Allicin attenuates calcium oxalate crystal deposition in the rat kidney by regulating gap junction function.

Renal calculus is a global common urological disease that is closely related to crystal adhesion and renal tubular epithelial cell impairment. Gap junctions (GJs) and their components (connexins and Cxs) are involved in various pathophysiology processes, but their roles in renal calculi progression are not well defined. Our previous RNA microarray analysis suggests that GJs are one of the key predicted pathways involved in the renal calcium oxalate (CaOx) crystal rat model. In the current study, we found that the Cx43 and Cx32 expression and the GJ function decreased significantly after stimulation with CaOx or sodium oxalate (NaOx) in NRK-52E, MDCK, and HK-2 cells, and Cx43 expression also decreased in renal tissues in renal CaOx crystal model rats. Inhibition of Cx43 in NRK-52E cells by small interference RNA significantly increased the CD44 and androgen receptor expression, and the adhesion between CaOx crystals and cells, which were consistent with the function of GJ inhibitors. On the other hand, after GJ function and Cx43 expression were increased by allicin, diallyl disulfide, or diallyl trisulfide, the impairment of NRK-52E cells by NaOx or other GJ inhibitors and the adhesion between CaOx crystals and renal cells decreased significantly. Furthermore, allicin also increased Cx43 expression and inhibited crystal deposition in rat kidneys. Taken together, our results provide a basis that GJs and Cx43 may participate in renal CaOx stone progression and that allicin, together with its analogues, could be potential drugs for renal calculus precaution.

Cell death-related molecules and biomarkers for renal cell carcinoma targeted therapy.

Renal cell carcinoma (RCC) is not sensitive to conventional radio- and chemotherapies and is at least partially resistant to impairments in cell death-related signaling pathways. The hallmarks of RCC formation include diverse signaling pathways, such as maintenance of proliferation, cell death resistance, angiogenesis induction, immune destruction avoidance, and DNA repair. RCC diagnosed during the early stage has the possibility of cure with surgery. For metastatic RCC (mRCC), molecular targeted therapy, especially antiangiogenic therapy (e.g., tyrosine kinase inhibitors, TKIs, such as sunitinib), is one of the main partially effective therapeutics. Various forms of cell death that may be associated with the resistance to targeted therapy because of the crosstalk between targeted therapy and cell death resistance pathways were originally defined and differentiated into apoptosis, necroptosis, pyroptosis, ferroptosis and autophagic cell death based on cellular morphology. Particularly, as a new form of cell death, T cell-induced cell death by immune checkpoint inhibitors expands the treatment options beyond the current targeted therapy. Here, we provide an overview of cell death-related molecules and biomarkers for the progression, prognosis and treatment of mRCC by targeted therapy, with a focus on apoptosis and T cell-induced cell death, as well as other forms of cell death.

Early and rapid prediction of postoperative infections following percutaneous nephrolithotomy in patients with complex kidney stones.

OBJECTIVES: To obtain more accurate and rapid predictors of postoperative infections following percutaneous nephrolithotomy (PCNL) in patients with complex kidney stones, and provide evidence for early prevention and treatment of postoperative infections. PATIENTS AND METHODS: A total of 802 patients with complex kidney stones who underwent PCNL, from September 2016 to September 2017, were recruited. Urine tests, urine cultures (UCs) and stone cultures (SCs) were performed, and the perioperative data were prospectively recorded. RESULTS: In all, 19 (2.4%) patients developed postoperative urosepsis. A multivariate logistic regression analysis revealed that an operating time of ≥100 min, urine test results with both positive urine white blood cells (WBC+) and positive urine nitrite (WBC+NIT+), positive UCs (UC+), and positive SCs (SC+) were independent risk factors of urosepsis. The incidence of postoperative urosepsis was higher in patients with WBC+NIT+ (10%) or patients with both UC+ and SC+ (UC+SC+; 8.3%) than in patients with negative urine test results or negative cultures (P < 0.01). Preoperative WBC+NIT+ was predictive of UC+SC+, with an accuracy of >90%. The main pathogens found in kidney stones were Escherichia coli (44%), Proteus mirabilis (14%) and Staphylococcus (7.4%); whilst the main pathogens found in urine were E. coli (54%), Enterococcus (9.4%) and P. mirabilis (7.6%). The incidence of E. coli was more frequent in the group with urosepsis than in the group without urosepsis (P < 0.05). CONCLUSIONS: WBC+NIT+ in preoperative urine tests could be considered as an early and rapid predictor of UC+SC+ and postoperative urosepsis. Urosepsis following PCNL was strongly associated with E. coli infections in patients with complex kidney stones.

Crosstalk between VEGFR and other receptor tyrosine kinases for TKI therapy of metastatic renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC), and is frequently accompanied by the genetic features of von Hippel-Lindau (VHL) loss. VHL loss increases the expression of hypoxia-inducible factors (HIFs) and their targets, including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF). The primary treatment for metastatic RCC (mRCC) is molecular-targeted therapy, especially anti-angiogenic therapy. VEGF monoclonal antibodies and VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are the main drugs used in anti-angiogenic therapy. However, crosstalk between VEGFR and other tyrosine kinase or downstream pathways produce resistance to TKI treatment, and the multi-target inhibitors, HIF inhibitors or combination strategies are promising strategies for mRCC. HIFs are upstream of the crosstalk between the growth factors, and these factors may regulate the expression of VEGR, EGF, PDGF and other growth factors. The frequent VHL loss in ccRCC increases HIF expression, and HIFs may be an ideal candidate to overcome the TKI resistance. The combination of HIF inhibitors and immune checkpoint inhibitors is also anticipated. Various clinical trials of programmed cell death protein 1 inhibitors are planned. The present study reviews the effects of current and potential TKIs on mRCC, with a focus on VEGF/VEGFR and other targets for mRCC therapy.

The analysis of microbial spectrum and antibiotic resistance of uropathogens isolated from patients with urinary stones.

PURPOSE: The characteristics and resistance patterns of urine bacteriology in patients with urinary tract stones have not been extensively studied. This study aims to investigate the microbial spectrum and antibiotic resistance of uropathogens isolated from urinary tract infections in patients with urinary stones and provide a basis for appropriate antimicrobial treatments. METHODS: The results of positive bladder midstream urine cultures and their antimicrobial susceptibility were retrospectively analysed from hospitalised patients with diagnosis of urinary calculi and urinary tract infections between January 2010 and December 2015. RESULTS: A total of 3892 samples were analysed during the study period: 2201 were female patients (56.6%) and 1691 were male patients (43.4%). The 4 most common uropathogens were Escherichia coli (48.7%), Klebsiella pneumoniae (10.4%), Enterococcus faecalis (8.7%) and Proteus mirabilis (5.2%). Both E. coli (60.8%) and Proteus mirabilis (7.5%) were higher in female patients than in male patients (32.8%; 2.3%; P < .05). ESBL-positive E. coli accounted for 59.5% of total number of E. coli, while ESBL-positive K. pneumoniae comprised 42.0% of total K. pneumoniae. The majority of uropathogens in patients with stones had high resistance to fluoroquinolones, ceftriaxone, ceftazidime, cefepime, penicillins, sulfonamides and monobactams (resistance >20%). CONCLUSIONS: The microbial spectrum in patients with urinary stones had a complex pattern. The uropathogens showed marked multidrug resistance and a large proportion of the uropathogens were able to produce ß-lactamase.

Connexin43 is associated with the progression of clear cell renal carcinoma and is regulated by tangeretin to sygergize with tyrosine kinase inhibitors.

BACKGROUND: The roles of Connexin43 (Cx43) in clear cell renal cell carcinoma (ccRCC) microenviroment remains to be poorly defined. METHODS: The expression profile, prognosis and immune analysis of Cx43 in various cancers, particularly in ccRCC were performed using TCGA database, and various biological function assays were applied to explore the physiological role of Cx43 and tangeretin in ccRCC. Western blot were applied to examine the protein expression and Kunming mice were used to evaluate preliminary safety or anti-tumor activity of tangeretin and sunitinib. RESULTS: Compared with the normal group, higher expression levels of Cx43 in ccRCC, and distinct associations between Cx43 expression and ccRCC prognosis or immune infiltration, were found. Notably, the expression of Cx43 was found to be highly correlated with that of receptor tyrosine kinases (RTKs), particularly with VEGFR1, VEGFR2 and VEGFR3. The expression of Cx43 and EGFR was also found to be higher in ccRCC than that in the para-cancerous specimens. Knocking down Cx43 expression decreased RCC cell viability, cell migration, p-EGFR, MMP-9 and survivin expression. Using 14 Chinese medicine monomers, tangeretin was screened and found to inhibit tumor cell viability and Cx43 expression. Tangeretin also enhanced the sensitivity of RCC cells to tyrosine kinase inhibitors (TKIs) sunitinib and sorafenib. However, the same concentration of tangeretin exerted a less prominent effect on normal renal cell viability. CONCLUSIONS: Cx43 is strongly associated with RTK expression and ccRCC progression, while tangeretin can inhibit RCC cell malignancy by inhibiting Cx43 expression and enhance the sensitivity of RCC cells to TKIs.

Safety of Surgery in benign Prostatic Hyperplasia Patients on Antiplatelet or Anticoagulant Therapy: A Systematic Review and Meta-Analysis.

PURPOSE: The management strategies of anticoagulant (AC) or antiplatelet (AP) therapy in the preoperative period of benign prostatic hyperplasia (BPH) is still controversial. Therefore, a meta-analysis to systematically evaluate the surgical safety for BPH patients on AC or AP therapy was performed. MATERIALS AND METHODS: The protocol for the review is available on PROSPERO (CRD42018105800). A literature search was performed by using MEDLINE, Web of Science, PubMed, Cochrane library, and Embase. Summarized odds ratios (OR), mean difference (MD) and 95% confidence intervals (CI) were used to assess the difference in outcomes. RESULTS: We identified 13 trials with a total of 3767 patients. An intragroup significant difference was found in bleeding complications and blood transfusions when undergoing transurethral resection of the prostate (TURP). For laser surgery, the intragroup significant difference was found in the result of blood transfusion. Bridging therapy would not cause a higher risk of bleeding complications and blood transfusion during the perioperative period. Besides, no difference existed in operation time, catheterization time, hospitalization, and thromboembolic events. CONCLUSION: Patients with BPH on perioperative AC/AP therapy would have a risk of postoperative hemorrhage after TURP or laser treatments. To reduce the risk of hemorrhage, bridging therapy could be a good choice.

LncRNA-miRNA-mRNA expression variation profile in the urine of calcium oxalate stone patients.

BACKGROUND: To explore long-non-coding RNA (lncRNA), microRNA (miRNA) and messenger RNA (mRNA) expression profiles and their biological functions in the urine samples in calcium oxalate (CaOx) patients. METHODS: Five CaOx kidney stone patients were recruited in CaOx stone group and six healthy people were included as control group, whose midstream morning urine was collected before the patients were given any medicine on admission. After total RNA was extracted from urine, microarray of miRNA, mRNA and lncRNA were applied to explore their expression variation. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to reveal the gene functions of the dysregulated lncRNA-associated competing endogenous RNA (ceRNA) network. Quantitative real-time PCR were performed on HK-2 cells treated with sodium oxalate (NaOx) to further screen out the differentially expression profiles of these RNAs. RESULTS: A total of nine miRNAs, 883 mRNAs and 1002 lncRNAs were differentially expressed in urine of CaOx patients compared with normal population. GO analysis revealed that most of mRNAs from ceRNA network were enriched in terms of respiratory burst, regulation of mitophagy, and protein kinase regulator activity. KEGG pathway analysis of these genes related to ceRNA network highlight their critical role in pentose phosphate pathway, glyoxylate and dicarboxylate metabolism, and Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling pathway. Five miRNAs (miR-6796-3p, miR-30d-5p, miR-3192-3p, miR-518b and miR-6776-3p), four mRNAs (NT5E, CDH4, CLEC14A, CCNL1) and six lncRNAs (lnc-TIGD1L2-3, lnc-KIN-1, lnc-FAM72B-4, lnc-EVI5L-1, lnc-SERPINI1-2, lnc-MB-6) from the HK-2 cells induced by NaOx were consistent with the expression changes of microarray results. CONCLUSION: The differential expressed miRNAs, mRNAs and lncRNAs may be associated with numerous variations of the signaling pathways or regulation of metabolism and kinase activity, providing potential biomarkers for early diagnosis of urolithiasis and new basis for further research of urolithiasis mechanism.

Use of the ureteral access sheath during ureteroscopy: A systematic review and meta-analysis.

The debate still rages on for the usefulness of ureteral access sheath (UAS). Therefore, a meta-analysis to discuss the effects of applying UAS during ureteroscopy was performed. The protocol for the review is available on PROSPERO (CRD42017052327). A literature search was conducted up to November, 2017 using the Web of science, PUBMED, EMBASE and Cochrane Library. The quality of articles was assessed by the Jadad scale and Newcastle Ottawa Scale (NOS). Egger's test and the trim-and-fill method were used to evaluate publication bias. Effect sizes were calculated by pooled odds ratio (ORs) and mean differences (MDs). Sensitivity analyses and subgroup analyses were performed to explore the origin of heterogeneity. Eight trials with a total of 3099 patients and 3127 procedures were identified. Results showed no significant difference in stone-free rate (SFR) (OR = 0.83, 95% CI 0.52-1.33, P = 0.45), intraoperative complications (OR = 1.16, 95% CI 0.81-7.69, P = 0.88), operative time (MD = 4.09, 95% CI -15.08-23.26, P = 0.68) and hospitalization duration (MD = -0.13, 95% CI -0.32-0.06, P = 0.18). However, the incidence of postoperative complications was higher in UAS group (OR = 1.46, 95% CI 1.06-2.00, P = 0.02). Evidence from meta-analysis indicated that the use of UAS during ureteroscopy did not manifest advantages. However, given the intrinsic restrictions of the quality of selected articles, more randomized controlled trials (RCTs) are warranted to update the findings of this analysis.

Does green tea consumption increase urinary oxalate excretion? Results of a prospective trial in healthy men.

OBJECTIVE: To investigate the impact of green tea on urinary oxalate excretion in healthy male volunteers. MATERIALS AND METHODS: The oxalate concentrations after different brewing times (2-60 min) of different qualities (2-8 g) of green tea were measured in in vitro experiment. In in vivo experiment, the effects on urine composition were assessed in 12 healthy men with an age of 24-29 years. Each subject was requested to collect two 24-h urine samples under normal dietary conditions. Green tea prepared from tea bags containing 2 g of tea leafs was consumed by the subjects for 7 consecutive days, and 24-h urine samples were collected and analyzed on days 6 and 7. After 3-week washout interval, all subjects consumed green tea containing 4 g of leaf tea for another 7 consecutive days. Two 24-h urine samples were collected on the last 2 days. Urine volume, pH, calcium, magnesium, sodium, phosphate, potassium, chloride, citrate, oxalate, urate and creatinine were measured. RESULTS: In the in vitro experiments, oxalate in solution increased with brewing time (p < 0.05) and tea quality (p < 0.05). In the in vivo experiment, 24-h urinary oxalate increased significantly (0.24 ± 0.09 mmol to 0.32 ± 0.13 mmol, p = 0.045) when tea was prepared from 2-g bags of green leaf tea. Consumption of green tea containing 4 g of leaf tea resulted in 24-h urinary oxalate increase (0.25 ± 0.25 mmol to 0.34 ± 0.22 mmol, p = 0.041). CONCLUSIONS: In vitro studies showed that there was a gradual increase in solution concentrations of oxalate that was associated with increased brewing time and increased quality of green tea. Studies in normal men showed that green tea consumption was associated with increased urinary exertion of oxalate.

Integrative Analysis of miRNA and mRNA Expression Profiles in Calcium Oxalate Nephrolithiasis Rat Model.

The microRNA (miRNA) expression profiles and their biological functions in calcium oxalate nephrolithiasis remain unclear. In this study, we investigate the miRNA and mRNA expression profiles of kidney tissues in calcium oxalate stone rats. 16 Sprague Dawley rats were divided into control group and stone-forming group. 24-hour urine samples and kidney tissues were collected for biochemical and histological determination after 4 weeks. MiRNA and mRNA microarray were applied to evaluate the miRNA and mRNA expression profiles. To validate the microarray results, the quantitative real-time PCR (qRT-PCR) was performed. A total of 38 miRNAs and 2728 mRNAs were significantly and differentially expressed in kidney tissues of stone-forming group versus control group. Gene Ontology (GO) analysis revealed that most of the target genes were enriched in terms of oxidation reduction, ion transport, inflammatory response, and response to wounding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of these targets highlights their critical role in cytokine-cytokine receptor interaction, gap junction, and chemokine signaling pathway. Furthermore, the reliability of the microarray-based results was confirmed by using qRT-PCR determination. The miRNA and mRNA expressions in calcium oxalate stone rat kidneys might provide a basis for further research on urolithiasis mechanism.

Prevalence of Spirometra mansoni in dogs, cats, and frogs and its medical relevance in Guangzhou, China.

BACKGROUND: Sparganosis is an important parasitic disease in Guangzhou and is mainly acquired through the consumption of frog meat or contact with fresh frogs infected by larval stages (spargana) of the tapeworm species Spirometra mansoni. METHODS: In this study, the prevalence of intestinal S. mansoni infections (with adult parasites) in dogs and cats and of extraintestinal S. mansoni infections (with spargana) in frogs was assessed. In addition, a questionnaire survey was carried out among residents in Guangzhou City in order to evaluate their awareness about the medical and epidemiological relevance of Spirometra and sparganosis. RESULTS: In total, the feces of 229 dogs and 116 cats were examined for eggs, and 1949 frogs were examined for spargana. Sixty-three dogs (27.5%) and 47 cats (40.5%) had eggs in their feces. Two hundred and sixteen out of 416 wild Rana tigrina rugulosa Wiegmann frogs examined were sparganum-positive, with an infection rate of 51.9%, while the infection rate in Rana limnocharis Boie was 35.1% (13/37). None of the tested farmed frogs (including R. tigrina rugulosa and Rana catesbeiana) was positive (0/1382). Analysis of the questionnaire revealed the following results: (1) about 41.0% of residents in Guangzhou had some knowledge of sparganosis or sparganum infection, and information in TV programs was the most important way that residents learned about sparganosis. (2) About 59.9% of the residents ate frog meat. Eating the meat, viscera, or blood of animals, e.g., frogs, snakes, pigs, chicken, mice, and birds, in an improper way might be the main means by which residents acquire the infection. (3) The risk of sparganum infection was higher in males than in females. CONCLUSIONS: A high sparganum infection rate was observed in the wild frogs sold in agricultural product markets in Guangzhou. The infection was also serious in cats and dogs in Guangdong Province. With lifestyles and eating habits resulting in sparganum infection, it is necessary to focus on market management and community education in order to prevent the transmission of this disease in Guangzhou.