Analyzing risk factors and constructing a predictive model for superficial esophageal carcinoma with submucosal infiltration exceeding 200 micrometers.

OBJECTIVE: Submucosal infiltration of less than 200 µm is considered an indication for endoscopic surgery in cases of superficial esophageal cancer and precancerous lesions. This study aims to identify the risk factors associated with submucosal infiltration exceeding 200 micrometers in early esophageal cancer and precancerous lesions, as well as to establish and validate an accompanying predictive model. METHODS: Risk factors were identified through least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression. Various machine learning (ML) classification models were tested to develop and evaluate the most effective predictive model, with Shapley Additive Explanations (SHAP) employed for model visualization. RESULTS: Predictive factors for early esophageal invasion into the submucosa included endoscopic ultrasonography or magnifying endoscopy> SM1(P<0.001,OR = 3.972,95%CI 2.161-7.478), esophageal wall thickening(P<0.001,OR = 12.924,95%CI,5.299-33.96), intake of pickled foods(P=0.04,OR = 1.837,95%CI,1.03-3.307), platelet-lymphocyte ratio(P<0.001,OR = 0.284,95%CI,0.137-0.556), tumor size(P<0.027,OR = 2.369,95%CI,1.128-5.267), the percentage of circumferential mucosal defect(P<0.001,OR = 5.286,95%CI,2.671-10.723), and preoperative pathological type(P<0.001,OR = 4.079,95%CI,2.254-7.476). The logistic regression model constructed from the identified risk factors was found to be the optimal model, demonstrating high efficacy with an area under the curve (AUC) of 0.922 in the training set, 0.899 in the validation set, and 0.850 in the test set. CONCLUSION: A logistic regression model complemented by SHAP visualizations effectively identifies early esophageal cancer reaching 200 micrometers into the submucosa.

A Dual-Function LipoAraN-E5 Coloaded with N4-Myristyloxycarbonyl-1-ß-d-arabinofuranosylcytosine (AraN) and a CXCR4 Antagonistic Peptide (E5) for Blocking the Dissemination of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a hematological malignancy with a high recurrence rate. The interaction of chemokine receptor 4/chemokine ligand 12 (CXCR4/CXCL12) mediates homing and adhesion of AML cells in bone marrow, leading to minimal residual disease in patients, which brings a hidden danger for future AML recurrence. Ara-C is a nonselective chemotherapeutic agent against AML. Due to its short half-life and severe side effects, a lipid-like Ara-C derivative (AraN) was synthesized and a dual-function LipoAraN-E5 (135 nm, encapsulation efficiency 99%) was developed, which coloaded AraN and E5, a peptide of the CXCR4 antagonist. LipoAraN-E5 effectively improved the uptake, enhanced the inhibition of leukemia cell proliferation, migration, and adhesion to stromal cells in bone marrow, and mobilized the leukemia cells from bone marrow to peripheral blood via interfering with the CXCR4/CXCL12 axis. LipoAraN-E5 prolonged the plasma half-life of AraN (8.31 vs 0.56 h) and was highly enriched in peripheral blood (3.67 vs 0.05 µmol/g at 8 h) and bone marrow (379 vs 148 µmol/g at 24 h). LipoAraN-E5 effectively prevented the infiltration of leukemia cells in peripheral blood, bone marrow, spleen, and liver, prolonged the mice survival, and showed outstanding antineoplastic efficacy with negligible toxicity, which were attributed to the ingenious design of AraN, the use of a liposomal delivery carrier, and the introduction of E5. Our work revealed that LipoAraN-E5 may be a promising nanocandidate against AML.

Ultraviolet Light Causes Skin Cell Senescence: From Mechanism to Prevention Principle.

The skin is an effective protective barrier that significantly protects the body from damage caused by external environmental factors. Furthermore, skin condition significantly affects external beauty. In today's era, which is of material and spiritual prosperity, there is growing attention on skincare and wellness. Ultraviolet radiation is one of the most common external factors that lead to conditions like sunburn, skin cancer, and skin aging. In this review, several mechanisms of UV-induced skin cell senescence are discussed, including DNA damage, oxidative stress, inflammatory response, and mitochondrial dysfunction, which have their own characteristics and mutual effects. As an illustration, mitochondrial dysfunction triggers electron evasion and the generation of more reactive oxygen species, leading to oxidative stress and the activation of the NLRP3 inflammasome, which in turn causes mitochondrial DNA (mt DNA) damage. Based on the current mechanism, suitable prevention and treatment strategies are proposed from sunscreen, dietary, and experimental medications respectively, aimed at slowing down skin cell aging and providing protection from ultraviolet radiation. The effects of ultraviolet rays on skin is summarized, offering insights and directions for future studies on mechanism of skin cell senescence, with an anticipation of discovering more effective prevention and cure methods.

Development of novel aza-stilbenes as a new class of selective MAO-B inhibitors for the treatment of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of nigrostriatal dopaminergic neurons. Inhibitors of monoamine oxidase B (MAO-B) have shown promise in alleviating motor symptoms and reducing oxidative stress associated with PD. In this study, we report the novel use of an azastilbene-based compound library for screening human (h)MAO-B, followed by optimization of initial hits to obtain compounds with low nanomolar inhibitory potencies (compound 9, IC50 = 42 nM) against hMAO-B. To ensure specificity and minimize false positives due to non-specific hydrophobic interactions, we performed comprehensive selectivity profiling against hMAO-A, butyrylcholinesterase (hBChE) and acetylcholinesterase (hAChE) - enzymes with hydrophobic active sites that are structurally distinct from hMAO-B. Docking analysis with Glide provided valuable insights into the binding interactions between the inhibitors and hMAO-B and also explained the selectivity against hMAO-A. In the cell-based model of Parkinson's disease, one of the compounds significantly reduced rotenone-induced accumulation of reactive oxygen species. In addition, these compounds showed a protective effect against acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor dysfunction in PD model mice and reduced MPTP-induced loss of striatal tyrosine hydroxylase-positive neurons in the substantia nigra. These results make azastilbene-based compounds a promising new class of hMAO-B inhibitors with potential therapeutic applications in Parkinson's disease and related neurodegenerative disorders.

Oleanolic acid improves 5-fluorouracil-induced intestinal damage and inflammation by alleviating intestinal senescence.

5-Fluorouracil (5-FU) is used as a standard first-line drug for colorectal cancer malignancy (CRC), but it brings a series of side effects such as severe diarrhea and intestinal damage. Our previous study found that a large number of senescent cells increased while 5-Fu induced intestinal damage, and anti-senescence drugs can alleviate its side effects of inflammatory damage. Oleanolic acid (OA) is a common pentacyclic triterpenoid mainly derived from food fungi and medicinal plants, and studies have shown that it mainly possesses hepatoprotective, enzyme-lowering, anti-inflammatory, and anti-tumor effects. But its role in senescence is still unclear. In the present study, we demonstrated for the first time that OA ameliorated 5-Fu-induced human umbilical vein endothelial cells (HUVECs) and human normal intestinal epithelial cells (NCM460) in a 5-Fu-induced cellular senescence model by decreasing the activity of SA-ß-gal-positive cells, and the expression of senescence-associated proteins (p16), senescence-associated genes (p53 and p21), and senescence-associated secretory phenotypes (SASPs: IL-1ß, IL-6, IL-8, IFN-γ and TNF-α). Meanwhile, in this study, in a BALB/c mouse model, we demonstrated that 5-FU induced intestinal inflammatory response and injury, which was also found to be closely related to the increase of senescent cells, and that OA treatment was effective in ameliorating these adverse phenomena. Furthermore, our in vivo and in vitro studies showed that OA could alleviate senescence by inhibiting mTOR. In colon cancer cell models, OA also enhanced the ability of 5-FU to kill HCT116 cells and SW480 cells. Overall, this study demonstrates for the first time the potential role of OA in counteracting the side effects of 5-FU chemotherapy, providing a new option for the treatment of colorectal cancer to progressively achieve the goal of high efficacy and low toxicity of chemotherapy.

Expression patterns of housekeeping genes and tissue-specific genes in black goats across multiple tissues.

Black goats are a significant meat breed in southern China. To investigate the expression patterns and biological functions of genes in various tissues of black goats, we analyzed housekeeping genes (HKGs), tissue-specific genes (TSGs), and hub genes (HUBGs) across 23 tissues. Additionally, we analyzed HKGs in 13 tissues under different feeding conditions. We identified 2968 HKGs, including six important ones. Interestingly, HKGs in grazing black goats demonstrated higher and more stable expression levels. We discovered a total of 9912 TSGs, including 134 newly identified ones. The number of TSGs for mRNA and lncRNA were nearly equal, with 127 mRNA TSGs expressed solely in one tissue. Additionally, the predicted functions of tissue-specific long non-coding RNAs (lncRNAs) targeting mRNAs corresponded with the physiological functions of the tissues.Weighted gene co-expression network analysis (WGCNA) constructed 30 modules, where the dark grey module consists almost entirely of HKGs, and TSGs are located in modules most correlated with their respective tissues. Additionally, we identified 289 HUBGs, which are involved in regulating the physiological functions of their respective tissues. Overall, these identified HKGs, TSGs, and HUBGs provide a foundation for studying the molecular mechanisms affecting the genetic and biological processes of complex traits in black goats.

Efferocytosis drives a tryptophan metabolism pathway in macrophages to promote tissue resolution.

Macrophage efferocytosis prevents apoptotic cell (AC) accumulation and triggers inflammation-resolution pathways. The mechanisms linking efferocytosis to resolution often involve changes in macrophage metabolism, but many gaps remain in our understanding of these processes. We now report that efferocytosis triggers an indoleamine 2,3-dioxygenase-1 (IDO1)-dependent tryptophan (Trp) metabolism pathway that promotes several key resolution processes, including the induction of pro-resolving proteins, such interleukin-10, and further enhancement of efferocytosis. The process begins with upregulation of Trp transport and metabolism, and it involves subsequent activation of the aryl hydrocarbon receptor (AhR) by the Trp metabolite kynurenine (Kyn). Through these mechanisms, macrophage IDO1 and AhR contribute to a proper resolution response in several different mouse models of efferocytosis-dependent tissue repair, notably during atherosclerosis regression induced by plasma low-density lipoprotein (LDL) lowering. These findings reveal an integrated metabolism programme in macrophages that links efferocytosis to resolution, with possible therapeutic implications for non-resolving chronic inflammatory diseases, notably atherosclerosis.

Melatonin Ameliorates Abnormal Sleep-Wake Behavior via Facilitating Lipid Metabolism in a Zebrafish Model of Parkinson's Disease.

Sleep-wake disorder is one of the most common nonmotor symptoms of Parkinson's disease (PD). Melatonin has the potential to improve sleep-wake disorder, but its mechanism of action is still unclear. Our data showed that melatonin only improved the motor and sleep-wake behavior of a zebrafish PD model when melatonin receptor 1 was present. Thus, we explored the underlying mechanisms by applying a rotenone model. After the PD zebrafish model was induced by 10 nmol/L rotenone, the motor and sleep-wake behavior were assessed. In situ hybridization and real-time quantitative PCR were used to detect the expression of melatonin receptors and lipid-metabolism-related genes. In the PD model, we found abnormal lipid metabolism, which was reversed by melatonin. This may be one of the main pathways for improving PD sleep-wake disorder.

Electrostatically Self-Assembled Magnetic Nanoparticles for High-Temperature Resistant and Friction-Controlled Lubrication System.

Magnetic-responsive surfactants are considered promising smart lubricating materials due to their significant stimulation response to applied magnetic fields. In this study, four magneto-responsive surfactants are successfully fabricated and encapsulated on the surface of molybdenum disulfide nanosheets (MoS2@C18H37N+(CH3)3[XCl3Br]-, X = Fe, Ce, Gd, and Ho) as base-oil components using electrostatic self-assembly, thereby constructing a multi-functional magnetic lubrication system (MoS2@STAX). Magnetorheological measurements confirm the remarkable responsiveness of MoS2@STACe lubricants at high shear rates and applied magnetic fields, which is further corroborated by the constant proximity of the magnet. The formation of dense carbon and tribo-chemical films between the friction interfaces at elevated temperatures is the primary factor contributing to the significant reduction in frictional wear. Notably, the magnetic lubricant demonstrates a pronounced response behavior when subjected to an applied magnetic field in the ceramic tribopair, even at lower magnetic fields. This work presents concepts for the development of high-temperature resistant and tunable lubrication additives by designing the material structure and controlling the magnetic stimulation.

Air-Processed Efficient Cesium-Based Two-Dimensional Perovskite Solar Cells Based on Asymmetric Chiral Ammonium Salts.

Cesium-based two-dimensional (2D) perovskites with attractive phase and environmental stability have broad application prospects in single-junction and tandem perovskite solar cells (PSCs). However, the severe nonradiative recombination and significant energy losses due to disordered phase orientations and phase distributions greatly hinder the carrier transport performance of cesium-based 2D PSCs and severely limit their photovoltaic performance. Here, we employ an asymmetric chiral spacer cation source, (R)-α-phenylethylamine acrylate (R-α-PEAAA), to prepare high-quality 2D cesium-based films with uniform phase distribution and high out-of-plane orientation by air processing, resulting in efficient carrier transport. More importantly, the asymmetric chiral spacer R-α-PEA has a stronger dipole moment than its isomer (PEA), which can regulate the dielectric properties of cesium-based 2D perovskites and promote charge dissociation. In addition, the chiral R-α-PEA can optimize the morphology and out-of-plane orientation of perovskite films, reduce trap density and nonradiative recombination loss, and optimize energy level alignment, thus enhancing carrier transport. As a result, cesium-based 2D PSCs (R-α-PEA2Cs4Pb5I16, n = 5) achieved a record power conversion efficiency of 19.71% and the unencapsulated device maintained over 90% efficiency after 1500 h of continuous light exposure and ambient storage (35 ± 5% relative humidity). This study provides an idea for the development of chiral 2D perovskite with efficient charge carrier transport toward efficient and stable cesium-based 2D PSCs.

Research progress of traditional Chinese medicine in the treatment of ischemic stroke by regulating mitochondrial dysfunction.

Ischemic stroke (IS) is a severe cerebrovascular disease with increasing incidence and mortality rates in recent years. The pathogenesis of IS is highly complex, with mitochondrial dysfunction playing a critical role in its onset and progression. Thus, preserving mitochondrial function is a pivotal aspect of treating ischemic brain injury. In response, there has been growing interest among scholars in the regulation of mitochondrial function through traditional Chinese medicine (TCM), including herb-derived compounds, individual herbs, and herbal prescriptions. This article reviews recent research on the mechanisms of mitochondrial dysfunction in IS and explores the potential of TCM in treating this condition by targeting mitochondrial dysfunction.

Asymptomatic multicentric Castleman disease: A potential early stage of idiopathic MCD.

According to the diagnostic criteria for HHV-8 (human herpesvirus-8) negative/idiopathic multicentric Castleman disease (iMCD) proposed by Castleman Disease Collaborative Network (CDCN) in 2017, there is a group of HHV-8 negative multicentric Castleman disease (MCD) patients who do not have symptoms and hyperinflammatory state and do not meet the iMCD criteria. This retrospective study enrolled 114 such patients, described as asymptomatic MCD (aMCD), from 26 Chinese centers from 2000-2021. With a median follow-up time of 46.5 months (range: 4-279 months), 6 patients (5.3%) transformed to iMCD. The median time between diagnosis of aMCD and iMCD in these 6 patients was 28.5 months (range: 3-60 months). During follow-up, 7 patients died; three of them died from progression of MCD. Despite that 37.7% patients received systemic treatment targeting MCD, this strategy was neither associated with a lower probability of iMCD transformation nor a lower death rate. The 5-year estimated survival of all aMCD patients was 94.1% (95% CI 88.8-99.6%). Transformation to iMCD was an important predictor of death (log-rank p=0.01) (5-year estimated survival 83.3%). This study suggests that aMCD patients may represent a potential early stage of iMCD, who may not require immediate treatment but should be closely monitored.

Tumor microenvironment-responsive manganese-based nano-modulator activate the cGAS-STING pathway to enhance innate immune system response.

BACKGROUND: Manganese ions (Mn2+) combined with adjuvants capable of damaging and lysing tumor cells form an antitumor nano-modulator that enhances the immune efficacy of cancer therapy through the cascade activation of the cyclic GMP-AMP interferon gene synthase-stimulator (cGAS-STING) pathway, which underscores the importance of developing antitumor nano-modulators, which induce DNA damage and augment cGAS-STING activity, as a critical future research direction. METHODS AND RESULTS: We have successfully synthesized an antitumor nano-modulator, which exhibits good dispersibility and biosafety. This nano-modulator is engineered by loading manganese dioxide nanosheets (M-NS) with zebularine (Zeb), known for its immunogenicity-enhancing effects, and conducting targeted surface modification using hyaluronic acid (HA). After systemic circulation to the tumor site, Mn2+, Zeb, and reactive oxygen species (ROS) are catalytically released in the tumor microenvironment by H+ and H2O2. These components can directly or indirectly damage the DNA or mitochondria of tumor cells, thereby inducing programmed cell death. Furthermore, they promote the accumulation of double-stranded DNA (dsDNA) in the cytoplasm, enhancing the activation of the cGAS-STING signalling pathway and boosting the production of type I interferon and the secretion of pro-inflammatory cytokines. Additionally, Zeb@MH-NS enhances the maturation of dendritic cells, the infiltration of cytotoxic T lymphocytes, and the recruitment of natural killer cells at the tumor site. CONCLUSIONS: This HA-modified manganese-based hybrid nano-regulator can enhance antitumor therapy by boosting innate immune activity and may provide new directions for immunotherapy and clinical translation in cancer.

Effects of social support on vision-related quality of life in older adults with dry eye disease: the chain mediating role of illness perception and coping style.

Objective: This study explored the effects of social support, illness perception, coping style, and vision-related quality of life (VRQOL) in older patients with dry eye disease (DED) using a chain mediation model. Methods: A total of 407 patients with DED from a tertiary hospital in Wuxi, Jiangsu Province, China, between June and December 2023 were selected as participants. A demographic questionnaire, the Social Support Rating Scale, the Brief Illness Perception Questionnaire, the Medical Coping Modes Questionnaire, and the National Eye Institute Visual Functioning questionnaire-25 were all given to them to complete. IBM SPSS (version 27.0) was used for data analysis, and Model 6 of the PROCESS Macro was used to test the predicted chain mediation model. Results: The positive association between social support and VRQOL demonstrated the mediation role of illness perception and coping style. Social support affected VRQOL via three pathways: illness perception (effect = 0.190), confrontational coping style (effect = 0.103), and a combination of illness perception and confrontational coping style (effect = 0.067), accounted for 23.60%, 12.80%, and 8.32% of the total effect, respectively. Conclusion: Social support in older patients with DED can significantly and positively predict the VRQOL. In addition to the independent mediating effect of illness perception and confrontational coping style, a chain-mediating effect exists between social support and VRQOL. The study serves as a valuable strategy for healthcare professionals to prevent and intervene in VRQOL for older patients with DED in the future.

Network pharmacology and experimental verification revealing valnemulin alleviates DSS-induced ulcerative colitis by inhibiting intestinal senescence.

Ulcerative colitis (UC) is a chronic inflammatory disease that is increasing in prevalence globally. Senescence is characterized by a specific chronic, low-grade, "sterile" inflammatory state known as inflammaging, suggesting that senescence may exacerbate the severity of UC. However, the link between UC and senescence remains unclear. Valnemulin (VAL) is a semi-synthetic derivative of a naturally occurring diterpenoid antibiotic (pleuromutilin), which can inhibit peptidyl transferase. Studies investigating the potential of valnemulin to inhibit senescence and alleviate colitis are currently limited. In this study, we revealed that dextran sulfate sodium (DSS), an inducer of UC, induces senescence in both colon epithelial NCM460 cells and colon tissues. Additionally, VAL, identified from a compound library, exhibited robust anti-senescence activity in DSS-treated NCM460 cells. Identified in our study as an anti-senescence agent, VAL effectively mitigated DSS-induced UC and colonic senescence in mice. Through network pharmacology analysis and experimental validation, the potential signaling pathway (AMPK/NF-κB) for VAL in treating UC was identified. We discovered that DSS significantly inhibited the AMPK signaling pathway and activated the NF-κB signaling pathway. However, supplementation with VAL remarkably restored AMPK activity and inhibited the NF-κB signaling pathway, which led to the inhibition of senescence. In summary, our study demonstrated that DSS-induced UC stimulates the senescence of colonic tissues, and VAL can effectively alleviate DSS-induced colonic damage and reduce colonic senescence. Our research findings provide a new perspective for targeting anti-senescence in the treatment of UC.

Predictive Factors for Tissue Inflammation in Patients with Benign Prostatic Hyperplasia: A Clinical Prediction Study.

INTRODUCTION: Benign prostatic hyperplasia (BPH) is a common condition in older men, marked by the noncancerous enlargement of the prostate gland. Inflammation of the prostate plays a significant role in the progression of BPH and the symptoms it causes. The objective of this study was to create a predictive model for prostatic inflammation in men with BPH based on important clinical factors. METHODS: A retrospective cohort study was conducted with 137 patients diagnosed with BPH. Data collected included various factors such as age, prostate volume (PV), preoperative international prostate symptom score, preoperative maximum urine flow rate (Qmax), preoperative post-void residue, weight of the excised tissue, body mass index, fasting blood glucose (FBG), cholesterol levels, prostate-specific antigen, blood calcium, blood phosphorus, blood uric acid, triglycerides, hypertension status, and presence of prostate calcifications. Multivariate logistic regression and LASSO regression analyses were performed to identify significant predictors and develop a nomogram. The model's performance was evaluated using receiver operating characteristic curves, calibration plots, and decision curve analysis (DCA). RESULTS: Among the patients, 9.49% showed no signs of prostatic inflammation, while 22.63% had mild, 47.45% had moderate, and 20.44% had severe inflammation. Factors such as PV, FBG, and prostate calcification were identified as important predictors of prostatic inflammation. The predictive model developed exhibited strong discrimination and calibration, as evidenced by a high area under the curve value, indicating reliable predictive accuracy. DCA further validated the clinical usefulness of the nomogram. CONCLUSION: The developed nomogram, incorporating PV, FBG, and prostate calcification, effectively predicts prostatic inflammation in men with BPH. This tool can aid in early intervention and targeted treatment, potentially improving patient outcomes. Further validation in diverse populations is recommended to enhance its generalizability and clinical applicability.

Deciphering macrobenthic biological traits in response to long-term eutrophication in Xiangshan Bay, China.

As an emerging global issue in coastal marine ecosystems, eutrophication may lead to profound ecological consequences or disasters. Six locations in Xiangshan Bay were sampled during 2012-2022 along the eutrophication gradient from the innermost bay with the most eutrophication to the outer bay with the least eutrophication. A trait-based method was adopted to explore the ecological effects of eutrophication on macrobenthic communities. The results showed that the community composition is mostly characterized by deposit feeders and predators with small (1-3 cm) and large (> 10 cm) body sizes, classified as indifferent and tolerant species (AMBI ecological groups), deposit feeders and predators (feeding mode), and a preference for a free living lifestyle. The RLQ and fourth-corner analyses further confirmed that there was a negative correlation between the abundance of small macrobenthic organisms (< 1 cm) and nitrate concentration. Phosphorus was a crucial influencing factor for macrobenthic spatial patterns and was strongly affected by the activities of deposit feeders and the decomposition of macrobenthos. Due to mass organic deposition resulting from increased primary production, long-term eutrophication had led to an increase in the proportion of detritus feeders. In addition, the significant negative correlation between the concentration of dissolved oxygen and first-order opportunistic species represented by the polychaete Capitella capitata indicated tolerance to hypoxia. The macrobenthic community in Xiangshan Bay had been negatively affected but maintains considerable stability in functional diversity and functional redundancy under the influence of long-term eutrophication.

Hypoxia activates macrophage-NLRP3 inflammasome promoting atherosclerosis via PFKFB3-driven glycolysis.

The onset and progression of atherosclerosis are closely linked to the involvement of macrophages. While the contribution of NLRP3 inflammasome activation to the creation of a local highly inflammatory microenvironment is well recognized, the precise triggers remain unclear. In this study, we aimed to investigate the regulatory mechanism of NLRP3 inflammasome activation in response to hypoxia-induced glycolysis involving PFKFB3 in the development of atherosclerosis. To develop an atherosclerosis model, we selected ApoE knockout mice treated with a high-fat western diet. We then quantified the expression of HIF-1α, PFKFB3, and NLRP3. In addition, we administered the PFKFB3 inhibitor PFK158 during atherosclerosis modeling. The glycolytic activity was subsequently determined through 18F-FDG micro-PET/CT, ex vivo glucose uptake, and ECAR analysis. Furthermore, we employed lipopolysaccharide (LPS) and TNF-α to induce the differentiation of bone marrow-derived macrophages (BMDMs) into M1-like phenotypes under both hypoxic and normoxic conditions. Our histological analyses revealed the accumulation of PFKFB3 in human atherosclerotic plaques, demonstrating colocalization with NLRP3 expression and macrophages. Treatment with PFK158 reduced glycolytic activity and NLRP3 inflammasome activation, thereby mitigating the occurrence of atherosclerosis. Mechanistically, hypoxia promoted glycolytic reprogramming and NLRP3 inflammasome activation in BMDMs. Subsequent blocking of either HIF-1α or PFKFB3 downregulated the NLRP3/Caspase-1/IL-1ß pathway in hypoxic BMDMs. Our study demonstrated that the HIF-1α/PFKFB3/NLRP3 axis serves as a crucial mechanism for macrophage inflammation activation in the emergence of atherosclerosis. The therapeutic potential of PFKFB3 inhibition may represent a promising strategy for atheroprotection.

Identification and validation of Rab GTPases RAB13 as biomarkers for peritoneal metastasis and immune cell infiltration in colorectal cancer patients.

Background: As one of the most common cancer, colorectal cancer (CRC) is with high morbidity and mortality. Peritoneal metastasis (PM) is a fatal state of CRC, and few patients may benefit from traditional therapies. There is a complex interaction between PM and immune cell infiltration. Therefore, we aimed to determine biomarkers associated with colorectal cancer peritoneal metastasis (CRCPM) and their relationship with immune cell infiltration. Methods: By informatic analysis, differently expressed genes (DEGs) were selected and hub genes were screened out. RAB13, one of the hub genes, was identificated from public databases and validated in CRC tissues. The ESTIMATE, CEBERSORT and TIMER algorithms were applied to analyze the correlation between RAB13 and immune infiltration in CRC. RAB13's expression in different cells were analyzed at the single-cell level in scRNA-Seq. The Gene Set Enrichment Analysis (GSEA) was performed for RAB13 enrichment and further confirmed. Using oncoPredict algorithm, RAB13's impact on drug sensitivity was evaluated. Results: High RAB13 expression was identified in public databases and led to a poor prognosis. RAB13 was found to be positively correlated with the macrophages and other immune cells infiltration and from scRNA-Seq, RAB13 was found to be located in CRC cells and macrophages. GSEA revealed that high RAB13 expression enriched in a various of biological signaling, and oncoPredict algorithm showed that RAB13 expression was correlated with paclitaxel sensitivity. Conclusion: Our study indicated clinical role of RAB13 in CRC-PM, suggesting its potential as a therapeutic target in the future.