HOXD10 attenuates renal fibrosis by inhibiting NOX4-induced ferroptosis.

In chronic kidney disease (CKD), renal fibrosis is an unavoidable result of various manifestations. However, its pathogenesis is not yet fully understood. Here, we revealed the novel role of Homeobox D10 (HOXD10) in CKD-related fibrosis. HOXD10 expression was downregulated in CKD-related in vitro and in vivo fibrosis models. UUO model mice were administered adeno-associated virus (AAV) containing HOXD10, and HOXD10 overexpression plasmids were introduced into human proximal tubular epithelial cells induced by TGF-ß1. The levels of iron, reactive oxygen species (ROS), lipid ROS, the oxidized glutathione/total glutathione (GSSG/GSH) ratio, malonaldehyde (MDA), and superoxide dismutase (SOD) were determined using respective assay kits. Treatment with AAV-HOXD10 significantly attenuated fibrosis and renal dysfunction in UUO model mice by inhibiting NOX4 transcription, ferroptosis pathway activation, and oxidative stress. High levels of NOX4 transcription, ferroptosis pathway activation and profibrotic gene expression induced by TGF-ß1/erastin (a ferroptosis agonist) were abrogated by HOXD10 overexpression in HK-2 cells. Moreover, bisulfite sequencing PCR result determined that HOXD10 showed a hypermethylated level in TGF-ß1-treated HK-2 cells. The binding of HOXD10 to the NOX4 promoter was confirmed by chromatin immunoprecipitation (ChIP) analysis and dual-luciferase reporter assays. Targeting HOXD10 may represent an innovative therapeutic strategy for fibrosis treatment in CKD.

Association between composite dietary antioxidant index and kidney stone prevalence in adults: data from National Health and Nutrition Examination Survey (NHANES, 2007-2018).

Background: The high prevalence of kidney stones in adults worldwide has prompted research into potential interventions, one of which involves exploring the consumption of antioxidants that may confer protective effects. However, the relationship between the composite dietary antioxidant index (CDAI), a crucial measure used to assess an individual's overall antioxidant capacity from daily dietary intake, and kidney stones remains unclear. Therefore, we conducted cross-sectional analysis to examine the association between CDAI and kidney stone prevalence. Methods: The analysis was conducted utilizing data from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018. Antioxidant intake was derived from two 24-h dietary recalls surveys, while CDAI, a comprehensive measure that includes antioxidants like vitamins A, C, and E, zinc, selenium, and carotenoids, was calculated. Multivariate logistic regression and restricted cubic spline (RCS) regression were utilized to examine the association between CDAI and the prevalence of kidney stones. Results: The study included a total of 28,516 participants, with 2,748 individuals having a history of kidney stones. The median of CDAI was -0.01 (-2.02, 2.37). Individuals in the fourth quartile of CDAI exhibited a significantly lower prevalence of kidney stones compared to those in the first quartile (Odds Ratio [OR] = 0.769 [0.633-0.935]), even after adjusting for potential confounding factors (including age, sex, race, education level, poverty income ratio, smoking status, drinking status, body mass index (BMI), energy intake levels, physical activity level, serum calcium concentration, estimated glomerular filtration rate (eGFR), hypertension, diabetes and supplement use). The RCS analysis revealed a non-linear relationship between CDAI and kidney stone prevalence, with inflection points identified at 0.06 (p for non-linearity = 0.039). Subgroup analysis demonstrated consistent CDAI-kidney stone prevalence associations across all subsets. Furthermore, a significant inverse correlation was observed between CDAI and inflammatory markers. Conclusion: This study provides evidence supporting a reciprocal correlation between adult dietary antioxidant intake, as measured by CDAI, and kidney stone prevalence. These findings emphasize the potential benefits of consuming dietary antioxidants in lowering the risk of kidney stone formation.

The characterization of traditional Chinese medicine natures and flavors using network pharmacology integrated strategy.

Background and aim: Due to the complexity of TCM ingredients and medication compatibility, TCM cannot be used like chemical medicines. The theory of "Four Natures and five Flavors" provides a theoretical basis for the use of TCM. "Four Natures and five Flavors" are originated from pharmacological rules based on clinical practices. Whereas, How to describe and characterize "Natures"(Warm, Hot, Cold and Cool) and "Flavors" (Pungent, Sour, Sweet, Bitter and Salty) scientifically remain the issue that needs to be solved. The aim of this study is to establish the TCM characterization models based on the integrated pharmacology network strategy and provide a deeper understanding of TCM theory. Experimental procedure: Five "Pungent-Neutral", nine "Sweet-Neutral and nine "Bitter-Neutral" TCMs were selected to characterize the "Flavors" (Pungent, Sweet and Bitter). Nine "Pungent-Warm" and nine "Bitter-Cold" TCMs were selected to characterize the "Natures" (Warm and Cold). The screened chemical ingredients were analyzed by classification and the screened characteristics targets were analyzed by GO and KEGG enrichment analysis. Results and conclusion: In the "Pungent" group, flavonoids are the most. "Pungent" may have immune-regulatory effects and potential anticancer activity. In the "Sweet" group, isoflavones are the most. "Sweet" are related to effectively invigorate health. Fatty acids in the "Warm" group are the most. Flavonoids in the "Cold' group are far more than other components. "Warm" and "Cold" are both related to fatty acid and energy metabolism.

T7 peptide-mediated co-delivery platform overcoming multidrug-resistant breast cancer: In vitro and in vivo evaluation.

P-glycoprotein (P-gp) overexpressed mutidrug resistance (MDR) is currently a key factor limiting the effectiveness of breast cancer chemotherapy. Systemic administration based on P-gp-associated mechanism leads to severe toxic side effects. Here, we designed a T7 peptide-modified mixed liposome (T7-MLP@DTX/SchB) that, by active targeting co-delivering chemotherapeutic agents and P-gp inhibitors, harnessed synergistic effects to improve the treatment of MDR breast cancer. This study established drug-resistant cell models and animal models. Subsequently, comprehensive evaluations involving cell uptake, cell apoptosis, cellular toxicity assays, in vivo tumor-targeting capability, and anti-tumor activity assays were conducted to assess the drug resistance reversal effects of T7-MLP@DTX/SchB. Additionally, a systematic assessment of the biosafety profile of T7-MLP@DTX/SchB was executed, including blood profiles, biochemical markers, and histopathological examination. It was found that this co-delivery strategy successfully exerted the synergistic effects, since there was a significant tumor growth inhibitory effect on multidrug-resistant breast cancer. Targeted modification with T7 peptide enhanced the therapeutic efficacy remarkably, while vastly ameliorating the biocompatibility compared to free drugs. The intriguing results supported the promising potential use of T7-MLP@DTX/SchB in overcoming MDR breast cancer treatment.

Activation of lipophagy ameliorates cadmium-induced neural tube defects via reducing low density lipoprotein cholesterol levels in mouse placentas.

Neural tube defects (NTDs) represent a prevalent and severe category of congenital anomalies in humans. Cadmium (Cd) is an environmental teratogen known to cause fetal NTDs. However, its underlying mechanisms remain elusive. This study aims to investigate the therapeutic potential of lipophagy in the treatment of NTDs, providing valuable insights for future strategies targeting lipophagy activation as a means to mitigate NTDs.We successfully modeled NTDs by Cd exposure during pregnancy. RNA sequencing was employed to investigate the transcriptomic alterations and functional enrichment of differentially expressed genes in NTD placental tissues. Subsequently, pharmacological/genetic (Atg5-/- placentas) experiments confirmed that inducing placental lipophagy can alleviate Cd induced-NTDs. We found that Cd exposure caused NTDs. Further analyzed transcriptomic data from the placentas with NTDs which revealed significant downregulation of low-density lipoprotein receptor associated protein 1(Lrp1) gene expression responsible for positive regulation of low-density lipoprotein cholesterol (LDL-C) transport. Correspondingly, there was an increase in maternal serum/placenta/amniotic fluid LDL-C content. Subsequently, we have discovered that Cd exposure activated placental lipophagy. Pharmacological/genetic (Atg5-/- placentas) experiments confirmed that inducing placental lipophagy can alleviate Cd induced-NTDs. Furthermore, our findings demonstrate that activation of placental lipophagy effectively counteracts the Cd-induced elevation in LDL-C levels. Lipophagy serves to mitigate Cd-induced NTDs by reducing LDL-C levels within mouse placentas.

Ultrasensitive Proteomics of Trace Cardiac Tissues with Anchor-Nanoparticles.

Pathological cardiac hypertrophy is a complex process that often leads to heart failure. Label-free proteomics has emerged as an important platform to reveal protein variations and to elucidate the mechanisms of cardiac hypertrophy. Endomyocardial biopsy is a minimally invasive technique for sampling cardiac tissue, but it yields only limited amounts of an ethically permissible specimen. After regular pathological examination, the remaining trace samples pose significant challenges for effective protein extraction and mass spectrometry analysis. Herein, we developed trace cardiac tissue proteomics based on the anchor-nanoparticles (TCPA) method. We identified an average of 6666 protein groups using ∼50 µg of myocardial interventricular septum samples by TCPA. We then applied TCPA to acquire proteomics from patients' cardiac samples both diagnosed as hypertrophic hearts and myocarditis controls and identified significant alterations in pathways such as regulation of actin cytoskeleton, oxidative phosphorylation, and cGMP-PKG signaling pathway. Moreover, we found multiple lipid metabolic pathways to be dysregulated in transthyretin cardiac amyloidosis compared to other types of cardiac hypertrophy. TCPA offers a new technique for studying pathological cardiac hypertrophy and can serve as a platform toolbox for proteomic research in other cardiac diseases.

Mitochondria regulate proliferation in adult cardiac myocytes.

Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfs1 (mitochondrial Rieske Iron-Sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, they underwent hyperplastic remodeling during which cardiomyocyte number doubled without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident. In ischemic hearts with RISP deletion, new cardiomyocytes migrated into the infarcted region, suggesting the potential for therapeutic cardiac regeneration. RNA-seq revealed upregulation of genes associated with cardiac development and proliferation. Metabolomic analysis revealed a decrease in alpha-ketoglutarate (required for TET-mediated demethylation) and an increase in S-adenosylmethionine (required for methyltransferase activity). Analysis revealed an increase in methylated CpGs near gene transcriptional start sites. Genes that were both differentially expressed and differentially methylated were linked to upregulated cardiac developmental pathways. We conclude that decreased mitochondrial function and increased glucose utilization can restore mitotic capacity in adult cardiomyocytes resulting in the generation of new heart cells, potentially through the modification of substrates that regulate epigenetic modification of genes required for proliferation.

Type one autoimmune pancreatitis based on clinical diagnosis: A case report.

BACKGROUND: Autoimmune pancreatitis (AIP) is a rare form of autoimmune-mediated pancreatitis, which is easily misdiagnosed as pancreatic cancer and thus treated surgically. We studied the diagnosis and treatment of a patient with type 1 AIP recently admitted to our hospital, and reviewed the literature to provide a reference for clinical diagnosis of AIP. CASE SUMMARY: The chief complaint was yellowing of the body, eyes and urine for 21 d. The patient's clinical presentation was obstructive jaundice and imaging suggested pancreatic swelling. It was difficult to distinguish between inflammation and tumor. Serum immunoglobulin G4 (IgG4) was markedly elevated. IgG4 is an important serological marker for type 1 AIP. The patient was diagnosed with AIP, IgG4-related cholangitis, acute cholecystitis and hepatic impairment. After applying hormonal therapy, the patient's symptoms improved significantly. At the same time, imaging suggested that pancreatic swelling subsided, and liver function and other biochemical indicators decreased. The treatment was effective. CONCLUSION: In patients with pancreatic swelling, the possibility of AIP should be considered.

Defining the Minimal and Optimal Thresholds for Lymph Node Resection and Examination for Intraductal Papillary Mucinous Neoplasm Derived Pancreatic Cancer: A Multicenter Retrospective Analysis.

OBJECTIVE: To establish minimal and optimal lymphadenectomy thresholds for intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) and evaluate their prognostic value. BACKGROUND: Current guidelines recommend a minimum of 12-15 lymph nodes (LNs) in PDAC. This is largely based on pancreatic intraepithelial neoplasia (PanIN)-derived PDAC, a biologically distinct entity from IPMN-derived PDAC. METHODS: Multicenter retrospective study including consecutive patients undergoing upfront surgery for IPMN-derived PDAC was conducted. The minimum cut-off for lymphadenectomy was defined as the maximum number of LNs where a significant node positivity difference was observed. Maximally selected log-rank statistic was used to derive the optimal lymphadenectomy cut-off (maximize survival). Kaplan-Meier curves and log-rank tests were used to analyze overall survival (OS) and recurrence-free survival (RFS). Multivariable Cox-regression was used to determine hazard ratios (HR) with 95% confidence intervals (95%CI). RESULTS: In 341 patients with resected IPMN-derived PDAC, the minimum number of LNs needed to ensure accurate nodal staging was 10 (P=0.040), whereas ≥20 LNs was the optimal number associated with improved OS (80.3 vs. 37.2 mo, P<0.001). Optimal lymphadenectomy was associated with improved OS [HR:0.57 (95%CI 0.39-0.83)] and RFS [HR:0.70 (95%CI 0.51-0.97)] on multivariable Cox-regression. On sub-analysis the optimal lymphadenectomy cut-offs for pancreatoduodenectomy, distal pancreatectomy, and total pancreatectomy were 20 (P<0.001), 23 (P=0.160), and 25 (P=0.008). CONCLUSION: In IPMN-derived PDAC, lymphadenectomy with at least 10 lymph nodes mitigates under-staging, and at least 20 lymph nodes is associated with the improved survival. Specifically, for pancreatoduodenectomy and total pancreatectomy, 20 and 25 lymph nodes were the optimal cut-offs.

Energy-efficient UAV communication: A NOMA scheme with resource allocation and trajectory optimization.

This work investigates a downlink nonorthogonal multiple access (NOMA) scheme with unmanned aerial vehicle (UAV) aided wireless communication, where a single UAV was regarded as an air base station (ABS) to communicate with multiple ground users. Considering the constraints of velocity and maneuverability, a UAV energy efficiency (EE) model was proposed via collaborative design resource allocation and trajectory optimization. Based on this, an EE maximization problem was formulated to jointly optimize the transmit power of ground users and the trajectory of the UAV. To obtain the optimal solutions, this nonconvex problem was transformed into an equivalent convex optimization problem on the basis of three user clustering algorithms. After several alternating iterations, our proposed algorithms converged quickly. The simulation results show an enhancement in EE with NOMA because our proposed algorithm is nearly 99.6% superior to other OMA schemes.

Regulation of Erythroid Differentiation via the HIF1α-NFIL3-PIM1 Signaling Axis Under Hypoxia.

Aims: Erythropoiesis is controlled by several factors, including oxygen level under different circumstances. However, the role of hypoxia in erythroid differentiation and the underlying mechanisms are poorly understood. We studied the effect and mechanism of hypoxia on erythroid differentiation of K562 cells and observed the effect of hypoxia on early erythropoiesis of zebrafish. Results: Compared with normal oxygen culture, both hemin-induced erythroid differentiation of K562 cells and the early erythropoiesis of zebrafish were inhibited under hypoxic treatment conditions. Hypoxia-inducible factor 1 alpha (HIF1α) plays a major role in the response to hypoxia. Here, we obtained a stable HIF1α knockout K562 cell line using the CRISPR-Cas9 technology and further demonstrated that HIF1α knockout promoted hemin-induced erythroid differentiation of K562 cells under hypoxia. We demonstrated an HIF1-mediated induction of the nuclear factor interleukin-3 (NFIL3) regulated in K562 cells under hypoxia. Interestingly, a gradual decrease in NFIL3 expression was detected during erythroid differentiation of erythropoietin-induced CD34+ hematopoietic stem/progenitor cells (HSPCs) and hemin-induced K562 cells. Notably, erythroid differentiation was inhibited by enforced expression of NFIL3 under normoxia and was promoted by the knockdown of NFIL3 under hypoxia in hemin-treated K562 cells. In addition, a target of NFIL3, pim-1 proto-oncogene, serine/threonine kinase (PIM1), was obtained by RNA microarray after NFIL3 knockdown. PIM1 can rescue the inhibitory effect of NFIL3 on hemin-induced erythroid differentiation of K562 cells. Innovation and Conclusion: Our findings demonstrate that the HIF1α-NFIL3-PIM1 signaling axis plays an important role in erythroid differentiation under hypoxia. These results will provide useful clues for preventing the damage of acute hypoxia to erythropoiesis.

Development of dynamic nomogram for predicting cancer-specific survival in hepatoid adenocarcinoma: A comprehensive SEER-based population analysis.

Hepatoid adenocarcinoma (HAC) is a poorly differentiated extrahepatic tumor that can produce alpha-fetoprotein (AFP). The literature does not provide a comprehensive understanding of the prognostic factors for HAC. Therefore, we present a novel nomogram to predict the cancer-specific survival (CSS) of patients with HAC. We analyzed 265 cases of HAC from the Surveillance, Epidemiology, and End Results (SEER) database spanning from 2004 to 2015. Using a Cox proportional hazard regression model, we identified several risk factors and incorporated them into our predictive nomogram. The nomogram's predictive ability was assessed by utilizing the concordance index (C-index), calibration curve, and receiver operating characteristic (ROC). Results from a multivariate Cox regression showed that CSS was independently correlated with liver metastasis, surgery, and chemotherapy. Our nomogram had a C-index of 0.71 (95% CI 0.71-0.96). Furthermore, calibration curves demonstrated concordance between the predicted survival probability from the nomogram and the observed survival probability. The areas under the curve (AUC) for 6-month, 1-, and 3-year survival were 0.80, 0.82, and 0.88, respectively. Our study successfully formulated a prognostic nomogram that offers promising predictions for the 6-month, 1-, and 3-year CSS of patients with HAC. This nomogram holds potential for practical use in guiding treatment decisions and designing clinical trials.

Knowledge, attitudes and practice towards postoperative nursing of patients with digit replantation and skin flap transplantation among new nurses in Beijing: a cross-sectional survey.

OBJECTIVE: To explore the knowledge, attitudes and practice (KAP) towards the postoperative nursing of patients with digit replantation and skin flap transplantation among new nurses. DESIGN: Cross-sectional survey. SETTING: Two tertiary medical centres in Beijing, China. PARTICIPANTS: New nurses with working experience within 2 years. PRIMARY AND SECONDARY OUTCOME MEASURES: The demographic characteristics of the nurses and their KAP towards the postoperative nursing of patients with digit replantation and skin flap transplantation were collected using a self-administered questionnaire. The primary outcome was the KAP scores towards the postoperative nursing of patients with digit replantation and skin flap transplantation. The secondary outcomes were the factors associated with the KAP scores and how the KAP dimensions interacted among them. RESULTS: A total of 206 valid questionnaires were collected. The mean KAP scores were 7.72±3.28 (total score 13; 59.3%), 37.95±6.05 (total score 50; 75.9%) and 38.23±6.12 (total score 45; 84.9%), indicating poor knowledge, moderately favourable attitudes and active practice. The structural equation model analysis showed that knowledge directly influences attitudes (ß=0.82, 95%CI 0.60 to 1.05, p<0.001) and that attitudes directly influence practices (ß=0.72, 95%CI 0.62 to 0.83, p<0.001). Knowledge had no direct influence on practices (ß=0.10, 95%CI -0.09 to 0.29, p=0.313), but the indirect influence was significant (ß=0.60, 95%CI 0.41 to 0.78, p<0.001). CONCLUSION: The lack of sufficient knowledge towards the postoperative nursing of patients with digit replantation and skin flap transplantation among nurses with <2 years of experience and the correlation among the KAP dimensions suggested the importance of proper training.

Mitochondrial dysfunction of peripheral blood mononuclear cells is associated with lung carcinogenesis.

The composition, quantity, and function of peripheral blood mononuclear cells (PBMCs) are closely correlated with tumorigenesis. However, the mechanisms of PBMCs in lung cancer are not clear. Mitochondria are energy factories of cells, and almost all cellular functions rely on their energy metabolism level. The present study aimed to test whether the mitochondrial function of PBMCs directly determines their tumor immune monitoring function. We recruited 211 subjects, including 105 healthy controls and 106 patients with recently diagnosed with lung cancer. The model of lung carcinogenesis induced by BaP was used in animal experiment, and the Bap carcinogenic metabolite, Benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide (BPDE), was used in cell experiment. We found that mitochondrial function of PBMCs decreased significantly in patients with new lung cancer, regardless of age. In vivo, BaP caused PBMC mitochondrial dysfunction in mice before the appearance of visible malignant tissue. Moreover, mitochondrial function decreased significantly in mice with lung cancers induced by BaP compared to those without lung cancer after BaP intervention. In vitro, BPDE also induced mitochondrial dysfunction and reduced the aggressiveness of PBMCs toward cancer cells. Furthermore, the changes in mitochondrial energy metabolism gene expression caused by BPDE are involved in this process. Thus, the mitochondrial function of PBMCs is a potential prognostic biomarker or therapeutic target to improve clinical outcomes in patients with lung cancer.

Predicting preoperative muscle invasion status for bladder cancer using computed tomography-based radiomics nomogram.

OBJECTIVES: The aim of the study is to assess the efficacy of the established computed tomography (CT)-based radiomics nomogram combined with radiomics and clinical features for predicting muscle invasion status in bladder cancer (BCa). METHODS: A retrospective analysis was conducted using data from patients who underwent CT urography at our institution between May 2018 and April 2023 with urothelial carcinoma of the bladder confirmed by postoperative histology. There were 196 patients enrolled in all, and each was randomized at random to either the training cohort (n = 137) or the test cohort (n = 59). Eight hundred fifty-one radiomics features in all were retrieved. For feature selection, the significance test and least absolute shrinkage and selection operator (LASSO) approaches were utilized. Subsequently, the radiomics score (Radscore) was obtained by applying linear weighting based on the selected features. The clinical and radiomics model, as well as radiomics-clinical nomogram were all established using logistic regression. Three models were evaluated using analysis of the receiver operating characteristic curve. An area under the curve (AUC) and 95% confidence intervals (CI) as well as specificity, sensitivity, accuracy, negative predictive value, and positive predictive value were included in the analysis. Radiomics-clinical nomogram's performance was assessed based on discrimination, calibration, and clinical utility. RESULTS: After obtaining 851 radiomics features, 12 features were ultimately selected. Histopathological grading and tortuous blood vessels were included in the clinical model. The Radscore and clinical histopathology grading were among the final predictors in the unique nomogram. The three models had an AUC of 0.811 (95% CI, 0.742-0.880), 0.845 (95% CI, 0.781-0.908), and 0.896 (95% CI, 0.846-0.947) in the training cohort and in the test cohort they were 0.808 (95% CI, 0.703-0.913), 0.847 (95% CI, 0.739-0.954), and 0.887 (95% CI, 0.803-0.971). According to the DeLong test, the radiomics-clinical nomogram's AUC in the training cohort substantially differed from that of the clinical model (AUC: 0.896 versus 0.845, p = 0.015) and the radiomics model (AUC: 0.896 versus 0.811, p = 0.002). The Delong test in the test cohort revealed no significant difference among the three models. CONCLUSIONS: CT-based radiomics-clinical nomogram can be a useful tool for quantitatively predicting the status of muscle invasion in BCa.

Anti-Inflammatory and α-Glucosidase Inhibitory Triterpenoid with Diverse Carbon Skeletons from the Fruits of Rosa roxburghii.

The fruits of Rosa roxburghii Tratt. are edible nutritional food with high medicinal value and have been traditionally used as Chinese folk medicine for a long time. In this study, 26 triterpenoids including four new pentacyclic triterpenoids, roxbuterpenes A-D (1, 4, 5, and 24), along with 22 known analogues (2, 3, 6-23, 25, and 26), were isolated from the fruits of R. roxburghii. Their chemical structures were determined on the basis of extensive spectroscopic analyses (including IR, HRESIMS and NMR spectroscopy). The absolute configuration of roxbuterpene A (1) was determined by an X-ray crystallographic analysis. This is the first report of the crystal structure of 5/6/6/6/6-fused system pentacyclic triterpenoid. Notably, roxbuterpenes A and B (1 and 4) possessed the A-ring contracted triterpenoid and nortriterpenoid skeletons with a rare 5/6/6/6/6-fused system, respectively. Compounds 1-7, 11, 13-15, 18-20, 24, and 25 exhibited moderate or potent inhibitory activities against α-glucosidase. Compounds 2, 4, 6, 11, and 14 showed strong activities against α-glucosidase with IC50 values of 8.4 ± 1.6, 7.3 ± 2.2, 13.6 ± 1.4, 0.9 ± 0.4, and 12.5 ± 2.4 µM, respectively (positive control acarbose, 10.1 ± 0.8 µM). Compounds 13, 14, and 16 moderately inhibited the release of NO (nitric oxide) with IC50 values ranging from 25.1 ± 2.0 to 51.4 ± 3.1 µM. Furthermore, the expressions of TNF-α (tumor necrosis factor-α) and IL-6 (interleukin-6) were detected by ELISA (enzyme-linked immunosorbent assay), and compounds 13, 14, and 16 exhibited moderate inhibitory effects on TNF-α and IL-6 release in a dose-dependent manner ranging from 12.5 to 50 µM.

Efficiency of endoscopic artificial intelligence in the diagnosis of early esophageal cancer.

BACKGROUND: The accuracy of artificial intelligence (AI) and experts in diagnosing early esophageal cancer (EC) and its infiltration depth was summarized and analyzed, thus identifying the advantages of AI over traditional manual diagnosis, with a view to more accurately assisting doctors in evaluating the patients' conditions and improving their cure and survival rates. METHODS: The PubMed, EMBASE, Cochrane, Google, and CNKI databases were searched for relevant literature related to AI diagnosis of early EC and its invasion depth published before August 2023. Summary analysis of pooled sensitivity, specificity, summary receiver operating characteristics (SROC) and area under the curve (AUC) of AI in diagnosing early EC were performed, and Review Manager and Stata were adopted for data analysis. RESULTS: A total of 19 studies were enrolled with a low to moderate total risk of bias. The pooled sensitivity of AI for diagnosing early EC was markedly higher than that of novices and comparable to that of endoscopists. Moreover, AI predicted early EC with markedly higher AUCs than novices and experts (0.93 vs. 0.74 vs. 0.89). In addition, pooled sensitivity and specificity in the diagnosis of invasion depth in early EC were higher than that of experts, with AUCs of 0.97 and 0.92, respectively. CONCLUSION: AI-assistance can diagnose early EC and its infiltration depth more accurately, which can help in its early intervention and the customization of personalized treatment plans. Therefore, AI systems have great potential in the early diagnosis of EC.

Activation of CTU2 expression by LXR promotes the development of hepatocellular carcinoma.

Cytosolic thiouridylase 2 (CTU2) is an enzyme modifying transfer RNAs post-transcriptionally, which has been implicated in breast cancer and melanoma development. And we found CTU2 participated in hepatocellular carcinoma (HCC) progression here. HepG2 cells as well as xenograft nude mice model were employed to investigate the role of CTU2 in HCC development in vitro and in vivo respectively. Further, we defined CTU2 as a Liver X receptor (LXR) targeted gene, with a typical LXR element in the CTU2 promoter. CTU2 expression was activated by LXR agonist and depressed by LXR knockout. Interestingly, we also found CTU2 took part in lipogenesis by directly enhancing the synthesis of lipogenic proteins, which provided a novel mechanism for LXR regulating lipid synthesis. Meanwhile, lipogenesis was active during cell proliferation, particularly in tumor cells. Reduction of CTU2 expression was related to reduced tumor burden and synergized anti-tumor effect of LXR ligands by inducing tumor cell apoptosis and inhibiting cell proliferation. Taken together, our study identified CTU2 as an LXR target gene. Inhibition of CTU2 expression could enhance the anti-tumor effect of LXR ligand in HCC, identifying CTU2 as a promising target for HCC treatment and providing a novel strategy for the application of LXR agonists in anti-tumor effect.

Virus-Induced Acute Respiratory Distress Syndrome Causes Cardiomyopathy Through Eliciting Inflammatory Responses in the Heart.

BACKGROUND: Viral infections can cause acute respiratory distress syndrome (ARDS), systemic inflammation, and secondary cardiovascular complications. Lung macrophage subsets change during ARDS, but the role of heart macrophages in cardiac injury during viral ARDS remains unknown. Here we investigate how immune signals typical for viral ARDS affect cardiac macrophage subsets, cardiovascular health, and systemic inflammation. METHODS: We assessed cardiac macrophage subsets using immunofluorescence histology of autopsy specimens from 21 patients with COVID-19 with SARS-CoV-2-associated ARDS and 33 patients who died from other causes. In mice, we compared cardiac immune cell dynamics after SARS-CoV-2 infection with ARDS induced by intratracheal instillation of Toll-like receptor ligands and an ACE2 (angiotensin-converting enzyme 2) inhibitor. RESULTS: In humans, SARS-CoV-2 increased total cardiac macrophage counts and led to a higher proportion of CCR2+ (C-C chemokine receptor type 2 positive) macrophages. In mice, SARS-CoV-2 and virus-free lung injury triggered profound remodeling of cardiac resident macrophages, recapitulating the clinical expansion of CCR2+ macrophages. Treating mice exposed to virus-like ARDS with a tumor necrosis factor α-neutralizing antibody reduced cardiac monocytes and inflammatory MHCIIlo CCR2+ macrophages while also preserving cardiac function. Virus-like ARDS elevated mortality in mice with pre-existing heart failure. CONCLUSIONS: Our data suggest that viral ARDS promotes cardiac inflammation by expanding the CCR2+ macrophage subset, and the associated cardiac phenotypes in mice can be elicited by activating the host immune system even without viral presence in the heart.