Prenatal p25-activated Cdk5 induces pituitary tumorigenesis through MCM2 phosphorylation-mediated cell proliferation.

Aberrant expression of cyclin-dependent kinase 5 (Cdk5) has been reported in pituitary adenomas. However, the role of Cdk5 in the tumorigenesis remains unclear. We show that prenatal p25-activated Cdk5 phosphorylates minichromosome maintenance protein 2 (Mcm2), enhancing minichromosome maintenance (MCM) family proteins and driving intermediate lobe-located melanotrope-originated pituitary tumorigenesis. In a mouse model with CaMKII promoter-driven transgenic induction of p25, we observed intermediate lobe-originated pituitary adenoma producing non-functional proopiomelanocortin (POMC)-derived peptides under persistent p25 overexpression. Single-cell RNA sequencing revealed Mcm2 may play an important role during tumor progression. Subsequently, Mcm2 was identified as a potential phosphorylated substrate of Cdk5, mediating the tumorous proliferation of melanotrope cells. Silencing Cdk5 or Mcm2 suppressed cell proliferation and colony formation in the 293T cell lines. Therefore, our findings provide a new mouse model of intermediate lobe-originated pituitary adenoma induced by p25/Cdk5 and unveil a previously unappreciated role of Cdk5 and Mcm2 in pituitary adenoma tumorigenesis.

Enhanced Sonodynamic Therapy for Deep Tumors Using a Self-Assembled Organoplatinum(II) Sonosensitizer.

Despite the promising advances in photodynamic therapy (PDT), it remains challenging to target and treat deep-seated solid tumors effectively. Herein, we developed an organoplatinum(II) complex (Pt-TPE) with self-assembly properties for sonodynamic therapy (SDT). Pt-TPE forms a nanofiber network structure through Pt-Pt and π-π stacking interactions. Notably, under ultrasound (US), Pt-TPE demonstrates unique self-assembly-induced singlet oxygen (1O2) generation due to a significantly enhanced singlet-triplet intersystem crossing (ISC). This generation of 1O2 occurs exclusively in the self-assembled state of Pt-TPE. Additionally, Pt-TPE exhibits sono-cytotoxicity against cancer cells by impairing mitochondrial membrane potential (MMP), inhibiting glucose uptake, and aerobic glycolysis. Furthermore, US-activated Pt-TPE significantly inhibits deep solid tumors in mice, achieving remarkable therapeutic efficacy even at penetration depths greater than 10 cm. This study highlights the potential of self-assembled metal complexes to enhance the efficacy of SDT for treating deep tumors.

Regulating Manganese-Site Electronic Structure via Reconstituting Nitrogen Coordination for Efficient Non-Oxygen-Dependent Sonocatalytic Therapy against Orthotopic Breast Cancer.

Sonocatalytic therapy (SCT) has emerged as a promising noninvasive modality for tumor treatment but is hindered by the insufficient generation of ultrasound-induced reactive oxygen species (ROS) and the hypoxic tumor microenvironments. Herein, we fabricated a carbon nanoframe-confined N-coordinated manganese single-atom sonocatalyst with a five-coordinated structure (MnN5 SA/CNF) using a phthalocyanine-mediated pyrolysis strategy. The precise coordination structure was identified by synchrotron X-ray absorption fine structure analyses. The MnN5 SA/CNF exhibits superior and nonoxygen-dependent sonocatalytic activity owing to the optimized coordination structure and cavitation effect enhanced by defects. Additionally, density functional theory studies reveal that the five-coordination structure downshifts the d-band center of Mn from -0.547 to -0.829 eV and enhances the desorption capacity for oxygen-containing intermediates, thus accelerating the catalytic process. Finally, the as-synthesized MnN5 SA/CNF demonstrates a significantly enhanced antitumor effect through mitochondrial apoptosis in an orthotopic breast cancer mouse model. This work explores the potential of SAzymes-supported biomedical interventions by leveraging enzymatic activity with sonocatalytic properties.

Microbial-Metabolomic Exploration of Tea Polyphenols in the Regulation of Serum Indicators, Liver Metabolism, Rumen Microorganisms, and Metabolism in Hu Sheep.

This study investigated the impact of tea polyphenols on serum indices, rumen microorganisms, rumen metabolism, and liver metabolism in Hu sheep. Sixty healthy lambs, aged three months and with similar average weights, were chosen and randomly assigned to control (CON), TP400, TP800, and TP1200 groups, each consisting of fifteen lambs. The control group received a basal diet, while the experimental groups were provided with basal diet supplemented with 400 mg/kg, 800 mg/kg, and 1200 mg/kg of tea polyphenols, respectively. Compared with the CON group, the addition of tea polyphenols to the diet significantly increased serum IgA, GSH-Px, and TSOD. In addition, tea polyphenols were able to increase rumen pH but had no significant effect on the rumen NH3-N, VFA molar content, and the microbial top 10 phylum and genus levels. Moreover, Firmicutes predominated in the network map of the top 80 abundant microorganisms at the genus level, identifying 13 biomarkers at the genus level. In addition, strong correlations were observed between liver and rumen metabolites, particularly between rumen succinic acid and liver alanyl-serine and methylmalonic acid. Furthermore, tea polyphenol additions changed the enrichment of liver and rumen metabolites in the top five KEGG metabolic pathways, but 400-1200 mg/kg additions had no negative impact on the liver and rumen. In summary, TP significantly influences rumen and liver metabolites in Hu sheep, enhancing lamb immunity and antioxidant capacity, with 400 mg/kg being the most effective dosage.

Metabolic and Immunological Implications of MME+CAF-Mediated Hypoxia Signaling in Pancreatic Cancer Progression: Therapeutic Insights and Translational Opportunities.

Pancreatic cancer is a devastating malignancy with a high mortality rate, poor prognosis, and limited treatment options. The tumor microenvironment (TME) plays a crucial role in tumor progression and therapy resistance. Multiple subpopulations of cancer-associated fibroblasts (CAFs) within the TME can switch between different states, exhibiting both antitumorigenic and protumorigenic functions in pancreatic cancer. It seems that targeting fibroblast-related proteins and other stromal components is an appealing approach to combat pancreatic cancer. This study employed single-cell transcriptome sequencing to identify MME (Membrane Metalloendopeptidase)-expressing CAFs in pancreatic cancer. Systematic screening was conducted based on tumor differentiation, lymph node metastasis, and T-stage parameters to identify and confirm the existence of a subpopulation of fibroblasts termed MME+CAFs. Subsequent analyses included temporal studies, exploration of intercellular communication patterns focusing on the hypoxia signaling pathway, and investigation of MME+CAF functions in the pancreatic cancer microenvironment. The pathway enrichment analysis and clinical relevance revealed a strong association between high MME expression and glycolysis, hypoxia markers, and pro-cancer inflammatory pathways. The role of MME+CAFs was validated through in vivo and in vitro experiments, including high-throughput drug screening to evaluate potential targeted therapeutic strategies. Single-cell transcriptome sequencing revealed tumor-associated fibroblasts with high MME expression, termed MME+CAF, exhibiting a unique end-stage differentiation function in the TME. MME+CAF involvement in the hypoxia signaling pathway suggested the potential effects on pancreatic cancer progression through intercellular communication. High MME expression was associated with increased glycolysis, hypoxia markers (VEGF), and pro-cancer inflammatory pathways in pancreatic cancer patients, correlating with lower survival rates, advanced disease stage, and higher oncogene mutation rates. Animal experiments confirmed that elevated MME expression in CAFs increases tumor burden, promotes an immunosuppressive microenvironment, and enhances resistance to chemotherapy and immunotherapy. The developed MME+CAF inhibitor IOX2 (a specific prolyl hydroxylase-2 (PHD2) inhibitor), combined with AG (Paclitaxel + Gemcitabine) and anti-PD1 therapy, demonstrated promising antitumor effects, offering a translational strategy for targeting MME in CAFs of pancreatic cancer. The study findings highlighted the significant role of MME+CAF in pancreatic cancer progression by shaping the TME and influencing key pathways. Targeting MME presented a promising strategy to combat the disease, with potential implications for therapeutic interventions aimed at disrupting MME+CAF functions and enhancing the efficacy of pancreatic cancer treatments.

A composite patch loaded with 2-Deoxy Glucose facilitates cardiac recovery after myocardial infarction via attenuating local inflammatory response.

Local inflammatory microenvironment in the early stage of myocardial infarction (MI) severely impaired cardiac recovery post-MI. Macrophages play a pivotal role in this process. A classical glycolytic inhibitor, 2-Deoxy-Glucose (2-DG), has been found to regulate the excessive pro-inflammatory macrophage polarization in the infarcted myocardium. This study investigated the effect of 2-DG-loaded chitosan/gelatin composite patch on the infarct microenvironment post-MI and its impact on cardiac repair. The results showed that the 2-DG patch significantly inhibited the expression of inflammatory cytokines, alleviated reactive oxygen species (ROS) accumulation, repressed the proinflammatory polarization of macrophages, attenuated local inflammatory microenvironment in the ischemic hearts, as well as improved cardiac function, reduced scar size, and promoted angiogenesis post-MI. In terms of mechanism, 2-DG exerts anti-inflammatory effects through inhibiting the NF-κB signaling pathway and reducing the assembly and activation of the NLRP3 inflammasome. These findings suggest that 2-DG composite patch may represent a promising therapeutic strategy for cardiac repair after MI.

Exploring the gut microbiome and immunological landscape in kidney cancer: a Mendelian randomization analysis.

Introduction: Kidney cancer (KC) is a significant health burden globally, with over 400,000 new cases estimated in 2020. The prognosis of KC is influenced by various factors, including tumor spread, pathological characteristics, and molecular genetic changes. Recent studies have emphasized the involvement of gut microbiota and the immune system's contribution in the onset of KC. This extensive research endeavor sought to investigate the potential associations between diverse immune cell phenotypes, specific gut microbiota species, and their impact on the risk of developing KC, alongside the examination of circulating inflammatory proteins. Methods: Adhering to the STROBE-MR guidelines, our investigation involved a two-stage Mendelian randomization (2SMR) analysis grounded on three fundamental assumptions: relevance, independence, and exclusion restriction. The exposure data utilized in this study originated from genome-wide association studies (GWAS) specifically designed to explore immune traits, inflammatory proteins, and gut microbiota compositions. Results: Our analysis identified 25 immune phenotypes, 4 circulating inflammatory proteins, and 12 gut microbiota features that exhibited significant causal associations with KC (P < 0.05). 10 immune phenotypes were protective against KC, while 15 were risk factors. Among the inflammatory proteins, CCL28 and IL-2 were protective, whereas FGF-23 and ß-NGF were risk factors. Gut microbiota features associated with reduced KC risk included biosynthetic pathways involving amino acids and specific bacterial genera, whereas others, like Butyrivibrio crossotus and Odoribacter splanchnicus, were risk factors. Conclusion: Immune, inflammatory, and gut microbiota factors impact KC development. Identified factors hint at biomarkers and therapeutic targets. It is very important to understand the relationship between these factors and KC.

The scoring system combined with radiomics and imaging features in predicting the malignant potential of incidental indeterminate small (<20 mm) solid pulmonary nodules.

OBJECTIVE: Develop a practical scoring system based on radiomics and imaging features, for predicting the malignant potential of incidental indeterminate small solid pulmonary nodules (IISSPNs) smaller than 20 mm. METHODS: A total of 360 patients with malignant IISSPNs (n = 213) and benign IISSPNs (n = 147) confirmed after surgery were retrospectively analyzed. The whole cohort was randomly divided into training and validation groups at a ratio of 7:3. The least absolute shrinkage and selection operator (LASSO) algorithm was used to debase the dimensions of radiomics features. Multivariate logistic analysis was performed to establish models. The receiver operating characteristic (ROC) curve, area under the curve (AUC), 95% confidence interval (CI), sensitivity and specificity of each model were recorded. Scoring system based on odds ratio was developed. RESULTS: Three radiomics features were selected for further model establishment. After multivariate logistic analysis, the combined model including Mean, age, emphysema, lobulated and size, reached highest AUC of 0.877 (95%CI: 0.830-0.915), accuracy rate of 83.3%, sensitivity of 85.3% and specificity of 80.2% in the training group, followed by radiomics model (AUC: 0.804) and imaging model (AUC: 0.773). A scoring system with a cutoff value greater than 4 points was developed. If the score was larger than 8 points, the possibility of diagnosing malignant IISSPNs could reach at least 92.7%. CONCLUSION: The combined model demonstrated good diagnostic performance in predicting the malignant potential of IISSPNs. A perfect accuracy rate of 100% can be achieved with a score exceeding 12 points in the user-friendly scoring system.

Mannosylated Fluoropolypeptide Nanovaccines Remodeling Tumor Immunosuppressive Microenvironment to Achieve Highly Potent Cancer Immunotherapy.

It is challenging for nanovaccines (NVs) to effectively deliver antigens/neoantigens to prime specifically potent immunities and remodel immunosuppressive tumor microenvironment (TME) for combating immune "cold" cancers. Herein, a novel kind of mannosylated fluoropolypeptide NVs of MFPCOFG (i.e., mannosylated fluoropoly(D,L-cysteine) ovalbumin-loaded Fe2+-gallic acid) is designed that synergistically integrates triple antigen-metal-thermoimmunity to remodel immunosuppressive TME and achieve highly potent immunities. MFPCOFG plus near-infrared irradiation (NIR) effectively facilitated antigen uptake and escape, induced the maturation and antigen cross-presentations of dendritic cells and macrophages, polarized anti-inflammatory macrophage phenotype M2 into tumoricial M1, primed potent CD4+/CD8+T cells responses, proinflammatory cytokines secretion and immune memory effects, showcasing triple antigen-metal-thermoimmunity outperforming combo/mono-immunity. Importantly, both MFPCOFG + NIR and personalized NVs can remarkably enhance the tumor infiltration of CD4+/CD8+T and NK cells to boost potent immunities and long-lasting memory effects, reduce regulatory T (Tregs) and M2 to remodel immunosuppressive TME in B16-OVA and 4T1 models, achieving superior tumor prevention, ablation, and tumor relapse and metastasis inhibition, as further orchestrated with anti-PD-1. Consequently, this work opens up a new avenue to design biocompatible polypeptide nanovaccines with potent immune-priming and TME-remodeling capabilities, holding great potentials to combat immune "cold" cancers with clinic-used anti-PD-1 for cancer immunotherapy and personalized immunotherapy.

An adaptive spatiotemporal filter for ultrasound localization microscopy based on density canopy clustering.

Ultrasound Localization Microscopy (ULM) facilitates structural and hemodynamic imaging of microvessels with a resolution of tens of micrometers. In ULM, the extraction of effective microbubble signals is crucial for image quality. Singular Value Decomposition (SVD) is currently the most prevalent method for microbubble signal extraction in ULM. Most existing ULM studies employ a fixed SVD filter threshold using empirical values which will lead to imaging quality degradation due to the insufficient separation of blood signals. In this study, we propose an adaptive and non-threshold SVD filter based on canopy-density clustering, termed DCC-SVD. This filter automatically classifies the components of the SVD based on the density of their spatiotemporal features, eliminating the need for parameter selection. In in vitro tube phantom, DCC-SVD demonstrated its ability to adaptive separation of blood and bubble signal at varying microbubble concentrations and flow rates. We compared the proposed DCC-SVD method with the Block-match 3D (BM3D) filter and a classical adaptive method called spatial similarity matrix (SSM), using concentration-variable in vivo rat brain data, as well as open-source rat kidney and mouse tumor datasets. The proposed DCC-SVD improved the global spatial resolution by approximately 4 µm from 30.39 µm to 26.02 µm. It also captured vessel structure absent in images obtained by other methods and yielded a smoother vessel intensity profile, making it a promising spatiotemporal filter for ULM imaging.

The challenge and opportunity of gut microbiota-targeted nanomedicine for colorectal cancer therapy.

The gut microbiota is an integral component of the colorectal cancer (CRC) microenvironment and is intimately associated with CRC initiation, progression, and therapeutic outcomes. We reviewed recent advancements in utilizing nanotechnology for modulating gut microbiota, discussing strategies and the mechanisms underlying their design. For future nanomedicine design, we propose a 5I principle for individualized nanomedicine in CRC management.

Diagnostic Significance of Serum Long Noncoding HOX Antisense Intergenic Ribonucleic Acid in Patients with Hepatitis B Virus Related Hepatocellular Carcinoma.

BACKGROUND/AIMS:  Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and the third leading cause of cancer-related mortality. Extensive literature suggests that long noncoding RNAs play a role in the progression of HCC and hold potential as diagnostic biomarkers for this disease. MATERIALS AND METHODS:  We examined the serum levels of HOX antisense intergenic RNA (HOTAIR) in 49 hepatitis patients, 31 liver cirrhosis (LC), and 37 HCC patients using quantitative real-time polymerase chain reaction. Correlations between serum HOTAIR levels and clinical data were evaluated in HCC patients. The receiver operating characteristic curve was utilized to analyze the diagnostic potency of HOTAIR. RESULTS:  The HOTAIR levels in serum were significantly higher in HCC patients compared to those with hepatitis (P = .003) and LC patients (P = .048). There was a significant association between the serum levels of HOTAIR and positivity of hepatitis B e antigen (HBeAg) (P = .039) as well as portal vein tumor thrombus (P = .040) in HCC patients. The area under the curve (AUC) for HOTAIR for distinguishing HCC from hepatitis and LC was 0.697. The combined AUC for HOTAIR, HBeAg, and alpha-fetoprotein (AFP) was 0.777. CONCLUSION:  Serum HOTAIR functions as a potential diagnostic marker for hepatitis B virus-related HCC. Combining HOTAIR with clinical data and AFP can reinforce the diagnostic precision on HCC.

Nuclear alpha-synuclein accelerates cell senescence and neurodegeneration.

BACKGROUND: The progression of Parkinson's disease (PD) is related to ageing. The accumulation of nuclear alpha-synuclein (α-syn) may accelerate the occurrence of neurodegenerative diseases, but its role in PD remains poorly understood. METHODS: In the present study, α-syn expression was specifically targeted to the nucleus by constructing an adeno-associated virus (AAV) vector in which a nuclear localization sequence (NLS) was added to the α-syn coding sequence. Virus-mediated gene transfer, behavioural tests, RNA-Seq, immunohistochemistry, western blotting, and quantitative real-time PCR were then performed. RESULTS: In vivo experiments using a mouse model showed that nuclear α-syn increased the severity of the PD-like phenotype, including the loss of dopaminergic neurons concomitant with motor impairment and the formation of α-syn inclusions. These nuclear inclusions contained α-syn species of high molecular weights and induced strong transcriptional dysregulation, especially induced high expression of p21 and senescence-associated secretory phenotype (SASP)-related genes. In addition, the transcriptional alterations induced by nuclear α-syn were associated with gliosis, inflammation, oxidative and DNA damage, and lysosomal dysfunction, and they eventually accelerated neuronal loss and neurodegeneration. CONCLUSIONS: Our results suggest that nuclear α-syn plays a crucial role in PD pathogenesis.

Race and Ethnicity, Socioeconomic Factors, and Epigenetic Age Acceleration in Survivors of Childhood Cancer.

Importance: Current research in epigenetic age acceleration (EAA) is limited to non-Hispanic White individuals. It is imperative to improve inclusivity by considering racial and ethnic minorities in EAA research. Objective: To compare non-Hispanic Black with non-Hispanic White survivors of childhood cancer by examining the associations of EAA with cancer treatment exposures, potential racial and ethnic disparity in EAA, and mediating roles of social determinants of health (SDOH). Design, Setting, and Participants: In this cross-sectional study, participants were from the St Jude Lifetime Cohort, which was initiated in 2007 with ongoing follow-up. Eligible participants included non-Hispanic Black and non-Hispanic White survivors of childhood cancer treated at St Jude Children's Research Hospital between 1962 and 2012 who had DNA methylation data. Data analysis was conducted from February 2023 to May 2024. Exposure: Three treatment exposures for childhood cancer (chest radiotherapy, alkylating agents, and epipodophyllotoxin). Main Outcomes and Measures: DNA methylation was generated from peripheral blood mononuclear cell-derived DNA. EAA was calculated as residuals from regressing Levine or Horvath epigenetic age on chronological age. SDOH included educational attainment, annual personal income, and the socioeconomic area deprivation index (ADI). General linear models evaluated cross-sectional associations of EAA with race and ethnicity (non-Hispanic Black and non-Hispanic White) and/or SDOH, adjusting for sex, body mass index, smoking, and cancer treatments. Adjusted least square means (ALSM) of EAA were calculated for group comparisons. Mediation analysis treated SDOH as mediators with average causal mediation effect (ACME) calculated for the association of EAA with race and ethnicity. Results: Among a total of 1706 survivors including 230 non-Hispanic Black survivors (median [IQR] age at diagnosis, 9.5 [4.3-14.3] years; 103 male [44.8%] and 127 female [55.2%]) and 1476 non-Hispanic White survivors (median [IQR] age at diagnosis, 9.3 [3.9-14.6] years; 766 male [51.9%] and 710 female [48.1%]), EAA was significantly greater among non-Hispanic Black survivors (ALSM = 1.41; 95% CI, 0.66 to 2.16) than non-Hispanic White survivors (ALSM = 0.47; 95% CI, 0.12 to 0.81). Among non-Hispanic Black survivors, EAA was significantly increased among those exposed to chest radiotherapy (ALSM = 2.82; 95% CI, 1.37 to 4.26) vs those unexposed (ALSM = 0.46; 95% CI, -0.60 to 1.51), among those exposed to alkylating agents (ALSM = 2.33; 95% CI, 1.21 to 3.45) vs those unexposed (ALSM = 0.95; 95% CI, -0.38 to 2.27), and among those exposed to epipodophyllotoxins (ALSM = 2.83; 95% CI, 1.27 to 4.40) vs those unexposed (ALSM = 0.44; 95% CI, -0.52 to 1.40). The association of EAA with epipodophyllotoxins differed by race and ethnicity (ß for non-Hispanic Black survivors, 2.39 years; 95% CI, 0.74 to 4.04 years; ß for non-Hispanic White survivors, 0.68; 95% CI, 0.05 to 1.31 years) and the difference was significant (1.77 years; 95% CI, 0.01 to 3.53 years; P for interaction = .049). Racial and ethnic disparities in EAA were mediated by educational attainment (

Role of Cancer Side Population Stem Cells in Ovarian Cancer Angiogenesis.

Ovarian cancer is one of the most common gynecologic malignancies. Recurrence and metastasis often occur after treatment, and it has the highest mortality rate of all gynecological tumors. Cancer stem cells (CSCs) are a small population of cells with the ability of self-renewal, multidirectional differentiation, and infinite proliferation. They have been shown to play an important role in tumor growth, metastasis, drug resistance, and angiogenesis. Ovarian cancer side population (SP) cells, a type of CSC, have been shown to play roles in tumor formation, colony formation, xenograft tumor formation, ascites formation, and tumor metastasis. The rapid progression of tumor angiogenesis is necessary for tumor growth; however, many of the mechanisms driving this process are unclear as is the contribution of CSCs. The aim of this review was to document the current state of knowledge of the molecular mechanism of ovarian cancer stem cells (OCSCs) in regulating tumor angiogenesis.

N-Phenyl-2-Pyridone-Derived Endoperoxide Suppressing both Lung Cancer and Idiopathic Pulmonary Fibrosis Progression by Three-Pronged Action.

We report an endoperoxide compound (E5) which can deliver three therapeutic components by a thermal cycloreversion, namely, singlet oxygen, triplet oxygen and 3-methyl-N-phenyl-2-pyridone (P5), thus targeting multiple mechanisms for treating non-small cell lung cancer and idiopathic pulmonary fibrosis. In aqueous environment, E5 undergoes clean reaction to afford three therapeutic components with a half-life of 8.3 hours without the generation of other by-products, which not only achieves good cytotoxicity toward lung cancer cells and decreases the levels of hypoxia-inducible factor 1α (HIF-1α) protein, but also inhibits the transforming growth factor ß1 (TGF-ß1) induced fibrosis in vitro. In vivo experiments also demonstrated the efficacy of E5 in inhibiting tumor growth and relieving idiopathic pulmonary fibrosis, while exhibiting good biocompatibility. Many lines of evidence reveal the therapeutic efficacy of singlet oxygen and 3-methyl-N-phenyl-2-pyridone for these two lung diseases, and triplet oxygen could downregulate HIF-1α and relieve tumor hypoxia which is a critical issue in photodynamic therapy (PDT). Unlike other combination therapies, in which multiple therapeutic agents are given in independent formulations, our work demonstrates single molecule endoperoxide prodrugs could be developed as new platforms for treatment of cancers and related diseases.

Human milk fat substitutes rich in 1,3-dioleoyl-2-palmitoylglycerol and 1-oleoyl-2-palmitoyl-3-linoleoylglycerol simultaneously: Preparation strategy and simulated infant in vitro digestion.

In this study, fractionated palm stearin, oleic acid, and linoleic acid were selected as the base materials to prepare human milk fat substitutes (HMFS) rich in OPO and OPL by enzymatic acidolysis combined with physical blending. Under optimum conditions, contents of OPO, OPL, and sn-2 palmitic acid in the OPO and OPL-rich triacylglycerols (TAGs) were higher than that in commercial OPO-rich TAGs, with values of 37.25%, 28.12%, and 79.44%, respectively. Physical blending the OPO and OPL-rich TAGs (47%), bovine milk fat (18%), sunflower oil (13%), coconut oil (13%), corn oil (8%), and palm oil (1%) can obtain HMFS with a fat composition that like HMF. The fatty acid, sn-2 saturated fatty acid, and TAG contents of HMFS were within the lower and upper limit of HMF. The lipolysis degree of infant formula (IF) with HMFS as fat source is 9.0% higher than that of commercial plant oil-based infant formula (PIF), and 3.4% lower than that of human milk. IF with HMFS as fat source released less saturated free fatty acids and more saturated monoacylglycerols during digestion than that of PIF, which would help improve the IF fat utilization by infants.

NRF3 suppresses the metastasis of triple-negative breast cancer cells by inhibiting ERK activation in a ROS-dependent manner.

PURPOSE: Our previous study demonstrated that NRF3 (NFE2L3, Nuclear Factor-erythroid 2-related factor 3) could suppress cell metastasis and proliferation in breast cancer. In this study, we investigated the mechanisms underlying its function in breast cancer. METHODS: In the present study, NRF3 expression and its clinical characteristics in breast cancer were analyzed using public datasets and clinical specimens. After breast cancer cells were overexpressed NRF3, FACS was used to detect the intracellular ROS levels. The migration and invasion activities of NRF3-ectopic expressed breast cancer cells were determined by transwell assay. To validate the role of ROS/ERK axis in the inhibitory effect of NRF3 in cell metastasis, ROS scavenger NAC was also included. RESULTS: We found that NRF3 mRNA was highly expressed, while NRF3 protein was extremely lowly expressed in breast cancer tissues compared with their normal counterparts, and low level NRF3 was associated with poorer prognosis in patients with triple negative breast cancer (TNBC). More interestingly, overexpression of NRF3 protein significantly increased cellular ROS production and dramatically decreased p-ERK level and cell migration in TNBC cells. Mechanistically, NRF3 protein was found to be mutually regulated by valosin-containing protein (VCP). Strikingly, VCP-knockdown dramatically increased NRF3 protein expression, but NRF3-knockin also decreased VCP expression in return. Moreover, antioxidant NAC treatment effectively increased the level of p-ERK and VCP expression, as well as cell migration and invasion abilities of TNBC cells. CONCLUSION: NRF3, a tumor suppressor downregulated by VCP, could attenuate cell metastasis in TNBC cells by increasing cellular ROS accumulation and subsequently inhibiting the ERK phosphorylation.

Atomically Resolved Transition Pathways of Iron Redox.

The redox transition between iron and its oxides is of the utmost importance in heterogeneous catalysis, biological metabolism, and geological evolution. The structural characteristics of this reaction may vary based on surrounding environmental conditions, giving rise to diverse physical scenarios. In this study, we explore the atomic-scale transformation of nanosized Fe3O4 under ambient-pressure H2 gas using in-situ environmental transmission electron microscopy. Our results reveal that the internal solid-state reactions dominated by iron diffusion are coupled with the surface reactions involving gaseous O or H species. During reduction, we observe two competitive reduction pathways, namely Fe3O4 → FeO → Fe and Fe3O4 → Fe. An intermediate phase with vacancy ordering is observed during the disproportionation reaction of Fe2+ → Fe0 + Fe3+, which potentially alleviates stress and facilitates ion migration. As the temperature decreases, an oxidation process occurs in the presence of environmental H2O and trace amounts of O2. A direct oxidation of Fe to Fe3O4 occurs in the absence of the FeO phase, likely corresponding to a change in the water vapor content in the atmosphere. This work elucidates a full dynamical scenario of iron redox under realistic conditions, which is critical for unraveling the intricate mechanisms governing the solid-solid and solid-gas reactions.

Neural Progenitor Cell-Mediated Magnetic Nanoparticles for Magnetic Resonance Imaging and Photothermal Therapy of Glioma.

Glioma is the most common primary malignant tumor in the brain. The diagnostic accuracy and treatment efficiency of glioma are facing great challenges due to the presence of the blood-brain barrier (BBB) and the high infiltration of glioma. There is an urgent need to explore the combination of diagnostic and therapeutic approaches to achieve a more accurate diagnosis, as well as guidance before and after surgery. In this work, we induced human induction of pluripotent stem cell into neural progenitor cells (NPCs) and synthesized nanoprobes labeled with enhanced green fluorescent protein (EGFP, abbreviated as MFe3O4-labeled EGFP-NPCs) for photothermal therapy. Nanoprobes carried by NPCs can effectively penetrate the BBB and target glioma for the purpose of magnetic resonance imaging and guiding surgery. More importantly, MFe3O4-labeled EGFP-NPCs can effectively induce local photothermal therapy, conduct preoperative tumor therapy, and inhibit the recurrence of postoperative glioma. This work shows that MFe3O4-labeled EGFP-NPCs is a promising nanoplatform for glioma diagnosis, accurate imaging-guided surgery, and effective photothermal therapy.