulating the electronic interactions between metal and coordination atoms is successfully reversed, thereby fabricating a zincophilic/hydrophobic asymmetric Zn-N3Py+1Pr-C (consisting of a Zn center coordinated with 3 pyridinic N atoms and 1 pyrrolic N atom) host, which realizes uniformed Zn deposition and a long lifespan with high DoD. The experimental and theoretical investigations demonstrate weakened interaction between pyrrolic N and metal center in the asymmetric Zn-N3Py+1Pr-C triggers downshift of the Zn 3d-band-center and a new localization nonbonding state in the N and C 2p-band, resulting in preferred Zn adsorption to water adsorption. Consequently, the asymmetric Zn-N3Py+1Pr-C host delivers small Zn nucleation overpotential and high Coulombic efficiency of 98.3% over 500 cycles. The symmetric cells with Zn-N3Py+1Pr-C@Zn anode demonstrate 500 h dendrite-free cycles at DoD up to 50%. The Zn-N3Py+1Pr-C@Zn/S-PANI full cell also shows a robust long-term cycle performance of 1000 cycles at 10 A g-1. This strategy of constructing zincophilic/hydrophobic Metal-N-C may open up their application for the dendrite-free metal anode.

A nomogram prediction model based on clinicopathological combined radiological features for metachronous liver metastasis of colorectal cancer.

Objective: To establish a nomogram prediction model (based on clinicopathological and radiological features) for the development of metachronous liver metastasis (MLM) in patients with colorectal cancer (CRC). Methods: This retrospective study included patients with CRC who underwent surgery at Changshu No.1 People's Hospital and the Second Affiliated Hospital of Soochow University between January 2016 and December 2018. The clinical, pathological, and radiological features of each patient were investigated. Risk factors for MLM were identified by univariable and multivariable analyses. The predictive nomogram for MLM development was constructed. The predictive performance of the nomogram was estimated by the receiver operating characteristics curve, calibration curve, and decision curve analysis. Results: This study included 161 patients with CRC [median age: 66 (range, 33-87) years]. Fifty-nine developed MLM after a median of 12 (range, 2-52) months after surgery. The multivariable logistic regression analysis showed that age >66 years (OR=3.471, 95% CI: 1.272-9.473, P=0.015), N2 stage (OR=6.534, 95% CI: 1.456-29.317, P=0.014), positive vascular invasion (OR=2.995, 95% CI: 1.132-7.926, P=0.027), positive tumor deposit (OR=4.451, 95% CI: 1.153-17.179, P=0.030), and linear (OR=6.774, 95% CI: 1.306-35.135, P=0.023) and nodal pericolic fat infiltration patterns (OR=8.762, 95% CI: 1.521-50.457, P=0.015) were independently associated with MLM. These five factors were used to create a nomogram. The area under the receiver operating characteristics curve of the nomogram was 0.866 (95% CI: 0.803-0.914), indicating favorable prediction performance. The calibration curve of the nomogram showed a satisfactory agreement between the predicted and actual probabilities. Conclusions: A nomogram prediction model based on five clinicopathological and radiological features might have favorable prediction performance for MLM in patients who underwent surgery for CRC. Hence, the present study proposes a nomogram that can easily be used to predict MLM after CRC surgery based on readily available features.

Advances in the study of antisense long­stranded non­coding RNAs in tumors (Review).

Long­stranded non­coding RNAs (lncRNAs) are RNAs that consist of >200 nucleotides. The majority of lncRNAs do not encode proteins but have been revealed to mediate a variety of important physiological functions. Antisense­lncRNAs (AS­lncRNAs) are transcribed from the opposite strand of a protein or non­protein coding gene as part of the antisense strand of the coding gene. AS­lncRNAs can serve an important role in the tumorigenesis, prognosis, metastasis and drug resistance of a number of malignancies. This has been reported to be exerted through various mechanisms, such as endogenous competition, promoter interactions, direct interactions with mRNAs, acting as 'scaffolds' to regulate mRNA half­life, interactions with 5­untranslated regions and regulation of sense mRNAs. AS­lncRNAs have been found to either inhibit or promote tumor aggressiveness by regulating cell proliferation, energy metabolism, inflammation, inflammatory­carcinoma transformation, invasion, migration and angiogenesis. In addition, accumulating evidence has documented that AS­lncRNAs can regulate tumor therapy resistance. Therefore, targeting aberrantly expressed AS­lncRNAs for cancer treatment may prove to be a promising approach to reverse therapy resistance. In the present review, research advances on the role of AS­lncRNAs in tumor occurrence and development were summarized, with the aim of providing novel ideas for further research in this field.

Application of Semi-supervised Fuzzy Clustering Based on Knowledge Weighting and Cluster Center Learning to Mammary Molybdenum Target Image Segmentation.

Breast cancer is commonly diagnosed with mammography. Using image segmentation algorithms to separate lesion areas in mammography can facilitate diagnosis by doctors and reduce their workload, which has important clinical significance. Because large, accurately labeled medical image datasets are difficult to obtain, traditional clustering algorithms are widely used in medical image segmentation as an unsupervised model. Traditional unsupervised clustering algorithms have limited learning knowledge. Moreover, some semi-supervised fuzzy clustering algorithms cannot fully mine the information of labeled samples, which results in insufficient supervision. When faced with complex mammography images, the above algorithms cannot accurately segment lesion areas. To address this, a semi-supervised fuzzy clustering based on knowledge weighting and cluster center learning (WSFCM_V) is presented. According to prior knowledge, three learning modes are proposed: a knowledge weighting method for cluster centers, Euclidean distance weights for unlabeled samples, and learning from the cluster centers of labeled sample sets. These strategies improve the clustering performance. On real breast molybdenum target images, the WSFCM_V algorithm is compared with currently popular semi-supervised and unsupervised clustering algorithms. WSFCM_V has the best evaluation index values. Experimental results demonstrate that compared with the existing clustering algorithms, WSFCM_V has a higher segmentation accuracy than other clustering algorithms, both for larger lesion regions like tumor areas and for smaller lesion areas like calcification point areas.

Improved effects of the b-value for 2000 sec/mm2 DWI on an accurate qualitative and quantitative assessment of rectal cancer.

BACKGROUND AND STUDY OBJECTIVES: A higher b-value Diffusion-weighted imaging (DWI) would improve the contrast between cancerous and noncancerous tissue. Apparent diffusion coefficient (ADC)-histogram analysis is a method that can provide statistical data and quantitative information on tumor heterogeneity. This study aimed to compare two high b-values (1000 and 2000 sec/mm2) DWI in tumor detection and diagnostic performance in identifying early-stage tumor rectal cancer. PATIENTS AND METHODS: This blinded and blinded retrospective study involved 56 patients with rectal cancer and 45 patients. Two radiologists evaluated the qualitative detection parameters and quantitative parameters of the ADC evaluated histogram and compared them between two DWI sequences (b-value for 1000 sec/mm2 and 2000 sec/mm2). The characteristic curves were used to assess diagnostic administration for the ADC histogram in discriminating early-stage tumors. RESULTS: The b-value for 2000 sec/mm2 DWI significantly improved AUCs, sensitivity, specificity, and precision and decreased false-positive rate for detection compared to the b-value for 1000 sec/mm2 (p < 0.05). The mean and fifth percentile ADC value for stage I using the b-value for 1000 sec/mm2 DWI was significantly higher than stage ≥ II (p = 0.036II and 0.016 respectively), as the well as fifth, 10th, mean ADC of the fifth, 10th, and 25th ADC percentile at b-value for 2000 sec/mm2 (p = 0.031, 0.014, 0.035 and 0.025 respectively). The AUCs of the fifth percentile ADC at b-value for 2000 sec/mm2 DWI in both readers in differentiating the stage Ⅰ tumor were the highest (0.732 and 0.751). CONCLUSION: The b-value for 2000 sec/mm2 DWI could improve the accurate detection of rectal cancer. The fifth percentile ADC at b-value for 2000 sec/mm2 sec/mm2 DWI was more useful for discriminating early stage than the b-value for 1000 sec/mm2 DWI.

Baicalin mitigates nephropathogenic infectious bronchitis virus infection-induced spleen injury via modulation of mitophagy and macrophage polarization in Hy-Line chick.

Nephropathogenic infectious bronchitis virus (NIBV) infections continue to pose a significant hazard in the poultry industry. Baicalin is a natural flavonoid that has been reported to have antiviral activity, but its function in NIBV infection largely remains unclear. In this study, the antiviral mechanism of baicalin in the spleen of NIBV-infected chicks was mainly elucidated in mitophagy and macrophage polarization. 28-day-old Hy-Line brown chicks were randomly divided into four groups: the group of chicks was treated intranasally (in) with normal saline (0.2 mL) and subsequently divided into two groups: the Con group (basic diet), the Con+BA group (basic diet+10 mg/kg Baicalin); another group of chicks was intranasally infected with SX9 (10-5/0.2 mL) and subsequently divided into two groups: the Dis group (basic diet), the Dis+BA group (basic diet+10 mg/kg Baicalin). Spleen tissues were collected at 3, 7, and 11 days post infection (dpi). NIBV copy number was strikingly decreased in the spleens under BA treatment with infectious time. Histopathological examination showed enlarged and hemorrhagic white pulp and no clearly defined boundary between white pulp and red pulp in the Dis group, which could be improved by BA treatment. Meanwhile, the loss of cristae structure and vacuolization in mitochondria caused by NIBV infection was repaired in the Dis+BA group by ultrastructure observation. In addition, BA treatment inhibited the induction of mitophagy by NIBV infection. BA treatment also promoted innate immunity by enhancing type I IFN levels. Moreover, BA treatment up-regulated M1-related cytokines (iNOS, TNF-α, IL-1ß, IL-6) and inhibited M2-related cytokines (ARG2, IL-4, IL-10, Pparg) at the mRNA and protein levels. However, the results from the splenic tissues at 11 dpi are opposite results from 3 and 7 dpi. Immunofluorescence analysis for M1 macrophage marker iNOS and M2 macrophage marker CD163 further validated this result. Collectively, BA inhibited mitophagy and triggered IFN activation, and M1 polarization, which contributed to the inhibition of NIBV infection.

Preparation of polyclonal antibodies to the chicken Beclin1 protein and its application in the detection of nephropathogenic infectious bronchitis virus.

Beclin1, also known as ATG6, has been shown to be closely related to coronavirus, however, the link between Beclin1 and nephropathogenic infectious bronchitis virus (NIBV) has been poorly investigated and there are no available antibodies specifically targeting the chicken Beclin1 protein. The study aimed to prepare and assay a polyclonal antibody to Beclin1, enabling a deeper understanding of the mechanism of action of Beclin1 in NIBV. In this study, we amplified the chicken Beclin1 target gene and constructed a recombinant plasmid using prokaryotic expression techniques, then obtained the recombinant target protein by induced expression. Finally, the serum is obtained by immunizing rabbits with the purified and concentrated protein. The results show that the antiserum potency of the ELISA assay was >1:204800. By western blotting and immunofluorescence, the antibodies we prepared specifically recognized the chicken Beclin1 protein, which is mainly found in the nucleus of trachea, lung, kidney, spleen and fabricant cells. NIBV infection significantly decreased the expression of Beclin1 in the trachea, but increased in others. We have successfully prepared specific rabbit anti-chicken Beclin1 polyclonal antibodies, and detected changes in tissues of diseased chickens infected with NIBV, laying the foundation for further studies on the role of Beclin1 in avian diseases.

A Highly Stretchable Force Sensitive and Temperature Sensitive Sensor Material with the Sandwich Structure of PDMS + PDMS/GaInSn + PDMS.

Flexible conductive sensor materials have received great attention for their sensitive electrical response to external conditions and their promising applications in flexible wearable and robotic applications. In this work, a highly stretchable force sensitive and temperature sensitive sensor material with a sandwich structure was prepared from the polydimethylsiloxane (PDMS) and the liquid metal (LM) gallium-indium-tin alloy (GaInSn). The sandwich structure (PDMS + PDMS/GaInSn + PDMS) was proven to prevent the "leakage" of LM. The preparation method of the sensing material was simple and time-saving (less than 1.5 h) and can be used for industrial production. The electrical performance analysis results confirmed that the resistance (R) of the material was sensitive to the external force, such as repeated stretching, compressing, bending, and impacting. The ΔR/R changed periodically and stably with the repeated stretching, when the GaInSn/Part A ≥ 0.4, the cyclic tensile strain ≤ 50%, and the cyclic tensile rate ≤ 2.5 mm/min. The R of the sensor materials was also responsive to the temperature, such as hot air and liquid nitrogen. In conclusion, this work provides a method for preparing sensing materials with the sandwich structure, which was confirmed to be sensitive to force and temperature without leaking LM, and it produced different types of R signals under different deformations and different temperatures.

Construction of a prognostic signature associated with liver metastases for prognosis and immune response prediction in colorectal cancer.

Background: As the most common gastrointestinal malignancy worldwide, liver metastases occur in half colorectal cancer (CRC) patients. Early detection can help treat them early and reduce mortality in patients with colorectal cancer liver metastases (CRLM). Finding useful biomarkers for CRLM is thus essential. Methods: The TCGA and GEO databases were used to download the expression profiles and clinical data of the patients. Differential analysis screened for genes associated with CRLM, and univariate Cox regression analysis identified genes associated with prognosis. The least absolute shrinkage and selection operator (LASSO) method further preferred genes to construct a prognostic signature. Kaplan-Meier survival curves were used to show patients' overall survival (OS). Receiver operating characteristic (ROC) curves showed the accuracy of the model. Risk scores and clinical characteristics of patients were included in multivariate Cox regression analysis to identify independent risk factors, and a nomogram was constructed. The proportion of immune cells and infiltration were assessed using the 'CIBERSORT' package and the 'ESTIMATE' package. Results: We constructed a signature consisting of seven CRLM-associated genes, and signature-based risk scores have great potential in estimating the prognosis of CRC patients. Moreover, the poor response to immunotherapy in high-risk patients might contribute to the poor prognosis of individuals. Furthermore, we found that overexpression of Hepcidin antimicrobial peptide (HAMP), the only gene highly expressed in CRC and liver metastatic tissues, promoted CRC development and that it was associated with tumor mutation burden (TMB), DNA mismatch repair (MMR) genes, and microsatellite instability (MSI) in various tumors. Finally, we found that in CRC patients, low expression of HAMP also represented a better immunotherapeutic outcome, reflecting the critical role of HAMP in guiding immunotherapy. Conclusion: We identified a prognostic signature containing 7 CRLM-associated genes, and the signature was specified as an independent predictor and a nomogram containing the risk score was built accordingly. In addition, the derived gene HAMP could help guide the exploration of profitable immunotherapeutic strategies.

Association of polycyclic aromatic hydrocarbons with osteoarthritis among adults: an analysis of the NHANES 2001-2016.

OBJECTIVES: Polycyclic aromatic hydrocarbons (PAHs) are environmental endocrine-disrupting compounds, which have been widely recognised as a risk factor for human health. However, the relationship between PAHs exposure and the risk of osteoarthritis has rarely been reported. This study aimed to investigate the association between individual and mixed exposure to PAHs and osteoarthritis. METHODS: In this cross-sectional study, participants aged ≥20 years with data on urinary PAHs and osteoarthritis were extracted from the National Health and Nutrition Examination Survey (NHANES) between 2001 and 2016. Logistic regression analysis was utilised to assess the relationship between individual PAHs exposure and osteoarthritis. The quantile-based g computation (qgcomp) analysis and Bayesian kernel machine regression (BKMR) analysis were performed to assess the effect of mixed exposure to PAHs on osteoarthritis, respectively. RESULTS: A total of 10,613 participants were enrolled, 980 (9.23%) of whom had osteoarthritis. Exposure to high levels of 1-hydroxynaphthalene (1-NAP) [odds ratio (OR)=1.06, 95% confidence interval (CI): 1.01-1.10], 3-hydroxyfluorene (3-FLU) (OR=1.09, 95%CI: 1.02-1.17), and 2-hydroxyfluorene (2-FLU) (OR=1.06, 95%CI: 1.01-1.13) were all associated with greater odds of osteoarthritis after adjusting for age, sex, body mass index, drinking alcohol, and hypertension. The qgcomp analysis showed that the joint weighted value of mixed PAHs exposure (OR=1.11, 95%CI: 1.02-1.22; p=0.017) was significantly related to higher odds of osteoarthritis. The BKMR analysis demonstrated that mixed exposure to PAHs was positively correlated with the risk of osteoarthritis. CONCLUSIONS: Both individual and mixed exposure to PAHs were positively correlated with the risk of osteoarthritis.

ZNF8-miR-552-5p Axis Modulates ACSL4-Mediated Ferroptosis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a common malignancy that is associated with poor prognosis in humans. Despite the development of targeted drugs, overall survival remains a significant challenge, and new therapeutic strategies are urgently needed. The aim of this study was to investigate the function of miR-552-5p in ferroptosis and the underlying mechanism, as well as to explore novel strategies for HCC treatment. CCK8 assay results showed that the viability of Huh-7 and Hep3B cells decreased significantly after transfection of the miR-552-5p inhibitor. In addition, we found that glutathione levels were depleted, intracellular Fe2+ levels were elevated, and the mean fluorescence intensity of C11-BODIPY was increased after miR-552-5p transfection. Transmission electron microscopy revealed that mitochondria became smaller and mitochondrial membrane intensity was increased in the inhibitor+RSL3 group. Mechanistically, a dual-luciferase reporter assay confirmed that miR-552-5p interacted with the 3' untranslated region (3' UTR) of acyl-CoA synthetase long-chain family member 4 (ACSL4) mRNA. qPCR and Western blotting results verified that miR-552-5p negatively regulated ACSL4 expression. In addition, we found that overexpression of ZNF8, which is a transcription factor, reduced intracellular miR-552-5p levels and enhanced sensitivity to ferroptosis. miR-552-5p reduces sensitivity to ferroptosis by targeting the 3' UTR of ACSL4 in HCC. The ZNF8-miR-552-5p-ACSL4 axis is involved in regulation of ferroptosis in HCC, and these findings may provide a new therapeutic target for treatment of HCC.

Integrin ß6 deficiency protects mice from experimental colitis and colitis-associated carcinoma by altering macrophage polarization.

Background: Given the key role of integrins in maintaining intestinal homeostasis, anti-integrin biologics in inflammatory bowel disease (IBD) are being investigated in full swing. However, the unsatisfactory efficacy and safety of current anti-integrin biologics in clinical trials limit their widespread use in clinic. Therefore, it is particularly important to find a target that is highly and specifically expressed in the intestinal epithelium of patients with IBD. Methods: The function of integrin αvß6 in IBD and colitis-associated carcinoma (CAC) with the underlying mechanisms has been less studied. In the present study, we detected the level of integrin ß6 within inflammation including colitis tissues in human and mouse. To investigate the role of integrin ß6 in IBD and CAC, integrin ß6 deficient mice were hence generated based on the construction of colitis and CAC model. Results: We noted that integrin ß6 was significantly upregulated in inflammatory epithelium of patients with IBD. Integrin ß6 deletion not only reduced infiltration of pro-inflammatory cytokines, but also attenuated disruption of tight junctions between colonic epithelial cells. Meanwhile, lack of integrin ß6 affected macrophage infiltration in mice with colitis. This study further revealed that lack of integrin ß6 could inhibit tumorigenesis and tumor progression in CAC model by influencing macrophage polarization, which was also involved in attenuating the degree of intestinal symptoms and inflammatory responses in mice suffering from colitis. Conclusions: The present research provides a potentially new perspective and option for the treatment of IBD and CAC.

Oxygen Anion Redox Chemistry Correlated with Spin State in Ni-Rich Layered Cathodes.

Despite the low cost and high capacity of Ni-rich layered oxides (NRLOs), their widespread implementation in electric vehicles is hindered by capacity decay and O release. These issues originate from chemo-mechanical heterogeneity, which is mainly related to oxygen anion redox (OAR). However, what to tune regarding OAR in NRLOs and how to tune it remains unknown. In this study, a close correlation between the OAR chemistry and Li/Ni antisite defects is revealed. Experiments and calculations show the opposite effects of aggregative and dispersive Li/Ni antisite defects on the NiO6 configuration and Ni spin state in NRLOs. The resulting broad or narrow spans for the energy bands caused by spin states lead to different OAR chemistries. By tuning the Li/Ni antisite defects to be dispersive rather than aggregative, the threshold voltage for triggering OAR is obviously elevated, and the generation of bulk-O2 -like species and O2 release at phase transition nodes is fundamentally restrained. The OAR is regulated from irreversible to reversible, fundamentally addressing structural degradation and heterogeneity. This study reveals the interaction of the Li/Ni antisite defect/OAR chemistry/chemo-mechanical heterogeneity and presents some insights into the design of high-performance NRLO cathodes.

Wumei Wan attenuates angiogenesis and inflammation by modulating RAGE signaling pathway in IBD: Network pharmacology analysis and experimental evidence.

BACKGROUND: Wumei Wan (WMW) has been used to address digestive disorder for centuries in traditional Chinese medicine. Previous studies have demonstrated its anti-colitis efficacy, but the underlying mechanism of its action remains to be further clarified. PURPOSE: To investigate the underlying mechanisms of WMW in the treatment of chronic ulcerative colitis (UC) through network pharmacology and experimental validation. METHODS: Traditional Chinese Medicine Systems Pharmacology (TCMSP) platform were used to identify the ingredients and potential targets of WMW. The microarray gene data GSE75214 datasets from GEO database was used to define UC-associated targets. Cytoscape3.7.2 was employed to construct the protein-protein interaction (PPI) network and compounds-disease targets network. GO enrichment analysis and KEGG pathway analysis were performed by R software for functional annotation. UPLC-TOF-MS/MS method was used to quantitatively analyze the active ingredients of WMW. For experimental validation, three cycles of 2% dextran sulfate sodium salt (DSS) were used to construct chronic colitis model. The hub targets and signal pathway were detected by qPCR, ELISA, western blotting , immunohistochemical and immunofluorescence. RESULTS: Through network analysis, 104 active ingredients were obtained from WMW, and 47 of these ingredients had potential targets for UC. A total of 41 potential targets of WMW and 13 hub targets were identified. KEGG analysis showed that WMW involved in advanced glycation end products-receptor of advanced glycation end products (AGE-RAGE) signaling pathway. Taxifolin, rutaecarpine, kaempferol, quercetin, and luteolin of WMW were the more highly predictive components related to the AGE-RAGE signaling pathway. In vivo validation, WMW improved DSS-induced colitis, reduced the expression of inflammatory cytokines and chemokines. Notably, it significantly decreased the mRNA expression of Spp1, Serpine1, Mmp2, Mmp9, Ptgs2, Nos2, Kdr and Icam1, which were associated with angiogenesis. In addition, we confirmed WMW inhibited RAGE expression and diminished DSS-induced epithelial barrier alterations CONCLUSION: Our results initially demonstrated the effective components and the strong anti-angiogenic activity of WMW in experimental chronic colitis. Sufficient evidence of the satisfactory anti-colitis action of WMW was verified in this study, suggesting its potential as a quite prospective agent for the therapy of UC.

CX3CL1 deficiency ameliorates inflammation, apoptosis and accelerates osteogenic differentiation, mineralization in LPS-treated MC3T3-E1 cells via its receptor CX3CR1.

BACKGROUND: Osteoporosis is a devastating skeletal disease responsible for bone fragility and fracture. CX3C chemokine ligand 1 (CX3CL1) is an inflammatory chemokine which has been identified to possess increased expression in the serum of postmenopausal osteoporotic patients. This paper was to illuminate the impacts of CX3CL1 on inflammation, apoptosis and osteogenic differentiation, mineralization in LPS-treated osteoblasts and investigate the regulatory mechanism. METHODS: The viability of MC3T3-E1 cells exposed to elevating doses of LPS was detected by CCK-8 assay. CX3CL1 and C-X3-C motif chemokine receptor 1 (CX3CR1) expression were detected by RT-qPCR and western blot. CX3CR1 expression was examined again following CX3CL1 depletion. The binding of CX3CL1 with CX3CR1 was testified through Co-IP assay. In MC3T3-E1 cells co-transduced with CX3CL1 interference and CX3CR1 overexpression plasmids following LPS exposure, cell activity and inflammation were separately estimated via CCK-8 assay and RT-qPCR. Apoptosis was measured by TUNEL assay and western blot. Osteoblast differentiation was evaluated by ALP activity assay, RT-qPCR and western blot. Osteoblast mineralization was assessed by ARS staining, RT-qPCR and western blot. Results The experimental data presented that LPS attenuated the viability and enhanced CX3CL1 and CX3CR1 expression in MC3T3-E1 cells in a dose-dependent manner. CX3CR1 interacted with CX3CL1 and was positively modulated by CX3CL1. The suppressive role of CX3CL1 absence in LPS-evoked viability decrease, inflammation and apoptosis in MC3T3-E1 cells was reversed by CX3CR1 elevation. Besides, CX3CR1 reversed the promoted osteoblast differentiation and mineralization imposed by CX3CL1 interference. CONCLUSIONS: CX3CL1 knockdown eased inflammation, apoptosis and promoted osteogenic differentiation, mineralization in MC3T3-E1 cells upon LPS exposure through down-regulating CX3CR1.

IGF2BP3-NRF2 axis regulates ferroptosis in hepatocellular carcinoma.

Poor sensitivity to sorafenib has been an important constraint on the efficacy of targeted therapy in advanced hepatocellular carcinoma (HCC). Therefore, it is particularly important to explore effective therapeutic targets to improve the sensitivity of HCC cells to sorafenib. Upregulation of IGF2BP3 is strongly associated with tumor invasion, early recurrence and poor prognosis in various human cancers, including HCC, but its roles in the sorafenib treatment of HCC remain unclear. In our study, IGF2BP3 knock-down significantly promoted ferroptosis in HCC cells through the evaluation of the Reactive Oxygen Species (ROS), Fe2+ and malondialdehyde (MDA) levels after sorafenib administration. In addition, NRF2 mRNA was identified as an important target of IGF2BP3 by bioinformatics analysis, RNA binding protein immunoprecipitation (RIP) and RNA pulldown experiments. More importantly, IGF2BP3, as an m6A (N6-Methyladenosine) reader, was shown to promote the stability of NRF2 mRNA by reading its m6A modification. Similar results were obtained from in vivo experiments. In summary, our study uncovered the role of IGF2BP3-NRF2 axis on ferroptosis in HCC, providing significant evidence for new anti-cancer strategies aimed at improving the efficacy of sorafenib.

Pathogenic or Therapeutic: The Mediating Role of Gut Microbiota in Non-Communicable Diseases.

Noncommunicable diseases (NCDs) lead to 41 million deaths every year and account for 71% of all deaths worldwide. Increasing evidence indicates that gut microbiota disorders are closely linked to the occurrence and development of diseases. The gut microbiota, as a potential transmission medium, could play a key role in the transmission and treatment of diseases. The gut microbiota makes noncommunicable diseases communicable. New methods of the prevention and treatment of these diseases could be further explored through the gut microbiota.

Integrin ß3 Promotes Resistance to EGFR-TKI in Non-Small-Cell Lung Cancer by Upregulating AXL through the YAP Pathway.

Integrin ß3 plays a key role in the resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), but the development of integrin ß3 inhibitors has been stalled due to the failure of phase III clinical trials for cancer treatment. Therefore, it is imperative to find a potentially effective solution to the problem of acquired resistance to EGFR-TKI for patients with integrin-ß3 positive non-small-cell lung cancer (NSCLC) by exploring novel downstream targets and action mechanisms of integrin ß3. In the present study, we observed that the expression of integrin ß3 and AXL was significantly upregulated in erlotinib-resistant NSCLC cell lines, which was further confirmed clinically in tumor specimens from patients with NSCLC who developed acquired resistance to erlotinib. Through ectopic expression or knockdown, we found that AXL expression was positively regulated by integrin ß3. In addition, integrin ß3 promoted erlotinib resistance in NSCLC cells by upregulating AXL expression. Furthermore, the YAP pathway, rather than pathways associated with ERK or AKT, was involved in the regulation of AXL by integrin ß3. To investigate the clinical significance of this finding, the current well-known AXL inhibitor R428 was tested, demonstrating that R428 significantly inhibited resistance to erlotinib, colony formation, epithelial-mesenchymal transformation and cell migration induced by integrin ß3. In conclusion, integrin ß3 could promote resistance to EGFR-TKI in NSCLC by upregulating the expression of AXL through the YAP pathway. Patients with advanced NSCLC, who are positive for integrin ß3, might benefit from a combination of AXL inhibitors and EGFR-TKI therapy.