The harmful effects of overlooking acute bacterial prostatitis.

Prostatitis is a major urological disease affecting 25%-50% of men over their lifetime. However, prostatitis is often overlooked in nonurologic departments due to its sometimes indeterminate symptoms. In this review, we describe how to recognize and treat acute bacterial prostatitis, which manifests as a clinical problem in other departments as well as urology, to help prevent this disease from being overlooked. There are several possible negative effects of not recognizing acute bacterial prostatitis (ABP). First, initial treatment can fail. In the hyperacute phase, common antibiotics are often effective, but in rare cases, such antibiotics may not be effective. In addition, once ABP progresses to form a prostate abscess, potentially avoidable surgical interventions are often needed. A second issue is the transition to chronic prostatitis. If chronic bacterial prostatitis progresses, treatment requires long-term antibiotic administration and the response rate is not high. Some patients may have to deal with urinary tract infections for the rest of their lives. Finally, there is the problem of overlooking the underlying disease. ABP is rare in healthy adult men without underlying disease, including sexually transmitted diseases as well as benign prostatic hyperplasia, urinary stones, and malignant tumors, and may not be obvious. When examining patients with fever of unknown origin, it is necessary to exclude not only infectious diseases but also collagen diseases and malignant tumors. If there are any doubts, we recommend a rectal exam and consultation with a urologist.

An Antibody of the Secreted Isoform of Disintegrin and Metalloprotease 9 (sADAM9) Inhibits Epithelial-Mesenchymal Transition and Migration of Prostate Cancer Cell Lines.

Prostate cancer (PC) is the most common cancer diagnosed in men worldwide. Currently, castration-resistant prostate cancer (CRPC), which is resistant to androgen deprivation therapy, has a poor prognosis and is a therapeutic problem. We investigated the antitumor effects on PC of an antibody neutralizing secreted disintegrin and metalloproteinase domain-containing protein 9 (sADAM9), which is a blood-soluble form. We performed proliferation assays, wound healing assays, invasion assays, Western blot (WB), and an in vivo study in which a sADAM9 neutralizing antibody was administered intratumorally to PC-bearing mice. In invasion assays, the sADAM9 neutralizing antibody significantly inhibited invasion in all cell lines (TRAMP-C2: p = 0.00776, LNCaP: p = 0.000914, PC-3: p = 0.0327, and DU145: p = 0.0254). We examined epithelial-mesenchymal transition (EMT) markers, one of the metastatic mechanisms, in WB and showed downregulation of Slug in TRAMP-C2, LNCaP, and DU145 and upregulation of E-cadherin in TRAMP-C2 and PC-3 by sADAM9 neutralization. In mouse experiments, the sADAM9 neutralizing antibody significantly suppressed tumor growth compared to controls (1.68-fold in TRAMP-C2, 1.89-fold in LNCaP, and 2.67-fold in PC-3). These results suggested that the sADAM9 neutralizing antibody inhibits invasion, migration, and tumor growth in PC. Previous studies examined the anti-tumor effect of knockdown of total ADAM9 or sADAM9, but this study used the new technology of neutralizing antibodies for sADAM9. This may be novel because there was no animal study using a neutralizing antibody for sADAM9 to see the relationship between ADAM9 expression and prostate cancer.

Prediction of clinically significant prostate cancer through urine metabolomic signatures: A large-scale validated study.

PURPOSE: Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk. METHODS: Urine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC). RESULTS: In Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS. CONCLUSION: This urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk.

A comparison of the impact of the COVID-19 pandemic on urological surgeries in Japan and Taiwan.

OBJECTIVE: We report the impact of the COVID-19 pandemic on urological surgeries and hospital policies at two hospitals in Japan and Taiwan. METHODS: We retrospectively surveyed the number of surgeries every 3 months in the Urology Department of Kobe University Hospital (KUH), Kobe, Japan before (January 2019-March 2020) and after (April 2020-September 2021) the COVID-19 outbreak, and in the Urology Department of Shuang Ho Hospital, Taipei Medical University (SHH-TMU), Taiwan before (January 2021-March 2021) and after (April 2021-September 2021) the outbreak, and compared the averages and types of surgery. RESULTS: In Kobe, COVID-19 patients were stratified such that other regional hospitals gave priority to treating COVID-19 while KUH gave priority to treating non-COVID-19 patients. In KUH, the number of surgeries did not change significantly, 237.2 ± 29.6 versus 246.3 ± 20.8 (p = 0.453). In Taiwan COVID-19 patients increased sharply in May 2021, and teaching hospitals in Taiwan were obliged to provide 20% of their total beds for COVID-19 patients. At SHH-TMU, there was a 33.3% drop in the number of surgeries during April-June 2021 compared to the pre-pandemic average. However, no significant changes were observed, 423.4 ± 68.4 versus 373 ± 91.0 (p = 0.298), because of the subsequent success in controlling the COVID-19 infection. CONCLUSIONS: The comparison of infection control measures between the two countries revealed that while both KUH and SHH-TMU successfully maintained the number of surgeries, the reasons for this were different for each.

p-Synephrine Indicates Internal Maturity of Citrus grandis (L.) Osbeck cv. Mato Peiyu-Reclaiming Functional Constituents from Nonedible Parts.

The processing of Citrus grandis Osbeck cv. Mato Peiyu (CGMP) fruits generates a considerable amount of waste, mainly the flavedo, albedo, and segment membrane; the generated waste yields severe environmental and economic challenges. In this study, we tried to reclaim some functional chemicals from the waste. Our data indicated that the essential oil content in the flavedo was 0.76-1.34%, with the major component being monoterpenes (93.75% in August, declining to 85.56% in November, including mainly limonene (87.08% to 81.12%) and others such as ß-myrcene). p-Synephrine (mg/100 g dry weight) declined accordingly (flavedo, 10.40 to 2.00; albedo, 1.80 to 0.25; segment membrane, 0.3 in August, 0.2 in September, and none since October). Polyphenols (in µg/g) included gallic acid (70.32-110.25, 99.27-252.89, and 105.78-187.36, respectively); protocatechuic acid (65.32-204.94, 26.35-72.35, and 214.98-302.65, respectively), p-coumaric acid (30.63-169.13, 4.32-17.00, and 6.68-34.32, respectively), ferulic acid (12.36-39.36, 1.21-10.25, and 17.07-39.63, respectively), and chlorogenic acid (59.19-199.36, 33.08-108.57, and 65.32-150.14, respectively). Flavonoids (in µg/g) included naringin (flavedo, 89.32-283.19), quercetin (181.05-248.51), nobiletin (259.75-563.7), hesperidin, and diosmin. The phytosterol content (mg/100 g) was 12.50-44.00 in the flavedo. The total dietary fiber in the segment membrane was 57 g/100 g. The antioxidant activity against the DPPH• and ABTS+• free radicals was moderately high. In conclusion, the waste of CGMP fruits is worth reclaiming for essential oil, p-synephrine, polyphenolics, and dietary fiber. Notably, p-synephrine content (flavedo: <8 mg/100 g dry weight, albedo: <2.0, or segment membrane: <0.4 mg) can serve as a marker of the internal maturation of CGMP fruits.

The intraureteral placement of the stent's distal end decreases stent-related urinary symptoms: a prospective randomized clinical trial.

PURPOSE: We compared intraureteral stent placement (CIU-SP) with conventional stent placement (C-SP) regarding the stent-related symptoms. METHODS: We randomized patients who underwent ureteroscopic lithotripsy into two groups. In CIU-SP group, a 16-cm or 18-cm stent was placed with its distal end above the ureterovesical junction. In C-SP group, a 22-cm or 24-cm stent was placed in a conventional method. Stent-related symptoms were assessed with the Ureteral Stent Symptom Questionnaire (USSQ) before the stent was removed, around 7 days after the operation. The primary outcome was the urinary symptoms; the secondary outcomes included postoperative pain and quality of life. RESULTS: We randomized 103 patients, of which 91 (45 in CIU-SP and 46 in C-SP) entered the final analysis. Regarding the primary endpoint, the CIU group had less urinary symptoms; the mean USSQ urinary symptom score was significantly lower in the CIU-SP versus C-SP group (25.5 ± 6.3 vs 31.7 ± 5.9, P < 0.001). The CIU-SP group also had more favorable profiles in the following outcomes: lower USSQ body pain score (15.5 ± 5.3 vs 20.1 ± 5.2, P < 0.001), lower overall pain score (3.2 ± 2.2 vs 5.7 ± 2.3, P < 0.001), less number of pain site (1.0 ± 0.9 vs 1.7 ± 0.9, P = 0.001, lower USSQ general health score (10.4 ± 3.7 versus 13.9 ± 3.4, P < 0.001), and lower USSQ work performance score (5.2 ± 3.3 versus 6.7 ± 2.8, P = 0.033). In either group, there was no complication of Clavien-Dindo Class 2 or greater. CONCLUSION: The complete intraureteral placement significantly decreases stent-related urinary symptoms and pain. It is also associated with better postoperative general health condition and is less likely to limit physical activity and work ability.

Volatile Variation of Theobroma cacao Malvaceae L. Beans Cultivated in Taiwan Affected by Processing via Fermentation and Roasting.

After being harvested, cacao beans are usually subjected to very complex processes in order to improve their chemical and physical characteristics, like tastefulness with chocolate characteristic flavors. The traditional process consists of three major processing stages: fermentation, drying, and roasting, while most of the fermentation is carried out by an on-farm in-box process. In Taiwan, we have two major cocoa beans, the red and the yellow. We proposed that the major factor affecting the variation in tastes and colors in the finished cocoa might be the difference between cultivars. To uncover this, we examined the effect of the three major processes including fermentation, drying and roasting on these two cocoa beans. Results indicated that the two cultivars really behaved differently (despite before or after processing with fermentation, drying, and roasting) with respect to the patterns of fatty acids (palmitic, stearic, oleic, and arachidonic); triacylglycerols:1,2,3-trioleoyl-glycerol (OOO); 1-stearoyl-2,3-oleoyl-glycerol (SOO); 1-stearoyl-sn-2-oleoyl-3-arachidoyl- glycerol (SOA); 1,3-distearyol-sn-2-oleoyl-glycerol (SOS); organic acids (citric, tartaric, acetic, and malic); soluble sugars (glucose and fructose); amino acids; total phenolics; total flavonoids; and volatiles. Our findings suggest that to choose specific processing conditions for each specific cocoa genotype is the crucial point of processing cocoa with consistent taste and color.

Molecular Action Mechanism of Coixol from Soft-Shelled Adlay on Tyrosinase: The Future of Cosmetics.

Coix lacryma-jobi var. ma-yuen L. Gramineae is widely cultivated in Taiwan. Literature regarding the molecular action mechanism of coixol on tyrosinase and the application of coicis seed extracts to the processing of facial masks is still lacking. Solvent extractability analysis revealed that most of the polyphenolics in coicis seeds were water soluble (3.17 ± 0.12 to 3.63 ± 0.07 µg/mLGAE). In contrast, the methanolic extract contained the most flavonoids (0.06 ± 0.00~0.26 ± 0.03 µg/mL QE) and coixol (11.43 ± 0.13~12.83 ± 0.14 µg/mL), showing potent antioxidant capability. Additionally, the contents of coixenolide (176.77 ± 5.91 to 238.60 ± 0.21 µg/g), phytosterol (52.45 ± 2.05 to 58.23 ± 1.14 mg/g), and polysaccharides (3.42 ± 0.10 to 4.41 ± 0.10 mg/g) were rather high. The aqueous extract (10 µg/mL) and the ethanolic extract (1 mg/mL) showed no cytotoxicity to B16F10 melanocytes. More attractively, the ethanolic extract at 1 mg/mL caused 48.4% inhibition of tyrosinase activity in B16F10 melanocytes, and 50.7% on human tyrosinase (hTyr) fragment 369-377. Conclusively, the coicis seed extracts containing abundant nutraceuticals with promising anti-hTyr activity and moisturizing capability can serve as good ingredients for facial mask processing.

The modulating effect of dietary protein intake on mortality in long-term hemodialysis patients: A nationwide population-based study.

AIMS OF THE STUDY: A high prevalence of protein-energy wasting and malnutrition among uremic patients is associated with an increase in morbidity and mortality. We aimed to investigate the modulating effect of daily dietary protein intake (DPI) evaluated by normalised protein catabolic rate (nPCR) on mortality in long-term haemodialysis (HD) patient from a nationwide population-based study. METHODS USED TO CONDUCT THE STUDY: By Taiwan Renal Registry Data System between 2005 and 2012, we divided the long-term HD patients into average nPCR < 1.2 and nPCR ≥ 1.2 groups according to the current guideline. The relation of nPCR with three-year all-cause and cardiovascular (CV) mortality were evaluated. The cox regression method for predicted mortality by nPCR was used. RESULTS OF THE STUDY: Among 88 330 HD patients, 58 122 (65.8%) patients were in average nPCR < 1.2 group and 30 208 (34.2%) in average nPCR ≥ 1.2 group. Both all-cause and cardiovascular (CV) mortality risks were increased in nPCR < 1.2 group after adjusting for demographics and laboratories cofactors in our multivariate cox regression model. Patients with nPCR < 1.2 and albumin ≥ 3.7 had a higher adjusted hazard ratio (aHR) for all-cause and CV mortality (1.16 [95% confidence interval (CI): 1.07-1.25, P < .001]; 1.15 [95% CI: 1.02-1.31, P = .03], respectively), compared with the reference group with nPCR ≥ 1.2 and albumin ≥ 3.7. Interestingly, there was no difference in mortality risk between low DPI subgroup (nPCR < 1.2 and Alb < 3.7) and the reference group (nPCR ≥ 1.2 and Alb < 3.7). Further stratification analysis revealed that low DPI subgroup (nPCR < 1.2, Alb ≥ 3.7 and TC ≥ 150) had an increased risk of both all-cause and CV mortality (aHR 1.14 [95% CI: 1.04-1.25, P = .005]; aHR 1.17 [95% CI: 1.02-1.35, P = .026], respectively). CONCLUSIONS DRAWN FROM THE STUDY: Low DPI (as presented by nPCR) independently correlated with all-cause and CV mortality among HD patients. Mortality risks were higher in low DPI patients even with normoalbuminaemia and non-hypocholesterolaemia. Further investigations on the importance of increasing DPI in HD patients is warranted.

AXL is crucial for E1A-enhanced therapeutic efficiency of EGFR tyrosine kinase inhibitors through NFI in breast cancer.

AXL which is a chemosensitizer protein for breast cancer cells in response to epidermal growth factor receptor-tyrosine kinase inhibitor and suppresses tumor growth. The clinical information show nuclear factor I (NFI)-C and NFI-X expression correlate with AXL expression in breast cancer patients. Following, we establish serial deletions of AXL promoter to identify regions required for Adenovirus-5 early region 1A (E1A)-mediated AXL suppression. All of the NFI family members were extensively studied for their expression and functions in regulating AXL. Moreover, E1A post-transcriptionally downregulates AXL expression through NFI. NFI-C and NFI-X, not NFI-A and NFI-B, resulting in cell death in response to EGFR-TKI. Our finding suggests that NFI-C and NFI-X are crucial regulators for AXL and significantly correlated with poor survival of breast cancer patients.

Can ultrasound irradiation be a therapeutic option for prostate cancer?

BACKGROUND: Focal therapies for prostate cancer (PC) can reduce adverse events and do not lead to androgen-independent progression. Ultrasound could be used for cancer treatments if the repetition frequency is fitted to the purpose. We investigated the possible therapeutic effect of ultrasound irradiation on PC cells. MATERIALS AND METHODS: We irradiated two PC cell lines, androgen-dependent LNCaP and -independent PC-3 with ultrasound (3.0 W/cm2 , 3 MHz, irradiation time rate: 20%) for 2 minutes for 1 day or 3 consecutive days at a repetition frequency of 1, 10, or 100 Hz in vitro. Cell proliferation and apoptosis were determined after irradiation. RESULTS: Cell proliferation of PC-3 was significantly inhibited after 1 day (P < .0001) and 3 days (P < .0001) of 10 Hz ultrasound irradiation, and that of LNCaP after 1 day (P < .0001) and 3 days (P < .0001) of irradiation. LNCaP was more sensitive to ultrasound at both lower and higher cell density but PC-3 was only sensitive at a lower cell density (P < .01). Irradiation with 10 Hz ultrasound-induced significantly more PC-3 apoptotic cells than control (1 day, P = .0137; 3 days, P = .0386) rather than irradiation with 1 Hz. Apoptosis via caspase-3 was induced at 10 Hz in 1-day (P < .05) irradiation in both cell lines. CONCLUSIONS: Ultrasound irradiation with even 1 day of 10 Hz significantly inhibited cell proliferation in both LNCaP and PC-3, especially by the remarkable induction of apoptosis in vitro. Our study indicated that ultrasound irradiation can be a therapeutic option for PC and further studies in vivo will be undertaken.

Testosterone regulates the intracellular bacterial community formation of uropathogenic Escherichia coli in prostate cells via STAT3.

BACKGROUND: UPEC can internalize clonally in prostate to form biofilm-like intracellular bacterial communities (IBCs) for recurrent or chronic infection. We previously indicated that the exposure of prostate cells to testosterone could suppress UPEC invasion and their persistent survival within cells by effectively inhibiting the JAK/STAT1 signaling pathway. However, the regulatory mechanism by which testosterone affects UPEC-induced prostatitis via STAT3, another latent transcription factor signaling pathway is still unclear. The present study aimed to clarify the role of STAT3 in the process of UPEC-induced inflammation and colonization in prostate epithelial cells. METHODS: The effects of testosterone-mediated inhibition were compared between the prostatitis by different UPEC strains (CFT073 and J96) through the specific GFP-UPEC-infected prostate cell model. Fluorescence microscopy was used for UPEC IBCs detection and quantifying, and Flow cytometry, RT-PCR and western blotting were used for analyzing related gene and protein expressions. Pretreatment of JAK and STAT3 inhibitors were also applied to verify the regulation of transduction pathway in testosterone-mediated anti-UPEC infection. RESULTS: This study revealed that testosterone effectively suppresses UPEC infection and IBC formation in prostate cells through the JAK/STAT3 pathway. The results show that CFT073 and J96 UPEC infection rates and colony numbers were dose-dependently reduced in RWPE-1 cells pretreated with 5 and 20 µg/mL testosterone at 0 and 24 h post-infection. Further, testosterone reduced the amounts of UPEC infecting and surviving within the prostate cells, as well as suppressed the size of IBCs formed. We demonstrated that pretreating testosterone effectively inhibited UPEC infection along with dose-dependent suppression of STAT3 and the phosphorylated-STAT3 expression in prostate cells, especially in 24 h J96 UPEC infected groups. The STAT inhibitor, SOCS3 also up-regulated at the same time. In addition, we pretreated the JAK1 or STAT3 inhibitor with testosterone to block the signaling transduction before CFT073 and J96 UPEC infection, and found the significant restoring in both the sizes of IBCs and bacterial numbers in RWPE-1 cells. Therefore, our results suggest that the suppression of STAT3 by testosterone treatment attenuate UPEC growing within IBCs and interfere with their infection to prostate cells. CONCLUSIONS: Overall, our study demonstrates that testosterone suppresses the initial infection of prostate epithelial cells by UPEC and reduces the survival of UPEC within IBCs after infection. These results indicate a critical role for STAT3 in facilitating UPEC infection and persistence, and its participation in driving testosterone-suppressive responses in prostate epithelial cells. In conclusion, this study suggests that testosterone may be beneficial in treating clinically recurrent UPEC infections and, thus, the persistent recurrence of prostatic inflammation.

Effect of Preoperative Dutasteride on Holmium Laser Enucleation of the Prostate.

PURPOSE: The aim of this study was to compare and investigate the efficacy of using the 5α-reductase inhibitor dutasteride after holmium laser enucleation of the prostate (HoLEP) to improve postoperative urination and surgery-related complications. METHODS: This is a retrospective observational study comparing patients who received or did not receive 5α-reductase inhibitors prior to HoLEP. Of a total of 270 patients, 40 received the 5α-reductase inhibitor dutasteride. We compared the factors including age, postoperative maximal flow rate (MFR; mL/s), postoperative prostate-specific antigen (PSA) (ng/mL), preoperative MFR (mL/s), preoperative PSA (ng/mL), prostate cancer (%), operative time (min), preoperative residual urine (mL), postoperative residual urine (mL), urinary incontinence (day 1; %), urinary incontinence (1 month; %), urinary incontinence (3 months; %), urethral catheter indwelling period (days), morcellation time (min), enucleation time (min), intraoperative complications (%), postoperative complications (%), prostate volume (mL), enucleated weight (g), and hospitalization period (days). RESULTS: Postoperative PSA (p = 0.0071), morcellation time (p = 0.0444), postoperative complications (p = 0.0350) and prostate volume (p = 0.0069), but not enucleated prostate weight (p = 0.8809), were significantly lower in the dutasteride group. Importantly, enucleation efficiency and morcellation efficiency did not show any significant difference between the dutasteride and the non-dutasteride groups. CONCLUSIONS: Use of a preoperative 5α-reductase inhibitor significantly correlated with surgery-related factors, with less morcellation time, fewer postoperative complications, and lower postoperative PSA. Surgeons performing HoLEP may wish to take these findings into account.

Surgical outcome of anatomical endoscopic enucleation of the prostate: A systemic review and meta-analysis.

An increasing number of evidences demonstrate the safety and efficacy of endoscopic enucleation of the prostate (EEP) using various energy devices. We performed a systemic literature search for all relevant randomised controlled trials (RCTs) comparing any EEP technique with TURP or open prostatectomy (OP). A total of 21 RCTs with 2,957 patients were included; the majority were studies of holmium laser or bipolar diathermy. Compared to TURP, EEP resulted in greater improvement in IPSS (MD: -0.56, 95% CI: -0.90 to -0.23), PVR (MD: -2.24, 95% CI: -4.45 to -0.03) and Qmax (MD: -1.07, 95% CI: -1.53 to -0.61). EEP was associated with more prostate tissue removed (MD: -9.73, 95% CI: -15.71 to -3.75), less haemoglobin loss (MD: -0.47, 95% CI: -0.70 to -0.23), shorter catheterisation time (MD: -22.82, 95% CI: -30.11 to -15.52) and shorter length of hospitalisation (MD: -1.05, 95% CI: -1.33 to -0.78). Compared to OP, EEP resulted in equivalent functional outcomes. However, EEP was associated with less haemoglobin loss (MD: -1.17, 95% CI: -1.98 to -0.37), shorter catheterisation time (MD: -89.74, 95% CI: -112.60 to -66.88) and shorter length of hospitalisation (MD: -3.91, 95% CI: -4.63 to -3.60). The current evidence supports that EEP can be considered as a new standard of the surgical management for BPH.

Bicalutamide Elicits Renal Damage by Causing Mitochondrial Dysfunction via ROS Damage and Upregulation of HIF-1.

Combined androgen blockade using bicalutamide (Bic) is a therapeutic choice for treating prostate cancer (PCa). However, even at regular clinical dosages, Bic frequently shows adverse effects associated with cardiovascular and renal damage. Previously, we found that Bic selectively damaged mesangial cells compared to tubular cells and in an in vivo rat model, we also found renal damage caused by Bic. In the present study, a rat mesangial cell model was used to further the investigation. Results indicated that Bic enhanced lactate dehydrogenase release, reactive oxygen species (ROS) production, lysosome population and kidney injury molecule-1 and decreased N-cadherin. Bic elicited mitochondrial swelling and reduced the mitochondrial potential, resulting in severe suppression of the oxygen consumption rate (OCR), maximum respiration and ATP production. The hypoxia-inducible factor (HIF)-1 transcriptional activity and messenger RNA were significantly upregulated in dose-dependent manners. The HIF-1 protein reached a peak value at 24 h then rapidly decayed. BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 and cleaved caspase-3 were dose-dependently upregulated by Bic (60 M) and that eventually led to cell apoptosis. It is suggested that Bic induces renal damage via ROS and modulates HIF-1 pathway and clinically, some protective agents like antioxidants are recommended for co-treatment.

Nifedipine Upregulates ATF6-α, Caspases -12, -3, and -7 Implicating Lipotoxicity-Associated Renal ER Stress.

Nifedipine (NF) is reported to have many beneficial effects in antihypertensive therapy. Recently, we found that NF induced lipid accumulation in renal tubular cells. Palmitic acid-induced renal lipotoxicity was found to be partially mediated by endoplasmic reticular (ER) stress, while it can also be elicited by NF in kidney cells; we examined the induction of suspected pathways in both in vitro and in vivo models. NRK52E cells cultured in high-glucose medium were treated with NF (30 µM) for 24-48 h. ER stress-induced lipotoxicity was explored by staining with thioflavin T and Nile red, transmission electron microscopy, terminal uridine nick-end labeling, and Western blotting. ER stress was also investigated in rats with induced chronic kidney disease (CKD) fed NF for four weeks. NF induced the production of unfolded protein aggregates, resulting in ER stress, as evidenced by the upregulation of glucose-regulated protein, 78 kDa (GRP78), activating transcription factor 6α (ATF6α), C/EBP-homologous protein (CHOP), and caspases-12, -3, and -7. In vitro early apoptosis was more predominant than late apoptosis. Most importantly, ATF6α was confirmed to play a unique role in NF-induced ER stress in both models. CKD patients with hypertension should not undergo NF therapy. In cases where it is required, alleviation of ER stress should be considered to avoid further damaging the kidneys.

Nifedipine Exacerbates Lipogenesis in the Kidney via KIM-1, CD36, and SREBP Upregulation: Implications from an Animal Model for Human Study.

Dysregulation of fatty acid oxidation and accumulation of fatty acids can cause kidney injury. Nifedipine modulates lipogenesis-related transcriptional factor SREBP-1/2 in proximal tubular cells by inhibiting the Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway in vitro. However, the mechanisms by which nifedipine (NF) modulates lipotoxicity in vivo are unclear. Here, we examined the effect of NF in a doxorubicin (DR)-induced kidney injury rat model. Twenty-four Sprague-Dawley rats were divided into control, DR, DR+NF, and high-fat diet (HFD) groups. The DR, DR+NF, and HFD groups showed hypertension and proteinuria. Western blotting and immunohistochemical analysis showed that NF significantly induced TNF-α, CD36, SREBP-1/2, and acetyl-CoA carboxylase expression and renal fibrosis, and reduced fatty acid synthase and AMPK compared to other groups (p < 0.05). Additionally, 18 patients with chronic kidney disease (CKD) who received renal transplants were enrolled to examine their graft fibrosis and lipid contents via transient elastography. Low-density lipoprotein levels in patients with CKD strongly correlated with lipid contents and fibrosis in grafted kidneys (p < 0.05). Thus, NF may initiate lipogenesis through the SREBP-1/2/AMPK pathway and lipid uptake by CD36 upregulation and aggravate renal fibrosis in vivo. Higher low-density lipoprotein levels may correlate with renal fibrosis and lipid accumulation in grafted kidneys of patients with CKD.

Astaxanthin Protects PC12 Cells against Homocysteine- and Glutamate-Induced Neurotoxicity.

Memory impairment has been shown to be associated with glutamate (Glu) excitotoxicity, homocysteine (Hcy) accumulation, and oxidative stress. We hypothesize that Glu and Hcy could damage neuronal cells, while astaxanthin (ATX) could be beneficial to alleviate the adverse effects. Using PC12 cell model, we showed that Glu and Hcy provoked a huge amount of reactive oxygen species (ROS) production, causing mitochondrial damage at EC50 20 and 10 mm, respectively. The mechanisms of action include: (1) increasing calcium influx; (2) producing ROS; (3) initiating lipid peroxidation; (4) causing imbalance of the Bcl-2/Bax homeostasis; and (5) activating cascade of caspases involving caspases 12 and 3. Conclusively, the damages caused by Glu and Hcy to PC12 cells can be alleviated by the potent antioxidant ATX.

Ultrasound-guided versus fluoroscopy-guided percutaneous nephrolithotomy: a systematic review and meta-analysis.

PURPOSE: To evaluate the efficacy and safety of ultrasound-guided (UG) versus fluoroscopy-guided (FG) percutaneous nephrolithotomy (PCNL). METHODS: A systematic search of PubMed (MEDLINE), Embase, and the Cochrane Library was conducted to identify randomized controlled trials that compared UG-PCNL with FG-PCNL, and a meta-analysis of those studies was completed. The primary outcomes assessed were stone-free rate (SFR) and complication rate. Secondary outcomes assessed were the successful access-creation rate, time necessary for entrance into the target calyx, auxiliary procedure rate, transfusion rate, hemoglobin decrease after surgery, surgery duration, and hospital stay. RESULTS: Eight studies comprising 966 patients were included in the meta-analysis. Compared with FG-PCNL, UG-PCNL had comparable stone-free rates [odds ratio (OR) 0.95; 95% confidence interval (CI) 0.67-1.35; p = 0.79] irrespective of the patient's position, and a favorable safety profile resulting in a lower complication rate (OR 0.56; 95% CI 0.36-0.86; p = 0.009). No statistical difference was found between UG and FG groups in secondary outcomes. CONCLUSIONS: UG-PCNL is as effective as FG-PCNL and has the advantage of lower complication rates. In addition, UG-PCNL could be performed with patients in the supine position without compromising its efficacy.

Nifedipine Modulates Renal Lipogenesis via the AMPK-SREBP Transcriptional Pathway.

Lipid accumulation in renal cells has been implicated in the pathogenesis of obesity-related kidney disease, and lipotoxicity in the kidney can be a surrogate marker for renal failure or renal fibrosis. Fatty acid oxidation provides energy to renal tubular cells. Ca2+ is required for mitochondrial ATP production and to decrease reactive oxygen species (ROS). However, how nifedipine (a calcium channel blocker) affects lipogenesis is unknown. We utilized rat NRK52E cells pre-treated with varying concentrations of nifedipine to examine the activity of lipogenesis enzymes and lipotoxicity. A positive control exposed to oleic acid was used for comparison. Nifedipine was found to activate acetyl Coenzyme A (CoA) synthetase, acetyl CoA carboxylase, long chain fatty acyl CoA elongase, ATP-citrate lyase, and 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase, suggesting elevated production of cholesterol and phospholipids. Nifedipine exposure induced a vast accumulation of cytosolic free fatty acids (FFA) and stimulated the production of reactive oxygen species, upregulated CD36 and KIM-1 (kidney injury molecule-1) expression, inhibited p-AMPK activity, and triggered the expression of SREBP-1/2 and lipin-1, underscoring the potential of nifedipine to induce lipotoxicity with renal damage. To our knowledge, this is the first report demonstrating nifedipine-induced lipid accumulation in the kidney.