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Phytomedicine : International Journal... Jun 2024Acute kidney injury (AKI) is a clinically common and serious renal dysfunction, characterized by inflammation and damage to tubular epithelial cells. Puerarin, an...
BACKGROUND
Acute kidney injury (AKI) is a clinically common and serious renal dysfunction, characterized by inflammation and damage to tubular epithelial cells. Puerarin, an isoflavone derivative isolated from Pueraria lobata, has been proven to possess exceptional effectiveness in reducing inflammation. However, the effects and underlying mechanisms of puerarin on AKI remain uncertain.
PURPOSE
This study investigated the possible therapeutic effects of puerarin on AKI and explored its underlying mechanism.
STUDY DESIGN AND METHODS
The effects of puerarin on AKI and macrophage polarization were investigated in lipopolysaccharide (LPS)-induced or unilateral ureteral obstruction (UUO)-induced mouse models in vivo and LPS-treated macrophages (Raw264.7) in vitro. Additionally, the effects of puerarin on inflammation-related signaling pathways were analyzed.
RESULTS
Administration of puerarin effectively alleviated kidney dysfunction and reduced inflammatory response in LPS-induced and UUO-induced AKI. In vitro, puerarin treatment inhibited the polarization of M1 macrophages and the release of inflammatory factors in Raw264.7 cells stimulated by LPS. Mechanistically, puerarin downregulated the activities of NF-κB p65 and JNK/FoxO1 signaling pathways. The application of SRT1460 to activate FoxO1 or anisomycin to activate JNK eliminated puerarin-mediated inhibition of JNK/FoxO1 signaling, leading to suppression of macrophage M1 polarization and reduction of inflammatory factors. Further studies showed that puerarin bound to Toll/interleukin-1 receptor (TIR) domain of MyD88 protein, hindering its binding with TLR4, ultimately resulting in downstream NF-κB p65 and JNK/FoxO1 signaling inactivation.
CONCLUSIONS
Puerarin antagonizes NF-κB p65 and JNK/FoxO1 activation via TLR4/MyD88 pathway, thereby suppressing macrophage polarization towards M1 phenotype and alleviating renal inflammatory damage.
PubMed: 38905846
DOI: 10.1016/j.phymed.2024.155813 -
Iranian Journal of Kidney Diseases May 2024Shenqi pill (SQP) can be used to treat various kidney related diseases, but its exact mechanism of action remains unclear. We intended to analyze the role and mechanism...
INTRODUCTION
Shenqi pill (SQP) can be used to treat various kidney related diseases, but its exact mechanism of action remains unclear. We intended to analyze the role and mechanism of SQP on renal interstitial fibrosis (RIF).
METHODS
After performing unilateral ureteral obstruction (UUO) surgery following the Institutional Animal Care and Use Committee guidelines, all rats were assigned into the sham group, UUO group, UUO + SQP 1.5 g/kg, UUO + SQP 3 g/kg, and UUO + SQP 6 g/kg groups. After treatment with SQP for 4 weeks, the appearance of kidney, serum creatinine (SCr), and blood urea nitrogen (BUN) levels were monitored in each group. The pathological injury, extracellular matrix (ECM), and Notch1 pathway-related protein levels were measured using H&E staining, Masson staining, immunohistochemistry, and Western blot, respectively.
RESULTS
SQP could obviously ameliorate the appearance of the kidney as well as the levels of SCr and BUN in UUO rats (SCr: 67.6 ± 4.64 μM, 59.66 ± 4.96 μM, 48.76 ± 4.44 μM, 40.43 ± 3.02 μM for UUO, low, medium, and high SQP treatment groups; BUN: 9.09 ± 0.97 mM, 7.72 ± 0.61 mM, 5.42 ± 0.42 mM, 4.24 ± 0.34 mM for UUO, low, medium, and high SQP treatment groups; P < .05). SQP also effectively mitigated renal tissue injury in UUO rats (P < .05). Moreover, we uncovered that SQP significantly inhibited Collagen I, α-SMA, Collagen IV, TGF-B1, Notch1, and Jag1 protein expressions in UUO rats kidney (P < .05).
CONCLUSION
Our data elucidated that SQP can alleviate RIF, and the mechanism may be related to the Notch1/Jag1 pathway. DOI: 10.52547/ijkd.7703.
Topics: Animals; Drugs, Chinese Herbal; Fibrosis; Male; Receptor, Notch1; Kidney; Ureteral Obstruction; Rats; Rats, Sprague-Dawley; Signal Transduction; Jagged-1 Protein; Blood Urea Nitrogen; Disease Models, Animal; Kidney Diseases; Creatinine; Transforming Growth Factor beta1; Actins
PubMed: 38904340
DOI: 10.52547/b56av842 -
BioRxiv : the Preprint Server For... Apr 2024The cannabinoid CB2 receptor (CB2R) is a potential therapeutic target for distinct forms of tissue injury and inflammatory diseases. To thoroughly investigate the role...
The cannabinoid CB2 receptor (CB2R) is a potential therapeutic target for distinct forms of tissue injury and inflammatory diseases. To thoroughly investigate the role of CB2R in pathophysiological conditions and for target validation , optimal pharmacological tool compounds are essential. Despite the sizable progress in the generation of potent and selective CB2R ligands, pharmacokinetic parameters are often neglected for studies. Here, we report the generation and characterization of a tetra-substituted pyrazole CB2R full agonist named RNB-61 with high potency ( 0.13-1.81 nM, depending on species) and a peripherally restricted action due to P-glycoprotein mediated efflux from the brain. H and C labelled RNB-61 showed apparent values < 4 nM towards human CB2R in both cell and tissue experiments. The >6000-fold selectivity over CB1 receptors and negligible off-targets , combined with high oral bioavailability and suitable systemic pharmacokinetic (PK) properties, prompted the assessment of RNB-61 in a mouse ischemia-reperfusion model of acute kidney injury (AKI) and in a rat model of chronic kidney injury/inflammation and fibrosis (CKI) induced by unilateral ureteral obstruction. RNB-61 exerted dose-dependent nephroprotective and/or antifibrotic effects in the AKI/CKI models. Thus, RNB-61 is an optimal CB2R tool compound for preclinical studies with superior biophysical and PK properties over generally used CB2R ligands.
PubMed: 38903103
DOI: 10.1101/2024.04.26.591311 -
Minerva Medica Jun 2024Managing non-cardiac comorbidities in heart failure (HF) requires a tailored approach that addresses each patient's specific conditions and needs. Regular communication... (Review)
Review
Managing non-cardiac comorbidities in heart failure (HF) requires a tailored approach that addresses each patient's specific conditions and needs. Regular communication and coordination among healthcare providers is crucial to providing the best possible care for these patients. Poorly controlled hypertension contributes to left ventricular remodeling and diastolic dysfunction, emphasizing the importance of optimal blood pressure control while avoiding adverse effects. Among HF patients with diabetes, SGLT2 inhibitors and mineralocorticoid receptor antagonists have shown promise in reducing HF-related morbidity and mortality. Chronic kidney disease exacerbates HF and vice versa, forming the vicious cardiorenal syndrome, so disease-modifying therapies should be maintained in HF patients with comorbid CKD, even with transient changes in kidney function. Anemia in HF patients may be multifactorial, and there is growing evidence for the benefit of intravenous iron supplementation in HF patients with iron deficiency with or without anemia. Obesity, although a risk factor for HF, paradoxically offers a better prognosis once HF is established, though developing treatment strategies may improve symptoms and cardiac performance. In HF patients with stroke and atrial fibrillation, anticoagulation therapy is recommended. Among HF patients with sleep-disordered breathing, continuous positive airway pressure may improve sleep quality. Chronic obstructive pulmonary disease often coexists with HF, and many patients can tolerate cardioselective beta-blockers. Cancer patients with comorbid HF require careful consideration of cardiotoxicity risks associated with cancer therapies. Depression is underdiagnosed in HF patients and significantly impacts prognosis. Cognitive impairment is prevalent in HF patients and impacts their self-care and overall quality of life.
Topics: Humans; Heart Failure; Pulmonary Disease, Chronic Obstructive; Comorbidity; Renal Insufficiency, Chronic; Hypertension; Sleep Apnea Syndromes; Neoplasms; Obesity; Anemia; Stroke; Atrial Fibrillation; Anticoagulants; Mineralocorticoid Receptor Antagonists; Cardio-Renal Syndrome
PubMed: 38899946
DOI: 10.23736/S0026-4806.24.09070-0 -
Nederlands Tijdschrift Voor Geneeskunde Jun 2024A 38-year-old woman with urosepsis and persistent unilateral hydronephrosis after antibiotic treatment. Antegrade pyelogram shows urine flow obstruction to the bladder....
A 38-year-old woman with urosepsis and persistent unilateral hydronephrosis after antibiotic treatment. Antegrade pyelogram shows urine flow obstruction to the bladder. The whole ureter shows multiple small smooth-walled round lucent filling defects projecting into the lumen. The diagnosis ureteritis cystica was made.
Topics: Humans; Female; Hydronephrosis; Adult; Urinary Tract Infections; Anti-Bacterial Agents; Ureteral Diseases
PubMed: 38888409
DOI: No ID Found -
World Journal of Surgery Jun 2024Major emergency abdominal surgery is associated with severe postoperative complications and high short- and long-term mortality. Despite recent advancements in...
BACKGROUND
Major emergency abdominal surgery is associated with severe postoperative complications and high short- and long-term mortality. Despite recent advancements in standardizing multidisciplinary care bundles, a subgroup of patients continues to face a heightened risk of short-term mortality. This study aimed to identify and describe the high-risk surgical patients and risk factors for short-term postoperative mortality.
METHODS
In this study, we included all patients undergoing major emergency abdominal surgery over 2 years and collected data on demographics, intraoperative variables, and short-term outcomes. The primary outcome measure was short-term mortality and secondary outcome measures were pre, intra, and postoperative risk factors for premature death. Multivariable binary regression analysis was performed to determine possible risk factors for short-term mortality.
RESULTS
Short-term mortality within 14 days of surgery in this cohort of 754 consecutive patients was 8%. Multivariable analysis identified various independent risk factors for short-term mortality throughout different phases of patient care. These factors included advanced age, preoperative history of myocardial infarction or ischemic heart disease, chronic obstructive pulmonary disease, liver cirrhosis, chronic kidney disease, and vascular bowel ischemia or perforation of the stomach or duodenum during the primary surgery.
CONCLUSION
Patients at high risk of early mortality following major emergency abdominal surgery exhibited distinct perioperative risk factors. This study underscores the importance of clinicians identifying and managing these factors in high-risk patients to ensure optimal care.
PubMed: 38886168
DOI: 10.1002/wjs.12254 -
Analytical Chemistry Jun 2024Kidney diseases have become an important global health concern due to their high incidence, inefficient diagnosis, and poor prognosis. Devising direct methods,...
Kidney diseases have become an important global health concern due to their high incidence, inefficient diagnosis, and poor prognosis. Devising direct methods, especially imaging means, to assess renal function is the key for better understanding the mechanisms of various kidney diseases and subsequent development of effective treatment. Herein, we developed a fluorinated ferrous chelate-based sensitive probe, 1,7-DO2A-Fe(II)-F18 (Probe ), for F magnetic resonance imaging (MRI). This highly fluorinated probe (containing 18 chemically equivalent F atoms with a fluorine content at 35 wt %) achieves a 15-time enhancement in signal intensity compared with the fluorine-containing ligand alone due to the appropriately regulated F relaxation times by the ferrous ion, which significantly increases imaging sensitivity and reduces acquisition time. Owing to its high aqueous solubility, biostability, and biocompatibility, this probe could be rapidly cleared by kidneys, which provides a means for monitoring renal dysfunction via F MRI. With this probe, we accomplish imaging of the impaired renal dysfunction caused by various kidney diseases including acute kidney injury, unilateral ureteral obstruction, and renal fibrosis at different stages. Our study illustrates the promising potential of Probe for real-time visualization of kidney dysfunction, which is beneficial for the study, diagnosis, and even stratification of different kidney diseases. Furthermore, the design strategy of our probe is inspiring for the development of more high-performance F MRI probes for monitoring various biological processes.
PubMed: 38885015
DOI: 10.1021/acs.analchem.4c02272 -
Frontiers in Endocrinology 2024The global prevalence of cardiovascular diseases (CVD) continues to rise steadily, making it a leading cause of mortality worldwide. Atherosclerosis (AS) serves as a... (Review)
Review
The global prevalence of cardiovascular diseases (CVD) continues to rise steadily, making it a leading cause of mortality worldwide. Atherosclerosis (AS) serves as a primary driver of these conditions, commencing silently at an early age and culminating in adverse cardiovascular events that severely impact patients' quality of life or lead to fatality. Dyslipidemia, particularly elevated levels of low-density lipoprotein cholesterol (LDL-C), plays a pivotal role in AS pathogenesis as an independent risk factor. Research indicates that abnormal LDL-C accumulation within arterial walls acts as a crucial trigger for atherosclerotic plaque formation. As the disease progresses, plaque accumulation may rupture or dislodge, resulting in thrombus formation and complete blood supply obstruction, ultimately causing myocardial infarction, cerebral infarction, and other common adverse cardiovascular events. Despite adequate pharmacologic therapy targeting LDL-C reduction, patients with cardiometabolic abnormalities remain at high risk for disease recurrence, highlighting the importance of addressing lipid risk factors beyond LDL-C. Recent attention has focused on the causal relationship between triglycerides, triglyceride-rich lipoproteins (TRLs), and their remnants in AS risk. Genetic, epidemiologic, and clinical studies suggest a causal relationship between TRLs and their remnants and the increased risk of AS, and this dyslipidemia may be an independent risk factor for adverse cardiovascular events. Particularly in patients with obesity, metabolic syndrome, diabetes, and chronic kidney disease, disordered TRLs and its remnants levels significantly increase the risk of atherosclerosis and cardiovascular disease development. Accumulation of over-synthesized TRLs in plasma, impaired function of enzymes involved in TRLs lipolysis, and impaired hepatic clearance of cholesterol-rich TRLs remnants can lead to arterial deposition of TRLs and its remnants, promoting foam cell formation and arterial wall inflammation. Therefore, understanding the pathogenesis of TRLs-induced AS and targeting it therapeutically could slow or impede AS progression, thereby reducing cardiovascular disease morbidity and mortality, particularly coronary atherosclerotic heart disease.
Topics: Humans; Cardiovascular Diseases; Lipoproteins; Triglycerides; Atherosclerosis; Animals; Dyslipidemias; Risk Factors
PubMed: 38883601
DOI: 10.3389/fendo.2024.1409653 -
The Journal of Pediatrics Jun 2024To assess the long-term outcome of renal oligohydramnios and risk factors for fetal, neonatal, and postneonatal death.
OBJECTIVE
To assess the long-term outcome of renal oligohydramnios and risk factors for fetal, neonatal, and postneonatal death.
STUDY DESIGN
This retrospective cohort study included fetuses with prenatally detected renal oligohydramnios between 2002 and 2023. Patients who were lost to follow-up were excluded. Fetal, neonatal, and long-term outcomes were evaluated, and their risk factors were analyzed.
RESULTS
Of 131 fetuses with renal oligohydramnios, 46 (35%) underwent a termination of pregnancy, 11 (8%) had an intrauterine fetal death, 26 (20%) had a neonatal death, nine (7%) had a postneonatal death, and 39 (30%) survived. Logistic regression analyses showed that an earlier gestational age at onset (odds ratio 1.16, 95% confidence interval (CI) 1.01-1.37) was significantly associated with intrauterine fetal death; anhydramnios (odds ratio 12.7, 95% CI 1.52-106.7) was significantly associated with neonatal death as a prenatal factor. Although neonatal survival rates for bilateral renal agenesis, bilateral multicystic dysplastic kidney (MCDK), and unilateral MCDK with contralateral renal agenesis were lower than for other kidney diseases, one case of bilateral renal agenesis and two of bilateral MCDK survived with fetal intervention. Kaplan-Meier overall survival rates were 57%, 55%, and 51% for 1, 3, and 5 years, respectively. In the Cox proportional hazards model, birth weight <2000 g (hazard ratio 7.33, 95% CI 1.48-36.1) and gastrointestinal comorbidity (hazard ratio 4.37, 95% CI 1.03-18.5) were significant risk factors for postneonatal death.
CONCLUSION
Long-term survival following renal oligohydramnios is a feasible goal and its appropriate risk assessment is important.
PubMed: 38880380
DOI: 10.1016/j.jpeds.2024.114151 -
Journal of Biomedical Informatics Jun 2024Existing approaches to fairness evaluation often overlook systematic differences in the social determinants of health, like demographics and socioeconomics, among...
OBJECTIVE
Existing approaches to fairness evaluation often overlook systematic differences in the social determinants of health, like demographics and socioeconomics, among comparison groups, potentially leading to inaccurate or even contradictory conclusions. This study aims to evaluate racial disparities in predicting mortality among patients with chronic diseases using a fairness detection method that considers systematic differences.
METHODS
We created five datasets from Mass General Brigham's electronic health records (EHR), each focusing on a different chronic condition: congestive heart failure (CHF), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), chronic liver disease (CLD), and dementia. For each dataset, we developed separate machine learning models to predict 1-year mortality and examined racial disparities by comparing prediction performances between Black and White individuals. We compared racial fairness evaluation between the overall Black and White individuals versus their counterparts who were Black and matched White individuals identified by propensity score matching, where the systematic differences were mitigated.
RESULTS
We identified significant differences between Black and White individuals in age, gender, marital status, education level, smoking status, health insurance type, body mass index, and Charlson comorbidity index (p-value < 0.001). When examining matched Black and White subpopulations identified through propensity score matching, significant differences between particular covariates existed. We observed weaker significance levels in the CHF cohort for insurance type (p = 0.043), in the CKD cohort for insurance type (p = 0.005) and education level (p = 0.016), and in the dementia cohort for body mass index (p = 0.041); with no significant differences for other covariates. When examining mortality prediction models across the five study cohorts, we conducted a comparison of fairness evaluations before and after mitigating systematic differences. We revealed significant differences in the CHF cohort with p-values of 0.021 and 0.001 in terms of F1 measure and Sensitivity for the AdaBoost model, and p-values of 0.014 and 0.003 in terms of F1 measure and Sensitivity for the MLP model, respectively.
DISCUSSION AND CONCLUSION
This study contributes to research on fairness assessment by focusing on the examination of systematic disparities and underscores the potential for revealing racial bias in machine learning models used in clinical settings.
PubMed: 38876453
DOI: 10.1016/j.jbi.2024.104677