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1.
Ren Fail ; 46(1): 2349113, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38721900

ABSTRACT

BACKGROUND: Type 3 cardiorenal syndrome (CRS type 3) triggers acute cardiac injury from acute kidney injury (AKI), raising mortality in AKI patients. We aimed to identify risk factors for CRS type 3 and develop a predictive nomogram. METHODS: In this retrospective study, 805 AKI patients admitted at the Department of Nephrology, Second Hospital of Shanxi Medical University from 1 January 2017, to 31 December 2021, were categorized into a study cohort (406 patients from 2017.1.1-2021.6.30, with 63 CRS type 3 cases) and a validation cohort (126 patients from 1 July 2021 to 31 Dec 2021, with 22 CRS type 3 cases). Risk factors for CRS type 3, identified by logistic regression, informed the construction of a predictive nomogram. Its performance and accuracy were evaluated by the area under the curve (AUC), calibration curve and decision curve analysis, with further validation through a validation cohort. RESULTS: The nomogram included 6 risk factors: age (OR = 1.03; 95%CI = 1.009-1.052; p = 0.006), cardiovascular disease (CVD) history (OR = 2.802; 95%CI = 1.193-6.582; p = 0.018), mean artery pressure (MAP) (OR = 1.033; 95%CI = 1.012-1.054; p = 0.002), hemoglobin (OR = 0.973; 95%CI = 0.96--0.987; p < 0.001), homocysteine (OR = 1.05; 95%CI = 1.03-1.069; p < 0.001), AKI stage [(stage 1: reference), (stage 2: OR = 5.427; 95%CI = 1.781-16.534; p = 0.003), (stage 3: OR = 5.554; 95%CI = 2.234-13.805; p < 0.001)]. The nomogram exhibited excellent predictive performance with an AUC of 0.907 in the study cohort and 0.892 in the validation cohort. Calibration and decision curve analyses upheld its accuracy and clinical utility. CONCLUSIONS: We developed a nomogram predicting CRS type 3 in AKI patients, incorporating 6 risk factors: age, CVD history, MAP, hemoglobin, homocysteine, and AKI stage, enhancing early risk identification and patient management.


Subject(s)
Acute Kidney Injury , Cardio-Renal Syndrome , Nomograms , Humans , Female , Male , Acute Kidney Injury/diagnosis , Acute Kidney Injury/etiology , Acute Kidney Injury/blood , Retrospective Studies , Middle Aged , Risk Factors , Cardio-Renal Syndrome/diagnosis , Cardio-Renal Syndrome/complications , Cardio-Renal Syndrome/etiology , Aged , Risk Assessment/methods , China/epidemiology , Logistic Models , Adult
2.
Nat Commun ; 15(1): 4140, 2024 May 16.
Article in English | MEDLINE | ID: mdl-38755138

ABSTRACT

The goal of this study is to examine the association between in utero drought exposure and epigenetic age acceleration (EAA) in a global climate change hot spot. Calculations of EAA in adults using DNA methylation have been found to accurately predict chronic disease and longevity. However, fewer studies have examined EAA in children, and drought exposure in utero has not been investigated. Additionally, studies of EAA in low-income countries with diverse populations are rare. We assess EAA using epigenetic clocks and two DNAm-based pace-of-aging measurements from whole saliva samples in 104 drought-exposed children and 109 same-sex sibling controls in northern Kenya. We find a positive association between in utero drought exposure and EAA in two epigenetic clocks (Hannum's and GrimAge) and a negative association in the DNAm based telomere length (DNAmTL) clock. The combined impact of drought's multiple deleterious stressors may reduce overall life expectancy through accelerated epigenetic aging.


Subject(s)
Climate Change , DNA Methylation , Droughts , Epigenesis, Genetic , Prenatal Exposure Delayed Effects , Humans , Female , Kenya , Male , Child , Prenatal Exposure Delayed Effects/genetics , Prenatal Exposure Delayed Effects/metabolism , Pregnancy , Aging/genetics , Saliva/metabolism , Child, Preschool
3.
Kidney Blood Press Res ; 49(1): 345-354, 2024.
Article in English | MEDLINE | ID: mdl-38615671

ABSTRACT

INTRODUCTION: This study evaluated the phenotypic and pathology characteristics of patients undergoing kidney biopsy at a single center, while also determining the frequency and factors associated with clinical outcomes. METHODS: The incidence and distribution of biopsy-proven kidney diseases in 2000-2019 were surveyed. Consecutive individuals diagnosed with membranous nephropathy (MN), immunoglobulin A nephropathy (IgAN), and minimal change disease (MCD) between August 2015 and December 2019 were enrolled in the prospective 2-year follow-up study. Outcomes included remission of proteinuria and kidney disease progression events. Multivariable-adjusted Cox proportional hazards model was applied. RESULTS: 4,550 kidney biopsies were performed in 2000-2019, showing a noticeable increase in the proportion of MN. 426 patients were enrolled in the follow-up cohort. 346 (81.2%) achieved remission of proteinuria, 39 (9.2%) suffered kidney disease progression and 51.3% of them were diagnosed with IgAN. Kidney pathological diagnosis (MN vs. MCD: hazard ratio [HR], 0.42; 95% confidence interval [95% CI], 0.31-0.57; IgAN vs. MCD: 0.58; 0.39-0.85), levels of 24-h urine protein at biopsy (1.04; 1.00-1.08) and presence of nodular mesangial sclerosis (0.70; 0.49-0.99) were significantly correlated with remission of proteinuria after adjusting for baseline variables. 24-h urine protein levels at biopsy (1.14; 1.04-1.25) and the presence of crescents (2.30; 1.06-4.95) were the independent risk factors for kidney disease progression events after adjusting for baseline variables. CONCLUSION: The increasing frequency of MN has been affirmed over the past 2 decades. The therapeutic status, clinical outcomes, and factors influencing these outcomes were presented in this single-center study for the three primary glomerular diseases.


Subject(s)
Disease Progression , Glomerulonephritis, IGA , Glomerulonephritis, Membranous , Kidney , Nephrosis, Lipoid , Humans , Glomerulonephritis, Membranous/pathology , Glomerulonephritis, Membranous/diagnosis , Glomerulonephritis, IGA/pathology , Glomerulonephritis, IGA/diagnosis , Nephrosis, Lipoid/pathology , Male , Female , Middle Aged , Adult , Biopsy , Kidney/pathology , Prospective Studies , Follow-Up Studies , Proteinuria/etiology
4.
Technol Health Care ; 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38393930

ABSTRACT

BACKGROUND: Diarrhea is a prevalent complication after renal transplantation. OBJECTIVE: To examine the risk factors for diarrhea after renal transplantation, evaluate their combined predictive values, and analyze the prognosis. METHODS: Clinical data of patients who underwent allogeneic renal transplantation in the Second People's Hospital of Shanxi Province from January 2019 to March 2020 were retrospectively analyzed, cases were screened and grouped, independent risk factors for diarrhea after renal transplantation were analyzed by univariate analysis and multivariate analysis, and their predictive value was evaluated by receiver operating characteristic (ROC) curve. The survival time of recipient grafts in diarrhea and non-diarrhea groups were evaluated by Kaplan-Meier and log-rank test. RESULTS: We included 166 recipients in the study and the incidence of diarrhea was 25.9%; univariate and logistic regression multivariate analyses revealed that independent risk factors for diarrhea in recipients were that the type of renal transplant donor was DCD (donation after circulatory death), immunity induction was onducted with basiliximab + antithymocyte globulin (ATG), and ATG alone, the type of mycophenolic acid (MPA) used was mycophenolate mofetil capsules, and delayed graft function (DGF) occurred after transplantation. The ROC curve indicated that the combination of the four factors had good accuracy in predicting the occurrence of diarrhea in recipients. The graft survival rate two years after the operation in the diarrhea group was significantly lower than that in the non-diarrhea group. CONCLUSION: Diarrhea affected the two-year survival rate of the graft. The type of donor, immunity induction scheme, and the type of MPA and DGF were independent risk factors for diarrhea in recipients, and the combination of the four factors had good prognostic prediction value.

5.
Future Oncol ; 20(4): 215-228, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38390682

ABSTRACT

Recently, there has been an increased focus on cancer stem cells (CSCs) due to their resilience, making them difficult to eradicate. This resilience often leads to tumor recurrence and metastasis. CSCs adeptly manipulate their surroundings to create an environment conducive to their survival. In this environment, myeloid-derived suppressor cells (MDSCs) play a crucial role in promoting epithelial-mesenchymal transition and bolstering CSCs' stemness. In response, CSCs attract MDSCs, enhancing their infiltration, expansion and immunosuppressive capabilities. This interaction between CSCs and MDSCs increases the difficulty of antitumor therapy. In this paper, we discuss the interplay between CSCs and MDSCs based on current research and highlight recent therapeutic strategies targeting either CSCs or MDSCs that show promise in achieving effective antitumor outcomes.


Cancer stem cells (CSCs) are a kind of tumor cell. These cells are hard to kill but contribute to tumor progression and metastasis. Myeloid-derived suppressor cells (MDSCs) exist in the tumor tissue and are unfriendly to the antitumor immune response. The interaction between CSCs and MDSCs has a protective effect on tumor progression. Therapeutic strategies targeting CSCs or MDSCs present potential to weaken the complex interaction between the two cell types. This review summarizes the current knowledge of CSCs­MDSCs interaction and offers fresh perspectives on the future development of antitumor therapies targeting CSCs or MDSCs.


Subject(s)
Myeloid-Derived Suppressor Cells , Humans , Neoplasm Recurrence, Local/pathology , Neoplastic Stem Cells/pathology , Tumor Microenvironment
6.
J Vis Exp ; (204)2024 Feb 09.
Article in English | MEDLINE | ID: mdl-38407282

ABSTRACT

We report on the detailed steps of a method to estimate the biomass of invasive plants based on UAV remote sensing and computer vision. To collect samples from the study area, we prepared a sample square assembly to randomize the sampling points. An unmanned aerial camera system was constructed using a drone and camera to acquire continuous RGB images of the study area through automated navigation. After completing the shooting, the aboveground biomass in the sample frame was collected, and all correspondences were labeled and packaged. The sample data was processed, and the aerial images were segmented into small images of 280 x 280 pixels to create an image dataset. A deep convolutional neural network was used to map the distribution of Mikania micrantha in the study area, and its vegetation index was obtained. The organisms collected were dried, and the dry weight was recorded as the ground truth biomass. The invasive plant biomass regression model was constructed using the K-nearest neighbor regression (KNNR) by extracting the vegetation index from the sample images as an independent variable and integrating it with the ground truth biomass as a dependent variable. The results showed that it was possible to predict the biomass of invasive plants accurately. An accurate spatial distribution map of invasive plant biomass was generated by image traversal, allowing precise identification of high-risk areas affected by invasive plants. In summary, this study demonstrates the potential of combining unmanned aerial vehicle remote sensing with machine learning techniques to estimate invasive plant biomass. It contributes significantly to the research of new technologies and methods for real-time monitoring of invasive plants and provides technical support for intelligent monitoring and hazard assessment at the regional scale.


Subject(s)
Computers , Intelligence , Biomass , Cluster Analysis , Machine Learning
7.
Am J Pathol ; 194(1): 101-120, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37827215

ABSTRACT

The Wnt/ß-catenin pathway represents a promising therapeutic target for mitigating kidney fibrosis. Corin possesses the homologous ligand binding site [Frizzled-cysteine-rich domain (Fz-CRD)] similar to Frizzled proteins, which act as receptors for Wnt. The Fz-CRD has been found in eight different proteins, all of which, except for corin, are known to bind Wnt and regulate its signal transmission. We hypothesized that corin may inhibit the Wnt/ß-catenin signaling pathway and thereby reduce fibrogenesis. Reduced expression of corin along with the increased activity of Wnt/ß-catenin signaling was found in unilateral ureteral obstruction (UUO) and ureteral ischemia/reperfusion injury (UIRI) models. In vitro, corin bound to the Wnt1 through its Fz-CRDs and inhibit the Wnt1 function responsible for activating ß-catenin. Transforming growth factor-ß1 inhibited corin expression, accompanied by activation of ß-catenin; conversely, overexpression of corin attenuated the fibrotic effects of transforming growth factor-ß1. In vivo, adenovirus-mediated overexpression of corin attenuated the progression of fibrosis, which was potentially associated with the inhibition of Wnt/ß-catenin signaling and the down-regulation of its target genes after UUO and UIRI. These results suggest that corin acts as an antagonist that protects the kidney from pathogenic Wnt/ß-catenin signaling and from fibrosis following UUO and UIRI.


Subject(s)
Kidney Diseases , Wnt Signaling Pathway , Mice , Animals , Wnt Signaling Pathway/physiology , beta Catenin/metabolism , Transforming Growth Factor beta1/metabolism , Kidney Diseases/genetics , Kidney Diseases/prevention & control , Kidney Diseases/metabolism , Kidney/pathology , Fibrosis , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism
8.
Medicine (Baltimore) ; 102(47): e36302, 2023 Nov 24.
Article in English | MEDLINE | ID: mdl-38013282

ABSTRACT

Bladder cancer (BC) is a malignant tumor that occurs in bladder mucosa. However, relationship between myosin light chain kinase (MYLK) and CALD1 and BC remains unclear. The BC datasets GSE65635 and GSE100926 were downloaded from gene expression omnibus by GPL14951 and GPL14550. Multiple datasets were merged and batched. Differentially expressed genes (DEGs) were screened and weighted gene co-expression network analysis was performed. gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome analysis, gene set enrichment analysis, immune infiltration analysis, survival analysis and Comparative Toxicogenomics Database were performed. TargetScan screened miRNAs that regulated central DEGs. 1026 DEGs were identified. According to GO analysis, DEGs were mainly enriched in cancer pathway, cGMP-PKG signaling pathway, Apelin signaling pathway and proteoglycans in cancer. The enrichment items are similar to GO and Kyoto Encyclopedia of Gene and Genome enrichment projects for DEGs, which were mainly enriched in cancer pathways and leukocyte trans-endothelial cell migration. Among enrichment projects of metascape, GO has regulation of the enzyme-linked receptor protein signaling pathway and silk-based process, as well as an enrichment network stained by enrichment terms and P values. Nine core genes (ACTA2, MYLK, MYH11, MYL9, ACTG2, TPM1, TPM2, TAGLN and CALD1) were obtained, which were highly expressed in tumor tissue samples and lowly expressed in normal tissue samples. Nine genes were associated with necrosis, inflammation, tumor, edema, and ureteral obstruction. MYLK and CALD1 are highly expressed in the BC. The higher expression of MYLK and CALD1, the worse prognosis.


Subject(s)
Myosin-Light-Chain Kinase , Urinary Bladder Neoplasms , Humans , Myosin-Light-Chain Kinase/genetics , Myosin-Light-Chain Kinase/metabolism , Computational Biology , Calmodulin-Binding Proteins/metabolism , Gene Expression Profiling , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , Calcium-Binding Proteins/metabolism
9.
J Insect Sci ; 23(5)2023 Sep 01.
Article in English | MEDLINE | ID: mdl-37804502

ABSTRACT

The transcriptomes of Agasicles hygrophila eggs and first instar larvae were analyzed to explore the olfactory mechanism of larval behavior. The analysis resulted in 135,359 unigenes and the identification of 38 odorant-binding proteins (OBPs), including 23 Minus-C OBPs, 8 Plus-C OBPs, and 7 Classic OBPs. Further analysis of differentially expressed genes (DEGs) revealed 10 DEG OBPs, with 5 (AhygOBP5, AhygOBP9, AhygOBP12, AhygOBP15 and AhygOBP36) up-regulated in first instar larvae. Verification of expression patterns of these 5 AhygOBPs using qPCR showed that AhygOBP9 and AhygOBP36 were mainly expressed in the adult stage with gradually increasing expression in the larval stage. AhygOBP5, AhygOBP12, and AhygOBP15 were not expressed in eggs and pupae, and their expression in larvae and adults showed no clear pattern. These 5 AhygOBPs may play an olfactory role in larval behavior, providing a basis for further investigation of their specific functions and clarifying the olfactory mechanism of A. hygrophila.


Subject(s)
Acanthaceae , Coleoptera , Receptors, Odorant , Animals , Coleoptera/genetics , Coleoptera/metabolism , Odorants , Ovum/metabolism , Gene Expression Profiling , Larva/genetics , Larva/metabolism , Transcriptome , Receptors, Odorant/genetics , Receptors, Odorant/metabolism , Acanthaceae/genetics , Acanthaceae/metabolism , Insect Proteins/genetics , Insect Proteins/metabolism , Phylogeny
10.
Front Oncol ; 13: 1189500, 2023.
Article in English | MEDLINE | ID: mdl-37675225

ABSTRACT

Transthoracic cardia resection is a technically well-established surgical procedure. However, acute cardiac tamponade in the early postoperative period is extremely rare. The occurrence is life-threatening to the patient. It also poses a great clinical challenge for perioperative management. To date, few cases of pericardial tamponade have been reported in gastric cancer resection performed after neoadjuvant chemotherapy combined with immunotherapy. We present the case of a 62-year-old woman who received neoadjuvant chemotherapy combined with immunotherapy before surgery, followed by transthoracic surgery. A life-threatening complication, pericardial tamponade, occurred in the early postoperative period. The successful outcome was achieved in through multidisciplinary collaboration.

11.
Front Public Health ; 11: 1264642, 2023.
Article in English | MEDLINE | ID: mdl-37744484

ABSTRACT

Introduction: Surgeons may experience physical and mental health problems because of their jobs, which may lead to chronic muscle damage, burnout, or even withdrawal. However, these are often ignored in camera-holder assistants during laparoscopic surgery. We aimed to analyze the differences between operating surgeons and camera-holder assistants. Methods: From January 1, 2022, to December 31, 2022, a cross-sectional survey was conducted to evaluate the muscle pain, fatigue, verbal scolding, and task load for operating surgeons and camera-holder assistants. The Nordic Musculoskeletal Questionnaire, the Space Administration Task Load Index, and the Surgical Task Load Index (SURG-TLX) were combined in the questionnaire. Results: 2,184 operations were performed by a total of 94 operating surgeons and 220 camera assistants. 81% of operating surgeons and 78% of camera-holder assistants reported muscle pain/discomfort during the procedure. The most affected anatomic region was the shoulders for operating surgeons, and the lower back for camera-holder assistants. Intraoperative fatigue was reported by 41.7% of operating surgeons and 51.7% of camera-holder assistants. 55.2% of camera-holder assistants reported verbal scolding from the operating surgeons, primarily attributed to lapses in laparoscope movement coordination. The SURG-TLX results showed that the distributions of mental, physical, and situational stress for operating surgeons and camera-holder assistants were comparable. Conclusion: Like operating surgeons, camera-holder assistants also face similar physical and mental health impairments while performing laparoscopic surgery. Improvements to the working conditions of the camera-holder assistant should not be overlooked.

12.
J Clin Invest ; 133(20)2023 10 16.
Article in English | MEDLINE | ID: mdl-37651203

ABSTRACT

Lung cancer progression relies on angiogenesis, which is a response to hypoxia typically coordinated by hypoxia-inducible transcription factors (HIFs), but growing evidence indicates that transcriptional programs beyond HIFs control tumor angiogenesis. Here, we show that the redox-sensitive transcription factor BTB and CNC homology 1 (BACH1) controls the transcription of a broad range of angiogenesis genes. BACH1 is stabilized by lowering ROS levels; consequently, angiogenesis gene expression in lung cancer cells, tumor organoids, and xenograft tumors increased substantially following administration of vitamins C and E and N-acetylcysteine in a BACH1-dependent fashion under normoxia. Moreover, angiogenesis gene expression increased in endogenous BACH1-overexpressing cells and decreased in BACH1-knockout cells in the absence of antioxidants. BACH1 levels also increased upon hypoxia and following administration of prolyl hydroxylase inhibitors in both HIF1A-knockout and WT cells. BACH1 was found to be a transcriptional target of HIF1α, but BACH1's ability to stimulate angiogenesis gene expression was HIF1α independent. Antioxidants increased tumor vascularity in vivo in a BACH1-dependent fashion, and overexpressing BACH1 rendered tumors sensitive to antiangiogenesis therapy. BACH1 expression in tumor sections from patients with lung cancer correlated with angiogenesis gene and protein expression. We conclude that BACH1 is an oxygen- and redox-sensitive angiogenesis transcription factor.


Subject(s)
Antioxidants , Basic-Leucine Zipper Transcription Factors , Lung Neoplasms , Humans , Antioxidants/pharmacology , Basic-Leucine Zipper Transcription Factors/genetics , Basic-Leucine Zipper Transcription Factors/metabolism , Hypoxia , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Animals , Mice
13.
Int J Mol Sci ; 24(15)2023 Jul 29.
Article in English | MEDLINE | ID: mdl-37569567

ABSTRACT

As one of the 100 most-threatening invasive alien species, the giant African snail (Achatina immaculata) has successfully invaded and established itself in most areas of southern China. Protection against recurrent pathogen infections is vital to biological invasion. Enhanced immune protection has been previously found in other invertebrates, but not in the unique immune system of the giant African snail. In the present study, the survival rate of the giant African snail was recorded following a second infection with lethal doses of Escherichia coli after a previous first injection using lipopolysaccharide (LPS), and the mechanism of immune enhancement was investigated by examining the cellular and transcriptomic response of the giant African snail after two successive stimuli using LPS. Snails injected first with LPS, sterilized physiologic (0.9%) saline (SPS), phosphate-buffered saline (PBS) or untreated (Blank) were rechallenged at 7d with E. coli (Ec), and were named as LPS + Ec, SPS + Ec, PBS + Ec, Ec, and Blank. The log-rank test shows the survival rate of the LPS + Ec group as significantly higher than that of other control groups after the second injection (p < 0.05). By performing cell counting and BrdU labeling on newly generated circulating hemocytes, we found that the total hemocyte count (THC) and the ratio of BrdU-positive cells to total cells increased significantly after primary stimulation with LPS and that they further increased after the second challenge. Then, caspase-3 of apoptosis protease and two antioxidant enzyme activities (CAT and SOD) increased significantly after infection, and were significantly higher in the second response than they had been in the first round. Moreover, transcriptome analysis results showed that 84 differentially expressed genes (DEGs) were expressed at higher levels in both the resting and activating states after the second immune response compared to the levels observed after the first challenge. Among them, some DEGs, including Toll-like receptor 4 (TLR4) and its downstream signaling molecules, were verified using qRT-PCR and were consistent with the transcriptome assay results. Based on gene expression levels, we proposed that these genes related to the TLR signaling cascade participate in enhanced immune protection. All results provide evidence that enhanced immune protection exists in the giant African snail.


Subject(s)
Gastropoda , Lipopolysaccharides , Animals , Lipopolysaccharides/pharmacology , Lipopolysaccharides/metabolism , Escherichia coli/metabolism , Bromodeoxyuridine , Gastropoda/metabolism , Immunologic Memory , Introduced Species
14.
Cell Rep ; 42(8): 112961, 2023 Aug 29.
Article in English | MEDLINE | ID: mdl-37561633

ABSTRACT

Refractory and relapsed B cell lymphomas are often driven by the difficult-to-target oncogene MYC. Here, we report that high MYC expression stimulates proliferation and protects B lymphoma cells from apoptosis under normal oxidative stress levels and that compounds including N-acetylcysteine (NAC) and vitamin C (VitC) induce apoptosis by reducing oxidative stress. NAC and VitC injections effectively reduce tumor growth in lymphoma cells with high MYC expression but not in those with low MYC expression. MYC knockdown confers tumor resistance to NAC and VitC, while MYC activation renders B cells sensitive to these compounds. Mechanistically, NAC and VitC stimulate MYC binding to EGR1 through Cys117 of MYC, shifting its transcriptional output from cell cycle to apoptosis gene expression. These results identify a redox-controlled mechanism for MYC's role in maintaining proliferation and preventing apoptosis, offering a potential therapeutic rationale for evaluating NAC or VitC in patients with MYC-driven B cell lymphoma.

15.
Mol Oncol ; 17(9): 1803-1820, 2023 09.
Article in English | MEDLINE | ID: mdl-37458534

ABSTRACT

Mitochondrial glycolysis and hyperactivity of the phosphatidylinositol 3-kinase-protein kinase B (AKT) pathway are hallmarks of malignant brain tumors. However, kinase inhibitors targeting AKT (AKTi) or the glycolysis master regulator pyruvate dehydrogenase kinase (PDKi) have failed to provide clinical benefits for brain tumor patients. Here, we demonstrate that heterogeneous glioblastoma (GB) and medulloblastoma (MB) cell lines display only cytostatic responses to combined AKT and PDK targeting. Biochemically, the combined AKT and PDK inhibition resulted in the shutdown of both target pathways and priming to mitochondrial apoptosis but failed to induce apoptosis. In contrast, all tested brain tumor cell models were sensitive to a triplet therapy, in which AKT and PDK inhibition was combined with the pharmacological reactivation of protein phosphatase 2A (PP2A) by NZ-8-061 (also known as DT-061), DBK-1154, and DBK-1160. We also provide proof-of-principle evidence for in vivo efficacy in the intracranial GB and MB models by the brain-penetrant triplet therapy (AKTi + PDKi + PP2A reactivator). Mechanistically, PP2A reactivation converted the cytostatic AKTi + PDKi response to cytotoxic apoptosis, through PP2A-elicited shutdown of compensatory mitochondrial oxidative phosphorylation and by increased proton leakage. These results encourage the development of triple-strike strategies targeting mitochondrial metabolism to overcome therapy tolerance in brain tumors.


Subject(s)
Brain Neoplasms , Cytostatic Agents , Humans , Proto-Oncogene Proteins c-akt/metabolism , Protein Phosphatase 2/metabolism , Cytostatic Agents/therapeutic use , Brain Neoplasms/drug therapy , Apoptosis , Brain , Cell Line, Tumor
17.
Drug Des Devel Ther ; 17: 1417-1432, 2023.
Article in English | MEDLINE | ID: mdl-37197367

ABSTRACT

Purpose: The glucagon-like peptide-1 receptor (GLP-1R) is an effective therapeutic target for type 2 diabetes mellitus (T2DM) and non-alcoholic steatohepatitis (NASH). Research has focused on small-molecule GLP-1R agonists because of their ease of use in oral formulations and improved patient compliance. However, no small-molecule GLP-1R agonists are currently available in the market. We aimed to screen for a potential oral small-molecule GLP-1R agonist and evaluated its effect on blood glucose and NASH. Methods: The Connectivity map database was used to screen for candidate small-molecule compounds. Molecular docking was performed using SYBYL software. Rat pancreatic islets were incubated in different concentrations glucose solutions, with cinchonine or Exendin (9-39) added to determine insulin secretion levels. C57BL/6 mice, GLP-1R-/- mice and hGLP-1R mice were used to conduct oral glucose tolerance test. In addition, we fed ob/ob mice with the GAN diet to induce the NASH model. Cinchonine (50 mg/kg or 100 mg/kg) was administered orally twice daily to the mice. Serum liver enzymes were measured using biochemical analysis. Liver tissues were examined using Hematoxylin-eosin staining, Oil Red O staining and Sirius Red staining. Results: Based on the small intestinal transcriptome of geniposide, a recognized small-molecule GLP-1R agonist, we identified that cinchonine exerted GLP-1R agonist-like effects. Cinchonine had a good binding affinity for GLP-1R. Cinchonine promoted glucose-dependent insulin secretion, which could be attenuated significantly by Exendin (9-39), a specific GLP-1R antagonist. Moreover, cinchonine could reduce blood glucose in C57BL/6 and hGLP-1R mice, an effect that could be inhibited with GLP-1R knockout. In addition, cinchonine reduced body weight gain and food intake in ob/ob-GAN NASH mice dose-dependently. 100 mg/kg cinchonine significantly improved liver function by reducing the ALT, ALP and LDH levels. Importantly, 100 mg/kg cinchonine ameliorated hepatic steatosis and fibrosis in NASH mice. Conclusion: Cinchonine, a potential oral small-molecule GLP-1R agonist, could reduce blood glucose and ameliorate NASH, providing a strategy for developing small-molecule GLP-1R agonists.


Subject(s)
Diabetes Mellitus, Type 2 , Non-alcoholic Fatty Liver Disease , Mice , Rats , Animals , Non-alcoholic Fatty Liver Disease/drug therapy , Blood Glucose , Glucagon-Like Peptide-1 Receptor/metabolism , Molecular Docking Simulation , Receptors, Glucagon/agonists , Receptors, Glucagon/metabolism , Receptors, Glucagon/therapeutic use , Mice, Inbred C57BL
18.
Front Oncol ; 13: 1114302, 2023.
Article in English | MEDLINE | ID: mdl-36910602

ABSTRACT

Background: The prediction model of postoperative pneumonia (POP) after lung cancer surgery is still scarce. Methods: Retrospective analysis of patients with lung cancer who underwent surgery at The Fourth Hospital of Hebei Medical University from September 2019 to March 2020 was performed. All patients were randomly divided into two groups, training cohort and validation cohort at the ratio of 7:3. The nomogram was formulated based on the results of multivariable logistic regression analysis and clinically important factors associated with POP. Concordance index (C-index), receiver operating characteristic (ROC) curve, calibration curve, Hosmer-Lemeshow goodness-of-fit test and decision curve analysis (DCA) were used to evaluate the predictive performance of the nomogram. Results: A total of 1252 patients with lung cancer was enrolled, including 877 cases in the training cohort and 375 cases in the validation cohort. POP was found in 201 of 877 patients (22.9%) and 89 of 375 patients (23.7%) in the training and validation cohorts, respectively. The model consisted of six variables, including smoking, diabetes mellitus, history of preoperative chemotherapy, thoracotomy, ASA grade and surgery time. The C-index from AUC was 0.717 (95%CI:0.677-0.758) in the training cohort and 0.726 (95%CI:0.661-0.790) in the validation cohort. The calibration curves showed the model had good agreement. The result of DCA showed that the model had good clinical benefits. Conclusion: This proposed nomogram could predict the risk of POP in patients with lung cancer surgery in advance, which can help clinician make reasonable preventive and treatment measures.

19.
Front Endocrinol (Lausanne) ; 14: 1084511, 2023.
Article in English | MEDLINE | ID: mdl-36967796

ABSTRACT

Introduction: Recent studies have indicated that the dosage of LMWH in patients with specific weights may be controversial. Therefore, we conducted a meta-analysis to explore an appropriate dosage of LMWH for the prevention and treatment of venous thromboembolism (VTE) in patients with obesity. Materials and methods: We searched the PubMed, EMBASE, and Cochrane Library databases up to July 23, 2022. Study selection, bias analysis, and information extraction were performed by three independent reviewers. The occurrence or recurrence of VTE and bleeding events were the primary outcomes we assessed. Results: Eleven studies (a total of 6266 patients) were included in the prevention group, and 6 studies (a total of 3225 patients) were included in the treatment group. For VTE prophylaxis, compared with the standard-dosage group, the high-dosage group had a lower incidence of VTE (OR: 0.47, 95% CI: 0.27-0.82, P=0.007) and a similar incidence of bleeding events (OR: 0.86, 95% CI: 0.69-1.08, P=0.020). For VTE therapy, compared to the standard-dosage group, the reduced-dosage group had a similar incidence of VTE recurrence (OR: 0.86, 95% CI: 0.11-6.84, P=0.89) but a lower incidence of bleeding events (OR: 0.30, 95% CI: 0.10-0.89, P=0.03). Conclusion: In patients with obesity, increasing the dosage of LMWH is a more appropriate option for the prevention of VTE. Due to the limited evidence, reducing the therapeutic dosage of LMWH requires careful consideration. Larger-scale, well-designed randomized controlled trials are necessary. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?, identifier ID=CRD42022298128.


Subject(s)
Heparin, Low-Molecular-Weight , Venous Thromboembolism , Humans , Heparin, Low-Molecular-Weight/therapeutic use , Venous Thromboembolism/drug therapy , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & control , Anticoagulants/therapeutic use , Anticoagulants/adverse effects , Hemorrhage/chemically induced , Hemorrhage/prevention & control
20.
Plant Physiol ; 192(2): 1204-1220, 2023 05 31.
Article in English | MEDLINE | ID: mdl-36974897

ABSTRACT

Mikania micrantha Kunth is a fast-growing global invasive weed species that causes severe damage to natural ecosystems and very large economic losses of forest and crop production. Although Puccinia spegazzinii can effectively inhibit the growth of M. micrantha and is used as a biological control strain in many countries, the mechanism of inhibiting the growth of M. micrantha is not clear. Here, we used a combination of phenotypic, enzyme activity, transcriptomic, and metabolomic approaches to study the response of M. micrantha after infection by P. spegazzinii. In the early stages of rust infection, jasmonic acid (JA), jasmonoyl-isoleucine (JA-Ile), and salicylic acid (SA) levels in infected leaves were significantly lower than those in uninfected leaves. In teliospore initial and developed stages of P. spegazzinii, JA and JA-Ile levels substantially increased by more than 6 times, which resulted in a significant decrease in the accumulation of defense hormone SA in infected leaves of M. micrantha. The contents of plant growth-promoting hormones were significantly reduced in the infected plants as a result of substantial downregulation of the expression of key genes related to hormone biosynthesis. Furthermore, rust infection led to high levels of reactive oxygen species in chloroplasts and the destruction of chlorophyll structure, which also led to decreased photosynthetic gene expression, net photosynthetic rate, activity of Rubisco, and levels of important organic acids in the Calvin cycle. We hypothesized that after P. spegazzinii infection, JA or JA-Ile accumulation not only inhibited SA levels to promote rust infection and development, but also impeded the rapid growth of M. micrantha by affecting plant growth hormones, carbon, and nitrogen metabolic pathways.


Subject(s)
Basidiomycota , Mikania , Mikania/genetics , Ecosystem , Hormones
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