Engineered microorganisms: A new direction in kidney stone prevention and treatment.

Numerous studies have shown that intestinal and urinary tract flora are closely related to the formation of kidney stones. The removal of probiotics represented by lactic acid bacteria and the colonization of pathogenic bacteria can directly or indirectly promote the occurrence of kidney stones. However, currently existing natural probiotics have limitations. Synthetic biology is an emerging discipline in which cells or living organisms are genetically designed and modified to have biological functions that meet human needs, or even create new biological systems, and has now become a research hotspot in various fields. Using synthetic biology approaches of microbial engineering and biological redesign to enable probiotic bacteria to acquire new phenotypes or heterologous protein expression capabilities is an important part of synthetic biology research. Synthetic biology modification of microorganisms in the gut and urinary tract can effectively inhibit the development of kidney stones by a range of means, including direct degradation of metabolites that promote stone production or indirect regulation of flora homeostasis. This article reviews the research status of engineered microorganisms in the prevention and treatment of kidney stones, to provide a new and effective idea for the prevention and treatment of kidney stones.

Ferroptosis and its emerging role in kidney stone formation.

Kidney stone is a common and highly recurrent disease in urology, and its pathogenesis is associated with various factors. However, its precise pathogenesis is still unknown. Ferroptosis describes a form of regulated cell death that is driven by unrestricted lipid peroxidation, which does not require the activation of caspase and can be suppressed by iron chelators, lipophilic antioxidants, inhibitors of lipid peroxidation, and depletion of polyunsaturated fatty acids. Recent studies have shown that ferroptosis plays a crucial role in kidney stone formation. An increasing number of studies have shown that calcium oxalate, urate, phosphate, and selenium deficiency induce ferroptosis and promote kidney stone formation through mechanisms such as oxidative stress, endoplasmic reticulum stress, and autophagy. We also offered a new direction for the downstream mechanism of ferroptosis in kidney stone formation based on the "death wave" phenomenon. We reviewed the emerging role of ferroptosis in kidney stone formation and provided new ideas for the future treatment and prevention of kidney stones.

A Novel Hydrodynamic Design Greatly Improves the Debris Clearance Rate of Flexible Ureteroscopy.

Objectives: To introduce a novel hydrodynamic design for a flexible ureteroscope that can increase stone debris clearance. Methods: Based on hydrodynamics, the new design allowed the ureteroscope to have six water jets. Fluid gushed from the six jets and would ultimately converge into an eddy. The safety and stone debris clearance efficiency were tested in a 3D-printed kidney model. Stone fragments between 0.5 and 1 mm were used to mimic the debris. A ureteroscope already approved for marketing was used as a control. Results: The new design did not change the local renal pressure and did not raise the whole renal pressure under irrigation at 80 or 100 mL/min but slightly raised it under irrigation at 120 mL/min. The pressures in the 2 g stone clearance procedures were 26.0, 33.1, and 37.5 cmH2O for the new design and 25.1, 30.2, and 39.3 cmH2O for the current design; in the 4 g stone clearance procedures, the pressures were 30.1, 37.2, and 40.0 cmH2O for the new design and 26.9, 30.8, and 39.8 cmH2O for the current design, all under conditions of 80, 100, and 120 mL/min irrigation, respectively. The new design significantly improved the stone clearance rate by ∼10-fold. It effectively cleared 2 and 4 g stones within 900 seconds under the three irrigation rates. In contrast, the current design cleared <10% of the stone debris in all tests. Conclusion: The new hydrodynamic design significantly improved the stone debris clearance rate without causing obviously increased renal pressure, and the improvement was maintained under different irrigation pressures and stone burdens.

Engineered baicalein-decorated zinc phosphates for synergistic alleviation of inflammatory bowel disease by repairing the mucosal barrier and relieving oxidative stress.

Orally administered baicalein-decorated zinc phosphates (ZnBM) were engineered for mucosal barrier improvement and intestinal inflammation relief. ZnBM with a size of 1.78 µm comprised 5.58 wt% baicalein and 13.17 wt% zinc. The incorporation of baicalein endowed ZnBM with excellent radical scavenging activities. ZnBM exhibited good stability with negligible zinc release in PBS solution for 2 days, and 32.82% of the zinc could reach the gut. In addition, ZnBM polarized macrophages into the anti-inflammatory M2 type and effectively scavenged intracellular reactive oxygen species (ROS) of lipopolysaccharide (LPS)-treated RAW264.7. Meanwhile, ZnBM effectively scavenged intracellular ROS of phorbol 12-myristate 13-acetate (PMA)-induced Caco-2 cells and exerted a reparative effect on the LPS-damaged Caco-2 monolayer, causing an obvious improvement of the barrier function. Reduced systemic exposure to FITC-dextran was observed to illustrate barrier restoration by ZnBM, which was achieved through upregulation of tight junction protein expression. Notably, the commonly used clinical drug 5-aminosalicylic acid is toxic to the liver and kidneys, and commercial ZnO caused the death of mice during treatment. Apparently, the therapeutic effect of ZnBM was significantly better than that of baicalein alone in chronic colitis. Overall, ZnBM exhibited outstanding therapeutic efficacy and is expected to treat colitis due to its effectiveness, biosecurity, facile preparation, and easy storage.

Causal relationship of genetically predicted circulating micronutrients levels with the risk of kidney stone disease: a Mendelian randomization study.

Background: Current studies have reported conflicting associations between circulating micronutrient levels and kidney stone disease (KSD). We aimed to elucidate the causal relationship between circulating micronutrient levels and KSD by a two-sample Mendelian randomization (MR) analysis. Methods: Total of 36 single nucleotide polymorphisms (SNPs) from published genome-wide association studies (GWAS) significantly associated with eight micronutrients (vitamin B12, folic acid, magnesium, iron, phosphorus, copper, zinc, and selenium) were used as instrumental variables. The GWAS summary data associated with KSD (8,060 cases and 301,094 controls) were obtained from the FinnGen consortium. Inverse variance weighted was the main MR analysis method. MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO), weighted median and MR-Egger were used to assess pleiotropy and heterogeneity. Results: Genetically predicted circulating vitamin B12 and zinc levels were causally associated with the risk of KSD (vitamin B12: OR: 1.17, 95% CI: 1.04-1.32, p = 0.008; zinc: OR: 1.15, 95% CI: 1.03-1.28, p = 0.015). We found no evidence that other circulating micronutrients were associated with risk of KSD. p-value for Cochrane Q test, MR Egger intercept test, and MR-PRESSO were >0.05, indicating no significant heterogeneity or horizontal pleiotropy in this MR analysis. Conclusion: Increasing circulating zinc levels may increase the risk of KSD. More studies are needed to provide evidence on whether genetically predicted circulating vitamin B12 and zinc levels are a risk factor for KSD.

Zinc-Rutin Particles Ameliorate DSS-Induced Acute and Chronic Colitis via Anti-inflammatory and Antioxidant Protection of the Intestinal Epithelial Barrier.

In patients suffering from inflammatory bowel diseases (IBDs), the immune system is disrupted and the intestinal barrier function is compromised. Here, six zinc-flavonoid particles were produced by one-step reaction via changing flavonoids (myricetin, quercetin, and rutin) and solvent (water and ethanol), and then their cytocompatibility and ability to scavenge H2O2, free radicals, and LPS-induced ROS were compared. Zinc-rutin particles (W-ZnRT) composed of rutin (78.92 wt %), Na12[ZnPO4]12·12H2O (6.76 wt %), and crystal water were screened out because W-ZnRT exhibited 80.8 ± 15% cell viability against RAW264.7, could rapidly scavenge 78.1 ± 1% of H2O2 and 71.6 ± 2% of DPPH within 30 min, and reduced LPS-increased intracellular ROS to normal levels. In addition, the therapeutic effects of rutin and W-ZnRT were also compared in dextran sulfate sodium (DSS)-induced acute and chronic colitis in mice. W-ZnRT was superior to rutin alone in chronic colitis (n = 9), although they were equally effective in acute colitis (n = 7). Compared to rutin, 11 oral doses of W-ZnRT (40 mg kg-1) significantly improved intestinal permeability (p = 0.0299) and colon length (p = 0.0025), reduced intestinal proinflammatory factors (IL-6, IL-1ß, and TNF-α), and upregulated tight junction proteins to maintain intestinal barrier function. Taken together, these results identified W-ZnRT as an efficient and safe therapeutic strategy for IBD.

Efficacy and safety of Water Vapor Thermal Therapy in the treatment of benign prostate hyperplasia: a systematic review and single-arm Meta-analysis.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a common chronic condition among men aged 50 or older, causing voiding and obstructive lower urinary tract symptoms. Water vapor thermal therapy (WVTT) using the Rezum® system is a new minimally invasive surgical technique that is increasingly reported as a treatment for BPH. METHODS: The protocol was submitted to the PROSPERO registry. We searched PubMed, Web of Science, Embase, Cochrane Library and ClinicalTrials.gov up to July 29, 2022. Quality assessment was carried out by a 20-item checklist form prepared by the Institute of Health Economics (IHE). Double arcsine transformation was performed to stabilize the variance of the original ratio. When I2 > 50%, the random effect model was used to calculate the pooled parameters. Otherwise, the fixed effect model was used. 95% confidence intervals (CIs) were calculated. A leave-one-out sensitivity analysis was performed to evaluate the impact of each study on the pooled outcomes, and finally, Egger's test was used to assess publication bias. RESULTS: A total of seven single-arm observational studies and one random controlled trial, including 1015 patients, were included. One year after WVTT, the International Prostate Symptom Score decreased by 11.37 (95% CI: -12.53, -10.21), the IPSS Quality of Life scale decreased by 2.59 (95% CI: -2.92, -2.26), the maximum urine flow rate increased by 5.26 ml/s (95% CI: 4.53, 5.99), and the postvoid residual decreased by 13.18 ml (95% CI: -24.32, -2.03). The most common complication was dysuria, with a pooled incidence of 21% (95% CI: 14%, 29%), and the second most common complication was hematuria, with a pooled incidence of 14% (95% CI: 10%, 18%). The pooled incidence of retreatment was 3% (95% CI: 2%, 5%). CONCLUSIONS: WVTT is an attractive alternative to medication or more invasive surgical procedures and can serve as first-line therapy for men with BPH.

A simple predictive model with internal validation for assessment of stone-left after ureteroscopic lithotripsy in upper ureteral stones.

Background: Stone free rate in upper ureteral stones is not as high. We sought to identify easily accessible risk factors attributing to stones left in the ureteroscopy in the treatment of upper ureteral calculi, and to build a simple and reliable predictive model. Methods: Patients treating only for upper ureteral stones in 2018 were retrospectively analyzed. Correlations between factors and the stone free rate were analyzed using bidirectional stepwise regression, curve fitting and binary logistic regression. Stone shape was judged by the gap between length and width in the two-dimensional section. A predictive nomogram model was built based on those selected variables (P<0.05). The area under the receiver operator characteristic curve (AUC) and calibration curve were used to access its discrimination and calibration. Decision curve analysis (DCA) was conducted to test the clinical usefulness. Results: Totally, 275 patients with 284 stones were enrolled in this research. Bidirectional stepwise regression showed that stone length had a significant effect on stone free, instead of width or burden. Stone shapes were also found playing a big role. Curve fitting showed that quasi-circular stones had a high risk of retropulsion, and eventually led to stone left. Finally, stone length, shape, modality, and the distance of stones to the ureteropelvic junction were enrolled in the model. Among them, the distance of the stone to the ureteropelvic junction showed a noticeable impact on stone left. AUC was 0.803 (95% CI: 0.730-0.876), and the calibration curve showed good calibration of the model (concordance index, 0.792). DCA indicated the model added net benefit to patients. Conclusions: The present predictive model based on those factors, stones length, shape, modality, and distance of the stone to the ureteropelvic junction was easy, reliable and useful.

Cost-effectiveness of anti-retropulsive devices varies according to the locations of proximal ureteral stones: a retrospective cohort study.

BACKGROUND: Anti-retropulsive devices are often used to prevent stone migration in the treatment of proximal ureteral calculi. They are helpful. However, in the meantime, they also add extra expenses. This study was carried out to investigate the best criteria for treating proximal ureteral stones with anti-retropulsive devices. METHODS: Data from all patients who underwent ureteroscopic holmium: YAG laser lithotripsy for solitary upper ureteral stones in 2018 were collected. Patients who encountered stone retropulsion during the process of inserting the ureteroscope were excluded. Patients were divided into either group URS or group URS + ARD depending on whether the anti-retropulsive device was used. Then, the stone-free rate, expenses and other criteria were compared between groups according to stone location. Stone-free was defined as no stones present. RESULTS: For stones located ≤ 30 mm from the ureteropelvic junction (UPJ), the stone-free rates for the URS group were 80% and 80% at one day and one month after the operation, respectively. Those for the URS + ARD group were 71.4% and 78.6% at one day and one month, respectively. For stones located 31-90 mm from the UPJ, the stone-free rates were 84.7% and 84.7% for the URS group and 89.6% and 95.5% for the URS + ARD group at one day and one month, respectively. A statistically significant difference occurred at one month. For stones located > 90 mm from the UPJ, the two groups were both stone free. In the URS + ARD group, expenses were higher. In addition, the mean diameter of residual stones derived from stones located at 31-90 mm from the UPJ was statistically smaller, and 4 of 7 residual stones passed spontaneously within one month, which was obviously more than that in other locations and the URS group. Other outcomes, including operation time and postoperative stay, showed no significant difference between the groups. CONCLUSION: Anti-retropulsive devices are indeed helpful, but they might be cost-effective for stones located solely in the middle part of the upper ureter, not for those too close to or far from the ureteropelvic junction.

The role of reactive oxygen species derived from different NADPH oxidase isoforms and mitochondria in oxalate-induced oxidative stress and cell injury.

Hyperoxaluria is a risk factor for urolithiasis and can cause renal epithelial cell injury secondary to oxidative stress. Reactive oxygen species (ROS) produced during cell damage originate from different sources and play different roles. Here, we explored the potential sources of ROS production and investigated the role of ROS from various sources in oxalate-induced oxidative stress and cell injury in normal rat kidney-52 epithelial (NRK-52E) cells. Oxalate-induced injury was assessed by lactate dehydrogenase (LDH) release experiments. 2,7-dichlorodihydrofluorescein diacetate and mitoSOX Red were used to determine the intracellular and mitochondrial ROS (mtROS) production, respectively. The expression level of Nox4, Nox2, and p22 protein was detected by Western blotting to observe the effect of oxalate on nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase (Nox). Furthermore, a specific NADPH oxidase subtype inhibitor and targeted mitochondrial antioxidants were used to preliminarily identify the role of ROS from different sources in renal tubular epithelial cell injury induced by oxalate. We found that oxalate inhibited cell viability, induced LDH release, and prompted intracellular and mitochondrial ROS (mtROS) production. Oxalate also decreased the protein expression level of Nox4 and increased the protein expression level of p22. Mitochondria were also a source of ROS production. In addition, Nox2 inhibitor or mtROS scavenging prevented oxalate-induced cell injury, reversed by an inhibitor of Nox4/1. We concluded that ROS from different sources might play different roles in oxalate-induced renal tubular epithelial cell injury. We also identified new potential targets for preventing or alleviating oxalate-induced renal tubular epithelial cell injury.

Stress Corrosion Behaviors of 316LN Stainless Steel in a Simulated PWR Primary Water Environment.

The effect of the strain rate, experimental temperature, Zn content in the test solution, and prefilming time on the mechanical properties was investigated by a tensile test with a slow strain rate, at a chemical solution of 2.2 ppm Li and 1200 ppm B in a static autoclave with 8.2 MPa. The experimental parameters clearly affected the tensile properties. The surface morphology, fractograph, and cross-sectional microstructure were analyzed by scanning electron microscopy and transmission electron microscopy. The δ (elongation) and UTS (ultimate tensile strength) of the samples tested in chemical solution were obviously lower than those of the samples tested under a nitrogen atmosphere. However, in general, all samples showed a ductile fracture characteristic and an excellent tensile property in all experimental conditions. The δ and UTS were first increased with increasing Zn content, and then decreased at both conditions of 9.26 × 10-7/s and 4.63 × 10-7/s strain rates. The difference values of tensile properties at different strain rates showed fluctuations with increasing Zn content. The δ increased with both increasing experimental temperature and prefilming time. The UTS first decreased with increasing prefilming time and then increased. The Iscc (stress corrosion cracking susceptibility) decreased with an increasing strain rate, experiment temperature, and prefilming time. Many particles with polyhedrons were formed on the sample surfaces, which was attributed to corrosion in a periodical location at the sample surface. The average length of the particles decreased with increasing Zn content, but increased with both increasing experimental temperatures and prefilming time. The corresponding mechanism is also discussed in this work.