Molecular mechanism of Rhizoma Polygonati in the treatment of nephrolithiasis: network pharmacology analysis and in vivo experimental verification.

Rhizoma Polygonati (RP) is the dried rhizome of the liliaceous plant. It has anti-inflammatory and anti-apoptosis effects. But its role in kidney stones has not been studied. The purpose of this study was to verify the effect of RP in the treatment of nephrolithiasis through network pharmacological analysis and in vivo experiments. The active compounds and protein targets of RP, as well as the potential targets of the nephrolithiasis were searched from the database. The protein-protein interaction (PPI) network diagram and the drug-compounds-targets-disease network were constructed. The enrichment analysis was performed by Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, the effect of RP on the prevention and treatment of nephrolithiasis was experimentally validated in vivo. Animal experiments showed that RP ameliorates renal function and reduced crystal deposition in a mouse model. It may act through anti-inflammation and anti-apoptosis. Our study showed that RP could prevent and treat nephrolithiasis by inhibiting apoptosis and inflammation, which provided a new efficacy and clinical application for RP.

Ae index is an independent predictor of kidney stone recurrence in overweight and obese patients.

BACKGROUND: Finding some convenient and economical indicators to initially screen overweight and obese patients at high risk of kidney stone recurrence can help them prevent stone recurrence with lower medical cost. The purpose of this article is to determine the clinical value of Ae index (Apo B × 1000/eGFR) as an independent predictor for kidney stone recurrence in overweight and obese populations. METHODS: We queried the electronic medical records of patients with kidney stone operated at our hospital from March 2016 to March 2022, and selected BMI ≥ 25 kg/m2 as the study population and divided the patients into stone recurrence group and non-recurrence group. Relevant parameters of routine blood and biochemical test, glycated serum protein (GSP), and history of hypertension and hyperglycemia were collected. Then the Chi-square test, independent samples t-test or Wilcoxon rank-sum test were used to calculate the differences between the two groups of data. Next, we performed univariate and multivariate logistic regression analysis to screen out the most significant variables Apo B and eGFR, and then we calculated the Ae index using the formula Apo B × 1000/eGFR, and analyzed the relationship between Ae index and kidney stone recurrence. RESULTS: Univariate analysis found that Apo B (OR:8.376,95%CI:3.093-22.680), Creatinine (OR:1.012,95%CI:1.003-1.021), Cystatin C(OR:2.747,95%CI:1.369-5.508), LDL-C (OR:1.588,95%CI:1.182-2.134), TC (OR:1.543,95%CI:1.198-1.988) were positively associated, eGFR (OR:0.980,95%CI:0.970-0.991) was negatively associated with kidney stone recurrence. And multivariate logistic regression analysis suggested that Apo B (OR:11.028, 95%CI:3.917-31.047) and eGFR (OR:0.976, 95%CI:0.965-0.988) were the most significant factors. Then we calculated Ae index and analyzed it, the sensitivity was 74.26% and the specificity was 60.00%, higher than either individual variable. Its smoothed curve revealed a non-linear relationship between them with the inflection point of 9.16. And the OR on the left side of the inflection point was 1.574 (95% CI: 1.228-2.018), whereas the OR on the right side of the inflection point was 1.088 (95% CI: 1.007-1.177). CONCLUSIONS: Ae index is an easily calculated and obtained index that has some predictive value for kidney stone recurrence in overweight and obese patients, which is of interest.

Establishment of a new predictive model for the recurrence of upper urinary tract stones.

PURPOSE: To construct a nomogram for evaluation of the recurrence risk of upper urinary tract stones in patients. METHODS: We retrospectively reviewed the clinical data of 657 patients with upper urinary tract stones and divided them into stone recurrence group and non-recurrence group. Blood routine, urine routine, biochemical, and urological CT examinations were searched from the electronic medical record, relevant clinical data were collected, including age, BMI, stones number and location, maximum diameter, hyperglycemia, hypertension, and relevant blood and urine parameters. The Wilcoxon rank-sum test, independent sample t test, and Chi-square test were used to preliminarily analyze the data of the two groups, then LASSO and logistic regression analysis were used to find out the significant difference indicators. Finally, R software was used to draw a nomogram to construct the model, and ROC curve was drawn to evaluate the sensitivity and specificity. RESULTS: The results showed that multiple stones (OR: 1.832, 95% CI 1.240-2.706), bilateral stones (OR: 1.779, 95% CI 1.226-2.582), kidney stones (OR: 3.268, 95% CI 1.638-6.518), and kidney ureteral stones (OR: 3.375, 95% CI 1.649-6.906) were high risk factors. And the stone recurrence risk was positively correlated with creatinine (OR: 1.012, 95% CI 1.006-1.018), urine pH (OR: 1.967, 95% CI 1.343-2.883), Apo B (OR: 4.189, 95% CI 1.985-8.841) and negatively correlated with serum phosphorus (OR: 0.282, 95% CI 0.109-0.728). In addition, the sensitivity and specificity of the prediction model were 73.08% and 61.25%, diagnosis values were greater than any single variable. CONCLUSION: The nomogram model can effectively evaluate the recurrence risk of upper urinary stones, especially suitable for stone postoperative patients, to help reduce the possibility of postoperative stone recurrence.

Nomogram for predicting risk factors of fever in patients with negative preoperative urine culture after retrograde intrarenal surgery.

PURPOSE: To determine the risk factors for postoperative fever after retrograde intrarenal surgery (RIRS) in patients with negative preoperative urine culture (UC), and to establish a nomogram for predicting postoperative fever based on these risk factors. METHODS: This study collected 322 patients with negative UC who received RIRS at the First Affiliated Hospital of Anhui Medical University from March 2019 to May 2022. The study population was divided into a fever group and a non-fever group. The risk factors of postoperative fever were determined by univariate and multivariate logistic regression analyses, and a nomogram was established. The nomogram was evaluated in terms of differentiation, calibration, and clinical practicability. RESULTS: In this study, 47 (14.6%) patients developed a fever after surgery. Multivariate logistic regression analysis showed that for patients with negative preoperative urine culture, urinary leucocyte esterase (P = 0.005), operative time (P = 0.019), and intraoperative hypotension (P = 0.028) were independent risk factors of postoperative fever, and a nomogram was constructed according to the above variables. The area under the curve (AUC) calculated by receiver operating characteristic (ROC) analysis was 0.807 (95% CI 0.739-0.876), indicating good discrimination. The calibration curves showed good consistency, and the clinical decision curve analysis (DCA) showed the clinical applicability of the model. CONCLUSIONS: For patients with negative preoperative urine culture, urine leukocyte esterase, operative time, and intraoperative hypotension are independent risk factors of postoperative fever. The new nomogram can better assess the risk of infection in patients with negative UC after RIRS.

Dietary Selenium Intake and Kidney Stones in Old Adults: an Analysis from NHANES 2011 to 2018.

The association between dietary selenium intake and kidney stones remains unclear. The purpose of this study was to explore the correlation between dietary selenium intake and kidney stones in older adults. A total of 6669 adults aged ≥ 60 years who had participated in the National Health and Nutrition Examination Survey (NHANES) during 2011-2018 were enrolled in the current study. The correlation between dietary selenium intake and kidney stones was assessed by the logistic regression analysis. Smooth curve fitting was used to explore the potential non-linear relationship and subgroup analyses were further adopted. After adjustment for multiple confounding factors, the odds ratio (OR) with 95% confidence interval (CI) of kidney stones for per standard deviation increment in dietary selenium intake was 0.92 (0.85, 1.00) overall. Compared with the lowest quartile, the ORs (95% CIs) with increasing quartiles were 0.88 (0.71, 1.08), 0.82 (0.66, 1.02), and 0.79 (0.64, 0.97). In addition, smooth curve fitting and stratified analyses showed that there was a non-linear and stable correlation between dietary selenium intake and the occurrence of kidney stones respectively. For adults aged over 60, dietary selenium intake was inversely correlated with kidney stones, and this relationship remained after adjusting for other confounding variables. Further researches are needed to explore the potential mechanism between dietary selenium intake and kidney stones.

Is the visceral adiposity index a potential indicator for the risk of kidney stones?

Objective: To determine whether the visceral adiposity index (VAI) was linked to the risk of kidney stones (KS) in the representative U.S. adults. Methods: We investigated 59842 participants who joined the 2007-2018 National Health and Nutrition Examination Survey. The association between the visceral adiposity index (VAI) and KS was identified by logistic regression analysis. Meanwhile, the subgroup analysis as well as the calculation of dose-response curves were also utilized to identify sensitive groups. Results: Data from 29384 participants were available, including 2781 self-reported ever experiencing KS diseases. Overall, the VAI was 0.74 (0.70, 0.78) in the KS group, while 0.55 (0.52, 0.57) in the control group. After adjusting for confounders, the prevalence of KS increased by 13% for each unit of VAI increment (OR = 1.13, 95% CI: 1.08, 1.19). Moreover, a linear relationship was found between the VAI and the prevalence of KS. By subgroup analysis, we found that a positive correlation between VAI and the risk of KS both in male (OR=1.14, 95%CI:1.07, 1.22) and female (OR=1.14, 95%CI:1.05, 1.24), White (OR=1.20, 95%CI:1.11, 1.28) and other race, all aged subgroups, nonhypertensive (OR=1.06, 95%CI:1.08, 1.25) and nondiabetic subgroups (OR=1.14, 95%CI:1.07, 1.21). Conclusions: Elevated VAI was strongly associated with KS in representative U.S. adults, which may be a promising indicator for the risk of kidney stones.

Cpd-42 protects against calcium oxalate nephrocalcinosis-induced renal injury and inflammation by targeting RIPK3-mediated necroptosis.

Calcium oxalate (CaOx) crystals, as the predominant component of human kidney stones, can trigger excessive cell death and inflammation of renal tubular epithelial cells, involved in the pathogenesis of nephrocalcinosis. Necroptosis mediated by receptor-interacting protein kinase 3 (RIPK3) serves a critical role in the cytotoxicity of CaOx crystals. Here, we assessed the therapeutic potential of a novel RIPK3 inhibitor, compound 42 (Cpd-42), for CaOx nephrocalcinosis by comparison with dabrafenib, a classic RIPK3 inhibitor. Our results demonstrated that Cpd-42 pretreatment attenuated CaOx crystals-induced renal tubular epithelial cell (TEC) injury by inhibiting necroptosis and inflammation in vitro and in vivo. Furthermore, in an established mouse model of CaOx nephrocalcinosis, Cpd-42 also reduced renal injury while improving the impaired kidney function and intrarenal crystal deposition. Consistent with this finding, Cpd-42 was confirmed to exhibit superior inhibition of necroptosis and protection against renal TEC injury compared to the classic RIPK3 inhibitor dabrafenib in vitro and in vivo. Mechanistically, RIPK3 knockout (KO) tubular epithelial cells pretreated with Cpd-42 did not show further enhancement of the protective effect on crystals-induced cell injury and inflammation. We confirmed that Cpd-42 exerted protective effects by specifically targeting and inhibiting RIPK3-mediated necroptosis to block the formation of the RIPK1-RIPK3 necrosome. Taken together, targeted inhibition of RIPK3-mediated necroptosis with Cpd-42 may provide a potential therapeutic approach for CaOx nephrocalcinosis.

Recent advances in iron homeostasis and regulation - a focus on epigenetic regulation and stroke.

Iron is an element with redox properties. It is active sites of many enzymes and plays an important role in various cellular and biological functions including ATP production and DNA synthesis. However, as a redox element, iron promotes free radical generation and lipid peroxidation, causing oxidative damage and cell death. Iron-mediated oxidation is a central player in ferroptosis, a type of cell death process that is different from apoptosis and necrosis. Thus, iron metabolism and homeostasis are sophisticatedly regulated. There has been exciting progress in understanding iron metabolism and regulation since hepcidin was recognized as the central regulator of iron homeostasis. Hepcidin mainly regulates the iron export function of the ferrous iron permease, ferroportin, which is the only known iron exporter expressed by mammalian cells. Particularly, epigenetic regulation has been a recent focus on iron homeostasis. Epigenetic phenomena have been demonstrated to modulate key proteins including hepcidin in iron metabolism. Here, we review the rapid progress in recent years in understanding molecular mechanisms of iron homeostasis with a focus on epigenetic regulation of hepcidin, ferritin, and ferroptosis. Interactions between methionine oxidation and iron is also discussed. Furthermore, many studies have suggested that the severity of neuronal damage after stroke is proportional to the magnitude of brain iron accumulation. Recent discoveries regarding iron metabolism in stroke is briefly discussed. Understanding the underlying mechanism in iron regulation could provide insight into the treatment of various intractable diseases including stroke.

Factors controlling permeability of the blood-brain barrier.

As the primary protective barrier for neurons in the brain, the blood-brain barrier (BBB) exists between the blood microcirculation system and the brain parenchyma. The normal BBB integrity is essential in protecting the brain from systemic toxins and maintaining the necessary level of nutrients and ions for neuronal function. This integrity is mediated by structural BBB components, such as tight junction proteins, integrins, annexins, and agrin, of a multicellular system including endothelial cells, astrocytes, pericytes, etc. BBB dysfunction is a significant contributor to the pathogeneses of a variety of brain disorders. Many signaling factors have been identified to be able to control BBB permeability through regulating the structural components. Among those signaling factors are inflammatory mediators, free radicals, vascular endothelial growth factor, matrix metalloproteinases, microRNAs, etc. In this review, we provide a summary of recent progress regarding these structural components and signaling factors, relating to their roles in various brain disorders. Attention is also devoted to recent research regarding impact of pharmacological agents such as isoflurane on BBB permeability and how iron ion passes across BBB. Hopefully, a better understanding of the factors controlling BBB permeability helps develop novel pharmacological interventions of BBB hyperpermeability under pathological conditions.

Glucose up-regulates HIF-1 alpha expression in primary cortical neurons in response to hypoxia through maintaining cellular redox status.

It has been suggested that hypoxia-inducible factor 1 (HIF-1), a key regulator in cell's adaptation to hypoxia, plays an important role in the fate of neurons during ischemia. However, the mechanism of HIF-1 regulation is still not fully understood in neurons subjected to ischemia. In this study, we demonstrated that glucose up-regulated the expression of HIF-1alpha, the oxygen-dependent subunit of HIF-1, in rat primary cortical neurons exposed to hypoxia. To understand the mechanism of glucose-regulated HIF-1alpha expression, we investigated the relationships between HIF-1alpha expression, reactive oxygen species (ROS), and redox status. Low levels of HIF-1alpha protein expression were observed in the neurons exposed to in vitro ischemic conditions that had high levels of ROS (oxidizing environments), and vice versa. The glutathione (GSH) precursor, N-acetyl cysteine, induced HIF-1alpha protein expression in hypoxic neurons while the GSH synthesis inhibitor, l-buthionine sulfoximine, inhibited the expression. Moreover, (-)-epicatechin gallate, a ROS scavenger, elevated HIF-1alpha expression in the neurons subjected to in vitro ischemia. Furthermore, results from a systemic hypoxia model showed that a reducing environment increased HIF-1alpha expression in rat brains. Taken together, these data presented the first evidence that glucose promoted HIF-1alpha stabilization through regulating redox status in primary neurons exposed to hypoxia. The results imply that hypoxia only may not be sufficient to stabilize HIF-1alpha and that a reducing environment is required to stabilize HIF-1alpha in neurons exposed to hypoxia.

Gene expression profiling of adult acute myeloid leukemia identifies novel biologic clusters for risk classification and outcome prediction.

To determine whether gene expression profiling could improve risk classification and outcome prediction in older acute myeloid leukemia (AML) patients, expression profiles were obtained in pretreatment leukemic samples from 170 patients whose median age was 65 years. Unsupervised clustering methods were used to classify patients into 6 cluster groups (designated A to F) that varied significantly in rates of resistant disease (RD; P < .001), complete response (CR; P = .023), and disease-free survival (DFS; P = .023). Cluster A (n = 24), dominated by NPM1 mutations (78%), normal karyotypes (75%), and genes associated with signaling and apoptosis, had the best DFS (27%) and overall survival (OS; 25% at 5 years). Patients in clusters B (n = 22) and C (n = 31) had the worst OS (5% and 6%, respectively); cluster B was distinguished by the highest rate of RD (77%) and multidrug resistant gene expression (ABCG2, MDR1). Cluster D was characterized by a "proliferative" gene signature with the highest proportion of detectable cytogenetic abnormalities (76%; including 83% of all favorable and 34% of unfavorable karyotypes). Cluster F (n = 33) was dominated by monocytic leukemias (97% of cases), also showing increased NPM1 mutations (61%). These gene expression signatures provide insights into novel groups of AML not predicted by traditional studies that impact prognosis and potential therapy.