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Journal of Family Medicine and Primary... May 2024Biomarkers to predict the onset and progression of chronic kidney disease (CKD) in children are lacking, and no such definite biomarkers have been implicated in the...
BACKGROUND
Biomarkers to predict the onset and progression of chronic kidney disease (CKD) in children are lacking, and no such definite biomarkers have been implicated in the diagnosis of CKD. We conducted this study to evaluate copeptin as a CKD marker and predict the disease progression by estimating the copeptin levels at baseline and 12 months follow-up in children with CKD stage 2 and above.
MATERIALS AND METHODS
This prospective single-centre cohort study was conducted in children under 14 years with CKD stages 2-4. Blood and urine samples were collected at enrolment and 1-year follow-up for routine investigations and serum copeptin, cystatin C and urinary neutrophil gelatinase-associated lipocalcin (uNGAL) estimation.
RESULTS
A total of 110 children (60 cases and 50 controls) were enrolled in the study. The mean estimated glomerular filtration rate (eGFR) of cases was 58.3 ± 18.7 ml/min/1.73 m. Among the cases, there was a significant rise in the serum copeptin levels from baseline 483.08 ± 319.2 pg/ml to follow-up at 1 year, that is, 1046.82 ± 823.53 pg/ml ( < 0.0001). A significant difference was noted in the baseline values of serum cystatin C, that is, 1512.98 ± 643.77 ng/ml and 719.68 ± 106.96 ng/ml ( < 0.0001), and uNGAL, that is, 13.53 ± 11.72 and 1.76 ± 2.37 ng/ml ( < 0.0001) between the cases and controls. There was no significant correlation (correlation coefficient = 0.10) between change in eGFR and copeptin levels during 12 months of follow-up.
CONCLUSION
No significant correlation was found between the change in eGFR and copeptin levels during 12 months of follow-up. This can be due to the slow deterioration of renal functions, as most of the cases had underlying congenital anomalies of the kidney and urinary tract (CAKUT), which is known to have a slow progression of CKD and a small sample size.
PubMed: 38948594
DOI: 10.4103/jfmpc.jfmpc_1707_23 -
Cancer Innovation Feb 2024Numerous studies have revealed a tight connection between tumor development and the coagulation system. However, the effects of coagulation on the prognosis and tumor...
BACKGROUND
Numerous studies have revealed a tight connection between tumor development and the coagulation system. However, the effects of coagulation on the prognosis and tumor microenvironment (TME) of clear cell renal cell carcinoma (ccRCC) remain poorly understood.
METHODS
We employed the consensus clustering method to characterize distinct molecular subtypes associated with coagulation patterns. Subsequently, we examined variations in the overall survival (OS), genomic profiles, and TME characteristics between these subtypes. To develop a prognostic coagulation-related risk score (CRRS) model, we utilized the least absolute shrinkage and selection operator Cox regression and stepwise multivariate Cox regression analyses. We also created a nomogram to aid in the clinical application of the risk score, evaluating the relationships between the CRRS and the immune microenvironment, responsiveness to immunotherapy, and targeted treatment. The clinical significance of PLAUR and its biological function in ccRCC were also further analyzed.
RESULTS
There were significant differences in clinical features, prognostic stratification, genomic variation, and TME characteristics between the two coagulation-related subtypes. We established and validated a CRRS using six coagulation-related genes that can be employed as an effective indicator of risk stratification and prognosis estimation for ccRCC patients. Significant variations in survival outcomes were observed between the high- and low-risk groups. The nomogram was proficient in predicting the 1-, 3-, and 5-year OS. Additionally, the CRRS emerged as a novel tool for evaluating the clinical effectiveness of immunotherapy and targeted treatments in ccRCC. Moreover, we confirmed upregulated PLAUR expression in ccRCC samples that was significantly correlated with poor patient prognosis. PLAUR knockdown notably inhibited ccRCC cell proliferation and migration.
CONCLUSION
Our data suggested that CRRS may be employed as a reliable predictive biomarker that can provide therapeutic benefits for immunotherapy and targeted therapy in ccRCC.
PubMed: 38948537
DOI: 10.1002/cai2.105 -
Integrative Medicine Research Jun 2024Investigating the effects of electroacupuncture (EA) treatment on cardiovascular function and aortic lipid profiles in spontaneously hypertensive rats (SHR) constitutes...
BACKGROUND
Investigating the effects of electroacupuncture (EA) treatment on cardiovascular function and aortic lipid profiles in spontaneously hypertensive rats (SHR) constitutes the foundational focus of this study. The overarching goal is to comprehensively elucidate the alterations brought about by EA treatment and to assess its potential as an alternative therapy for hypertension.
METHODS
Consecutive EA treatments were administered to SHR, and the effects on systolic blood pressure, cardiac function, and hypertension-related neuronal signals were assessed. Aortic lipid profiles in vehicle-treated SHR and EA-treated SHR groups were analyzed using mass spectrometry-based lipid profiling. Additionally, the expression of Cers2 and GNPAT, enzymes involved in the synthesis of specific aortic lipids, was examined.
RESULTS
The study demonstrated that consecutive EA treatments restored systolic blood pressure, improved cardiovascular function, and normalized hypertension-related neuronal signals in SHR. Analysis of the aortic lipid profiles revealed distinct differences between the vehicle-treated SHR group and the EA-treated SHR group. Specifically, EA treatment significantly altered the levels of aortic sphingomyelin and phospholipids, including very long-chain fatty acyl-ceramides and ether phosphatidylcholines. These changes in aortic lipid profiles correlated significantly with systolic blood pressure and cardiac function indicators. Furthermore, EA treatment significantly altered the expression of Cers2 and GNPAT.
CONCLUSIONS
The findings suggest that EA may influence cardiovascular functions and aortic lipid profiles in SHR.
PubMed: 38948488
DOI: 10.1016/j.imr.2024.101041 -
Frontiers in Pharmacology 2024The escalation of global population aging has accentuated the prominence of senile diabetes mellitus (SDM) as a consequential public health concern. Oxidative stress and...
Network analysis combined with experimental assessment to explore the therapeutic mechanisms of New Shenqi Pills formula targeting mitochondria on senile diabetes mellitus.
BACKGROUND
The escalation of global population aging has accentuated the prominence of senile diabetes mellitus (SDM) as a consequential public health concern. Oxidative stress and chronic inflammatory cascades prevalent in individuals with senile diabetes significantly amplify disease progression and complication rates. Traditional Chinese Medicine (TCM) emerges as a pivotal player in enhancing blood sugar homeostasis and retarding complication onset in the clinical management of senile diabetes. Nonetheless, an evident research gap persists regarding the integration of TCM's renal tonification pharmacological mechanisms with experimental validation within the realm of senile diabetes therapeutics.
AIMS
The objective of this study was to investigate the mechanisms of action of New Shenqi Pills (SQP) in the treatment of SDM and make an experimental assessment.
METHODS
Network analysis is used to evaluate target pathways related to SQP and SDM. Mitochondrial-related genes were obtained from the MitoCarta3.0 database and intersected with the common target genes of the disease and drugs, then constructing a protein-protein interaction (PPI) network making use of the GeneMANIA database. Representative compounds in the SQP were quantitatively measured using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to ensure quality control and quantitative analysis of the compounds. A type 2 diabetes mice (C57BL/6) model was used to investigate the pharmacodynamics of SQP. The glucose lowering efficacy of SQP was assessed through various metrics including body weight and fasting blood glucose (FBG). To elucidate the modulatory effects of SQP on pancreatic beta cell function, we measured oral glucose tolerance test (OGTT), insulin histochemical staining and tunel apoptosis detection, then assessed the insulin-mediated phosphoinositide 3-kinase (PI3K)/protein kinase A (Akt)/glycogen synthase kinase-3β (GSK-3β) pathway in diabetic mice via Western blotting. Additionally, we observe the structural changes of the nucleus, cytoplasmic granules and mitochondria of pancreatic islet β cells.
RESULTS
In this investigation, we identified a total of 1876 genes associated with senile diabetes, 278 targets of SQP, and 166 overlapping target genes, primarily enriched in pathways pertinent to oxidative stress response, peptide response, and oxygen level modulation. Moreover, an intersection analysis involving 1,136 human mitochondrial genes and comorbidity targets yielded 15 mitochondria-related therapeutic targets. Quality control assessments and quantitative analyses of SQP revealed the predominant presence of five compounds with elevated concentrations: Catalpol, Cinnamon Aldehyde, Rehmanthin D, Trigonelline, and Paeonol Phenol. Vivo experiments demonstrated notable findings. Relative to the control group, mice in the model group exhibited significant increases in body weight and fasting blood glucose levels, alongside decreased insulin secretion and heightened islet cell apoptosis. Moreover, β-cells nuclear condensation and mitochondrial cristae disappearance were observed, accompanied by reduced expression levels of p-GSK-3β protein in islet cells ( < 0.05 or < 0.01). Conversely, treatment groups administered SQP and Rg displayed augmented expressions of the aforementioned protein markers ( < 0.05 or < 0.01), alongside preserved mitochondrial cristae structure in islet β cells.
CONCLUSION
Our findings suggest that SQP can ameliorate diabetes by reducing islet cell apoptosis and resist oxidative stress. These insulin-mediated PI3K/AKT/GSK-3β pathway plays an important regulatory role in this process.
PubMed: 38948458
DOI: 10.3389/fphar.2024.1339758 -
World Journal of Experimental Medicine Jun 2024Mitochondrial dysfunction is a key driver of cardiovascular disease (CVD) in metabolic syndrome and diabetes. This dysfunction promotes the production of reactive oxygen... (Review)
Review
Mitochondrial dysfunction is a key driver of cardiovascular disease (CVD) in metabolic syndrome and diabetes. This dysfunction promotes the production of reactive oxygen species (ROS), which cause oxidative stress and inflammation. Angiotensin II, the main mediator of the renin-angiotensin-aldosterone system, also contributes to CVD by promoting ROS production. Reduced activity of sirtuins (SIRTs), a family of proteins that regulate cellular metabolism, also worsens oxidative stress. Reduction of energy production by mitochondria is a common feature of all metabolic disorders. High SIRT levels and 5' adenosine monophosphate-activated protein kinase signaling stimulate hypoxia-inducible factor 1 beta, which promotes ketosis. Ketosis, in turn, increases autophagy and mitophagy, processes that clear cells of debris and protect against damage. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), a class of drugs used to treat type 2 diabetes, have a beneficial effect on these mechanisms. Randomized clinical trials have shown that SGLT2i improves cardiac function and reduces the rate of cardiovascular and renal events. SGLT2i also increase mitochondrial efficiency, reduce oxidative stress and inflammation, and strengthen tissues. These findings suggest that SGLT2i hold great potential for the treatment of CVD. Furthermore, they are proposed as anti-aging drugs; however, rigorous research is needed to validate these preliminary findings.
PubMed: 38948421
DOI: 10.5493/wjem.v14.i2.91519 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024To explore the effects of microRNA-342-3p/MgMn-dependent protein phosphatase 1E (miR-342-3p/PPM1E) on the proliferation, migration, and invasion of clear cell renal cell...
OBJECTIVE
To explore the effects of microRNA-342-3p/MgMn-dependent protein phosphatase 1E (miR-342-3p/PPM1E) on the proliferation, migration, and invasion of clear cell renal cell carcinoma (ccRCC) cells.
METHODS
The gene chips GSE12105, GSE23085, GSE66271, and GSE66270 were searched, and the relationship between miR-342-3p, PPM1E, and the clinical malignant phenotypes of ccRCC was analyzed. ACHN and 769-P cells were transfected with miR-342-3p inhibitor. The effects of miR-342-3p on cell proliferation, migration, and invasion were examined. ACHN cell line with stable and high expression of miR-342-3p was constructed, and the tumorigenicity of the cell line in BALB/c nude mice was observed. The targeted relationship between miR-342-3p and was verified by dual-luciferase reporter gene assay. The cells were transfected with miR-342-3p mimic and pcDNA- plasmids to observe whether PPM1E could reverse the effects of miR-342-3p overexpression on the proliferation, migration, and invasion of the cells.
RESULTS
The expression of miR-342-3p was upregulated in ccRCC, and there were significant differences among patients with tumors of different T stages and G stages and those with different prognoses (<0.05). The overall survival in the miR-342-3p high-expression group was significantly shorter than that in the low-expression group (<0.05). Compared with those in the miR-NC group, the miR-342-3p level was significantly downregulated in the inhibitor group, and the cell proliferation ability and the numbers of migrating and invading cells were also significantly decreased (<0.05). Compared with the miR-NC group, miR-342-3p group had significantly increased volume and mass of tumor tissues and miR-342-3p level, but significantly decreased level of mRNA (<0.05). The expression of PPM1E was downregulated in ccRCC, and there were significant differences among patients with tumors of different M stages, N stages, and G stages, and different recurrence statuses (<0.05). The miR-342-3p could inhibit the expression of PPM1E in a targeted way. Compared with the miR-NC group, the miR-342-3p group had significantly increased cell proliferation ability and increased numbers of migrating and invading cells (<0.05). However, PPM1E could reverse the promotion effect of miR-342-3p mimic on ccRCC cells (<0.05).
CONCLUSION
The miR-342-3p can inhibit PPM1E expression in a targeted way, and thus promotes the proliferation, migration, and invasion of ccRCC cells.
Topics: MicroRNAs; Carcinoma, Renal Cell; Cell Proliferation; Cell Movement; Humans; Animals; Kidney Neoplasms; Mice; Mice, Nude; Protein Phosphatase 2C; Cell Line, Tumor; Mice, Inbred BALB C; Neoplasm Invasiveness
PubMed: 38948282
DOI: 10.12182/20240560403 -
MethodsX Jun 2024Lead (Pb) is a neurotoxin, and children are vulnerable due to their evolving physiology and high-risk behaviours. Soil remediation interventions have proven effective in...
Lead (Pb) is a neurotoxin, and children are vulnerable due to their evolving physiology and high-risk behaviours. Soil remediation interventions have proven effective in reducing Pb exposure. The primary objective is to measure the effectiveness of soil remediation at abandoned used lead acid battery (ULAB) recycling sites, nearby household cleaning, and community awareness in reducing blood lead levels (BLLs) in children. Additionally, this study aims to examine associations of Pb exposure with hematological, cardiovascular, renal, immunological, and endocrinological parameters in children aged 0-12 years. This study employs a quasi-experimental design, with abandoned ULAB sites as intervention sites and two control sites in Bangladesh. The intervention includes soil remediation coupled with community education. Data will be collected prior to the intervention and at a 12-month follow-up, including a comprehensive Pb exposure survey and collect environmental, turmeric samples, and blood from the child. Pb concentrations in environmental samples and turmeric samples will be determined using XRF analyser. Child BLL will be measured using Graphite Furnace Atomic Absorption Spectrometry (GF-AAS) and proposed biochemical parameters will be analysed using routine laboratory methods. This study could provide valuable insights for designing targeted interventions in similar settings and mitigating exposure to Pb.
PubMed: 38948243
DOI: 10.1016/j.mex.2024.102772 -
PeerJ 2024PLAUR has been found upregulated in various tumors and closely correlated with the malignant phenotype of tumor cells. The aim of this study was to investigate the...
BACKGROUND
PLAUR has been found upregulated in various tumors and closely correlated with the malignant phenotype of tumor cells. The aim of this study was to investigate the relationship between PLAUR and clear cell renal cell carcinoma (ccRCC) and its potential mechanism of promoting tumor progression.
METHODS
The expression levels and clinical significance of PLAUR, along with the associated signaling pathways, were extensively investigated in ccRCC samples obtained from The Cancer Genome Atlas (TCGA). PLAUR expression in 20 pairs of ccRCC tumor tissues and the adjacent tissues was assessed using qRT-PCR and IHC staining. Additionally, a series of experiments were conducted to investigate the impact of PLAUR suppression on cellular proliferation, migration, invasion, cell cycle progression, and apoptosis in ccRCC. The Western blot analysis was employed to investigate the expression levels of pivotal genes associated with the PI3K/AKT/mTOR signaling pathway.
RESULTS
The expression of PLAUR was significantly upregulated in ccRCC compared to normal renal tissues, and higher PLAUR expression in ccRCC was associated with a poorer prognosis than low expression. The functional investigations demonstrated that knockdown of PLAUR significantly attenuated the proliferation, migration, and invasion capabilities of ccRCC cells. Concurrently, PLAUR knockdown effectively induced cellular apoptosis, modulated the cell cycle, inhibited the EMT process, and attenuated the activation of the PI3K/AKT/mTOR signaling pathway. PLAUR may represent a key mechanism underlying ccRCC progression.
CONCLUSIONS
The involvement of PLAUR in ccRCC progression may be achieved through the activation of the PI3K/AKT/mTOR signaling pathway, making it a reliable biomarker for the identification and prediction of ccRCC.
Topics: Humans; Carcinoma, Renal Cell; TOR Serine-Threonine Kinases; Kidney Neoplasms; Signal Transduction; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Disease Progression; Cell Proliferation; Cell Line, Tumor; Male; Female; Apoptosis; Cell Movement; Middle Aged; Gene Expression Regulation, Neoplastic; Prognosis; Up-Regulation
PubMed: 38948215
DOI: 10.7717/peerj.17555 -
Frontiers in Physiology 2024Proximal tubule (PT) cells maintain a high-capacity apical endocytic pathway to recover essentially all proteins that escape the glomerular filtration barrier. The multi...
Proximal tubule (PT) cells maintain a high-capacity apical endocytic pathway to recover essentially all proteins that escape the glomerular filtration barrier. The multi ligand receptors megalin and cubilin play pivotal roles in the endocytic uptake of normally filtered proteins in PT cells but also contribute to the uptake of nephrotoxic drugs, including aminoglycosides. We previously demonstrated that opossum kidney (OK) cells cultured under continuous fluid shear stress (FSS) are superior to cells cultured under static conditions in recapitulating essential functional properties of PT cells . To identify drivers of the high-capacity, efficient endocytic pathway in the PT, we compared FSS-cultured OK cells with less endocytically active static-cultured OK cells. Megalin and cubilin expression are increased, and endocytic uptake of albumin in FSS-cultured cells is > 5-fold higher compared with cells cultured under static conditions. To understand how differences in receptor expression, distribution, and trafficking rates contribute to increased uptake, we used biochemical, morphological, and mathematical modeling approaches to compare megalin traffic in FSS- versus static-cultured OK cells. Our model predicts that culturing cells under FSS increases the rates of all steps in megalin trafficking. Importantly, the model explains why, despite seemingly counterintuitive observations (a reduced fraction of megalin at the cell surface, higher colocalization with lysosomes, and a shorter half-life of surface-tagged megalin in FSS-cultured cells), uptake of albumin is dramatically increased compared with static-grown cells. We also show that FSS-cultured OK cells more accurately exhibit the mechanisms that mediate uptake of nephrotoxic drugs compared with static-grown cells. This culture model thus provides a useful platform to understand drug uptake mechanisms, with implications for developing interventions in nephrotoxic injury prevention.
PubMed: 38948083
DOI: 10.3389/fphys.2024.1404248 -
Theranostics 2024Immune checkpoint inhibitors (ICI) are routinely used in advanced clear cell renal cell carcinoma (ccRCC). However, a substantial group of patients does not respond to...
Immune checkpoint inhibitors (ICI) are routinely used in advanced clear cell renal cell carcinoma (ccRCC). However, a substantial group of patients does not respond to ICI therapy. Radiation is a promising approach to increase ICI response rates since it can generate anti-tumor immunity. Targeted radionuclide therapy (TRT) is a systemic radiation treatment, ideally suited for precision irradiation of metastasized cancer. Therefore, the aim of this study is to explore the potential of combined TRT, targeting carbonic anhydrase IX (CAIX) which is overexpressed in ccRCC, using [Lu]Lu-DOTA-hG250, and ICI for the treatment of ccRCC. In this study, we evaluated the therapeutic and immunological action of [Lu]Lu-DOTA-hG250 combined with aPD-1/a-CTLA-4 ICI. First, the biodistribution of [Lu]Lu-DOTA-hG250 was investigated in BALB/cAnNRj mice bearing Renca-CAIX or CT26-CAIX tumors. Renca-CAIX and CT26-CAIX tumors are characterized by poor versus extensive T-cell infiltration and homogeneous versus heterogeneous PD-L1 expression, respectively. Tumor-absorbed radiation doses were estimated through dosimetry. Subsequently, [Lu]Lu-DOTA-hG250 TRT efficacy with and without ICI was evaluated by monitoring tumor growth and survival. Therapy-induced changes in the tumor microenvironment were studied by collection of tumor tissue before and 5 or 8 days after treatment and analyzed by immunohistochemistry, flow cytometry, and RNA profiling. Biodistribution studies showed high tumor uptake of [Lu]Lu-DOTA-hG250 in both tumor models. Dose escalation therapy studies in Renca-CAIX tumor-bearing mice demonstrated dose-dependent anti-tumor efficacy of [Lu]Lu-DOTA-hG250 and remarkable therapeutic synergy including complete remissions when a presumed subtherapeutic TRT dose (4 MBq, which had no significant efficacy as monotherapy) was combined with aPD-1+aCTLA-4. Similar results were obtained in the CT26-CAIX model for 4 MBq [Lu]Lu-DOTA-hG250 + a-PD1. analyses of treated tumors revealed DNA damage, T-cell infiltration, and modulated immune signaling pathways in the TME after combination treatment. Subtherapeutic [Lu]Lu-DOTA-hG250 combined with ICI showed superior therapeutic outcome and significantly altered the TME. Our results underline the importance of investigating this combination treatment for patients with advanced ccRCC in a clinical setting. Further investigations should focus on how the combination therapy should be optimally applied in the future.
Topics: Animals; Carcinoma, Renal Cell; Mice; Immune Checkpoint Inhibitors; Kidney Neoplasms; Carbonic Anhydrase IX; Humans; Cell Line, Tumor; Radioisotopes; Lutetium; Female; Antigens, Neoplasm; Tissue Distribution; Tumor Microenvironment; Tumor Protein, Translationally-Controlled 1; Xenograft Model Antitumor Assays; Combined Modality Therapy; Mice, Inbred BALB C; Antibodies, Monoclonal
PubMed: 38948062
DOI: 10.7150/thno.96944