Renal pedicle lymphatic ligation for non-parasitic chyluria via retroperitoneal laparoscopic surgery: a single-center 12-year experience.

Background: Chyluria is a rare disease in which chylous is excreted in the urine. Currently, management of chyluria includes conservative treatments and surgical measures. This study aimed to report our experience in treating non-parasitic chyluria with retroperitoneal laparoscopic ligation of the renal lymphatic vessels. Methods: Data from 52 patients who underwent retroperitoneoscopic ligation of the renal lymphatic vessels for non-parasitic chyluria between December 2009 and May 2022 were reviewed. After general anesthesia, the patients were passively placed in the healthy lateral decubitus position and underwent three-port retroperitoneal laparoscopy. Detailed medical data, including demographic characteristics, intraoperative outcomes, postoperative data, and complications, were reviewed. Results: Fifty-two patients received surgery treatment at our institution. The mean disease course was 89.3 months. The mean age was 58.8 years, with females accounting for 57.7% (30/52); the majority of patients (33/52) had the laterality of chyluria on the left and 9 (17.3%) had a history of previous thoracic or abdominal surgery. Compared with the urine and blood data before the operation and on the first day after the operation, urinary protein, urinary tract infection, urinary red blood cells, hemoglobin, albumin, and serum total protein significantly improved 3 months after the operation. However, there were no significant differences in blood creatinine and blood urea nitrogen levels among the three groups. The mean surgery time was about 110.0 minutes, and the estimated total blood loss was 81.2 mL. The postoperative drainage volume was 229.9 mL. The average time to start a liquid diet and to be out of bed were 1.5 and 1.9 days, respectively. Transient postoperative gross hematuria occurred in eight patients, and complications occurred in five patients after surgery. The mean length of hospitalization was 6.6 days. The follow-up duration ranged from 3 to 152 months, and except for three patients who did not respond to treatment, the remaining patients had no recurrence and did not require reoperation. Conclusions: Our long-term follow-up results showed that renal pedicle lymphatic ligation via retroperitoneal laparoscopic surgery is an effective, safe, and reliable surgical option for patients with non-parasitic chyluria.

Knockdown of lncRNA MALAT1 attenuates renal interstitial fibrosis through miR-124-3p/ITGB1 axis.

Renal interstitial fibrosis (RIF) considered the primary irreversible cause of chronic kidney disease. Recently, accumulating studies demonstrated that lncRNAs play an important role in the pathogenesis of RIF. However, the underlying exact mechanism of lncRNA MALAT1 in RIF remains barely known. Here, the aim of our study was to investigate the dysregulate expression of lncRNA MALAT1 in TGF-ß1 treated HK2/NRK-49F cells and unilateral ureteral obstruction (UUO) mice model, defining its effects on HK2/NRK-49F cells and UUO mice fibrosis process through the miR-124-3p/ITGB1 signaling axis. It was found that lncRNA MALAT1 and ITGB1 was significantly overexpression, while miR-124-3p was downregulated in HK2/NRK-49F cells induced by TGF-ß1 and in UUO mice model. Moreover, knockdown of lncRNA MALAT1 remarkably downregulated the proteins level of fibrosis-related markers, ITGB1, and upregulated the expression of epithelial marker E-cadherin. Consistently, mechanistic studies showed that miR-124-3p can directly binds to lncRNA MALAT1 and ITGB1. And the protect effect of Len-sh-MALAT1 on fibrosis related protein levels could be partially reversed by co-transfected with inhibitor-miR-124-3p. Moreover, the expression trend of LncRNA MALAT1/miR-124-3p/ITGB1 in renal tissues of patients with obstructive nephropathy (ON) was consistent with the results of cell and animal experiments. Taken together, these results indicated that lncRNA MALAT1 could promote RIF process in vitro and in vivo via the miR-124-3p/ITGB1 signaling pathway. These findings suggest a new regulatory pathway involving lncRNA MALAT1, which probably serves as a potential therapeutic target for RIF.

High-Performance Solar-Blind Ultraviolet Photodetectors Based on ß-Ga2O3 Thin Films Grown on p-Si(111) Substrates with Improved Material Quality via an AlN Buffer Layer Introduced by Metal-Organic Chemical Vapor Deposition.

We have achieved significantly improved device performance in solar-blind deep-ultraviolet photodetectors fabricated from ß-Ga2O3 thin films grown via metal-organic chemical vapor deposition (MOCVD) on p-Si(111) substrates by improving material quality through the use of an AlN buffer layer. High-structural-quality ß-Ga2O3 films with a (-201) preferred orientation are obtained after the introduction of the AlN buffer. Under 3 V bias, the dark current reaches a minimum of 45 fA, and the photo-to-dark current ratio (PDCR) reaches 8.5 × 105 in the photodetector with the metal-semiconductor-metal (MSM) structure. The peak responsivity and detectivity are 38.8 A/W and 2.27 × 1015 cm·Hz1/2/W, respectively, which are 16.5 and 230 times that without the buffer layer. Additionally, benefiting from the introduction of the AlN layer, the photodetection performance of the ß-Ga2O3/AlN/Si heterojunction is significantly improved. The PDCR, peak responsivity, and detectivity for the ß-Ga2O3/AlN/p-Si photodetector at 5 V bias are 2.7 × 103, 11.84 A/W, and 8.31 × 1013 cm·Hz1/2/W, respectively. The improved structural quality of ß-Ga2O3 is mainly attributed to the decreased in-plane lattice mismatch of 2.3% for ß-Ga2O3(-201)/AlN(002) compared to that of 20.83% for ß-Ga2O3(-201)/Si(111), as well as the elimination of the native amorphous SiOx surface layer on the Si substrate during the initial growth of oxide thin films.

KIF11 is a potential prognostic biomarker and therapeutic target for adrenocortical carcinoma.

Background: Adrenocortical carcinoma (ACC) is a rare endocrine neoplasia with poor prognosis. Emerging evidence suggests that kinesin family member 11 (KIF11) protein is overexpressed in several tumors and associated with the onset and progression of certain types of cancer; however, its biological functions and mechanisms in ACC progression have not been studied yet. Therefore, this study evaluated the clinical significance and therapeutic potential of the KIF11 protein in ACC. Methods: The Cancer Genome Atlas (TCGA) database (n=79) and Genotype Tissue Expression (GTEx) database (n=128) were utilized to explore the expression of KIF11 in ACC and normal adrenal tissues. The TCGA datasets were then data mined and statistically analyzed. R survival analysis and univariate and multivariate Cox regression analyses were used to evaluate the effect of KIF11 expression on the survival rates, and a nomogram was used to predict its impact on prognosis. The clinical data from 30 ACC patients' from Xiangya Hospital were also analyzed. The effects of KIF11 on the proliferation and invasion of ACC NCI-H295R were further validated in vitro. Results: Analytical data from the TCGA and GTEx databases showed that KIF11 expression was upregulated in ACC tissues and associated with T (primary tumor), and M (metastasis) and stages of tumor progression. Increased KIF11 expression was significantly associated with shorter overall survival, disease-specific survival, and progression-free intervals. Clinical data from Xiangya Hospital illustrated that increased KIF11 had a significantly positive correlation with shorter overall survival, T and pathological stages, and tumor recurrence risk. Monastrol, a specific inhibitor of KIF11, was further confirmed to significantly inhibit the proliferation and invasion of ACC NCI-H295R cell in vitro. The nomogram demonstrated KIF11 was an excellent predictive biomarker in patients with ACC. Conclusions: The findings demonstrate that KIF11 could be a predictor of poor prognosis and thus possibly serve as a novel therapeutic target for ACC.

Rapid Response Solar Blind Deep UV Photodetector with High Detectivity Based On Graphene:N/ßGa2 O3 :N/GaN p-i-n Heterojunction Fabricated by a Reversed Substitution Growth Method.

This work reports a high-detectivity solar-blind deep ultraviolet photodetector with a fast response speed, based on a nitrogen-doped graphene/ßGa2 O3 /GaN p-i-n heterojunction. The i layer of ßGa2 O3 with a Fermi level lower than the central level of the forbidden band of 0.2 eV is obtained by reversed substitution growth with oxygen replacing nitrogen in the GaN matrix, indicating the majority carrier is hole. X-ray diffractometershows that the transformation of GaN into ßGa2 O3 with (-201) preferred orientation at temperature above 900 °C in an oxygen ambient. The heterojunction shows enhanced self-powered solar blind detection ability with a response time of 3.2 µs (rise)/0.02 ms (delay) and a detectivity exceeding 1012 Jones. Under a reverse bias of -5 V, the photoresponsivity is 8.3 A W-1 with a high Ilight /Idark ratio of over 106 and a detectivity of ≈9 × 1014 Jones. The excellent performance of the device is attributed to 1) the continuous conduction band without a potential energy barrier, 2) the larger built-in potential in the heterojunction because of the downward shift of Fermi energy level in ß-Ga2 O3 , and 3) an enhanced built-in electric field in the ßGa2 O3 due to introducing p-type graphene with a high hole concentration of up to ≈1020 cm-3 .

A high responsivity, high detectivity, and high response speed MSM UVB photodetector based on SnO2 microwires.

We report a high performance UVB photodetector with a metal-semiconductor-metal device structure based on high crystal quality SnO2 microwires prepared by chemical vapor deposition. Under 10 V bias, a low dark current of 3.69 × 10-9 A and a high light-to-dark current ratio of 1630 were achieved. The device showed a high responsivity of about 1353.0 A·W-1 under 322 nm light illumination. The detectivity of the device is as high as 5.4 × 1014 Jones, which ensures the detection of weak signals in the UVB spectral region. Due to the small amount of deep-level defect-induced carrier recombination, the light response rise time and fall time are shorter than 0.08 s.

Antioxidant Carboxymethyl Chitosan Carbon Dots with Calcium Doping Achieve Ultra-Low Calcium Concentration for Iron-Induced Osteoporosis Treatment by Effectively Enhancing Calcium Bioavailability in Zebrafish.

Iron overloads osteoporosis mainly occurs to postmenopausal women and people requiring repeated blood transfusions. Iron overload increases the activity of osteoclasts and decreases the activity of osteoblasts, leading to the occurrence of osteoporosis. Conventional treatment options include calcium supplements and iron chelators. However, simple calcium supplementation is not effective, and it does not have a good therapeutic effect. Oxidative stress is one of the triggers for osteoporosis. Therefore, the study focuses on the antioxidant aspect of osteoporosis treatment. The present work revealed that antioxidant carboxymethyl chitosan-based carbon dots (AOCDs) can effectively treat iron overload osteoporosis. More interestingly, the functional modification of AOCDs by doping calcium gluconate (AOCDs:Ca) is superior to the use of any single component. AOCDs:Ca have the dual function of antioxidant and calcium supplement. AOCDs:Ca effectively improve the bioavailability of calcium and achieve ultra-low concentration calcium supplement for the treatment of iron-induced osteoporosis in zebrafish.

Risk factors and clinical outcomes of incomplete endoscopic resection of small rectal neuroendocrine tumors in southern China: a 9-year data analysis.

Background: The histologically complete resection (CR) rate of small rectal neuroendocrine tumors (RNETs) is unsatisfactory at the first endoscopy. Risk factors and clinical outcomes associated with incomplete resection (IR) have not been explicitly elucidated. This study aims to explore the relevant factors of IR. Methods: This retrospective study reviewed patients with small RNETs (≤10 mm) in eight centers from January 2013 to December 2021. Clinicopathological characteristics and clinical outcomes were compared between the CR and IR groups, and the polypectomy and advanced treatment groups. Results: Of the 326 patients included, 83 (25.5%) were diagnosed with IR. Polypectomy (odds ratio [OR] = 16.86), a central depression (OR = 7.50), and treatment in the early period (OR = 2.60) were closely associated with IR. Further analysis revealed that an atypical hyperemic appearance (OR = 7.49) and treatment in the early period (OR = 2.54) were significantly associated with the inappropriate use of polypectomy (both P < 0.05). In addition, a total of 265 (81.3%) were followed up with a median follow-up period of 30.9 months. No death, metastasis, or recurrence was found during the follow-up period. Conclusions: Polypectomy, a central depression, and treatment in the early period were risk factors for IR. Further, an atypical hyperemic appearance and treatment in the early period were significant predisposing factors for inappropriate choice of polypectomy. For histologically incompletely resected small RNETs, follow-up may be a safe and feasible alternative to rigorous salvage therapy.

Ultrahigh Detectivity Broad Spectrum UV Photodetector with Rapid Response Speed Based on p-ß Ga2 O3 /n-GaN Heterojunction Fabricated by a Reversed Substitution Doping Method.

An excellent broad-spectrum (220-380 nm) UV photodetector, covering the UVA-UVC wavelength range, with an ultrahigh detectivity of ≈1015  cm Hz1/2 W-1 , is reported. It is based on a p-ß Ga2 O3 /n-GaN heterojunction, in which p-ß Ga2 O3 is synthesized by thermal oxidation of GaN and a heterostructure is constructed with the bottom n-GaN. XRD shows the oxide layer is (-201) preferred oriented ß-phase Ga2 O3 films. SIMS and XPS indicate that the residual N atoms as dopants remain in ß Ga2 O3 . XPS also demonstrates that the Fermi level is 0.2 eV lower than the central level of the band gap, indicating that the dominant carriers are holes and the ß Ga2 O3 is p-type conductive. Under a bias of -5 V, the photoresponsivity is 56 and 22 A W-1 for 255 and 360 nm, respectively. Correspondingly, the detectivities reach an ultrahigh value of 2.7 × 1015  cm Hz1/2 W-1 (255 nm) and 1.1 × 1015  cm Hz1/2 W-1 (360 nm). The high performance of this UV photodetector is attributed mainly to the continuous conduction band of the p-ß Ga2 O3 /n-GaN heterojunction without a potential energy barrier, which is more helpful for photogenerated electron transport from the space charge region to the n-type GaN layer.

Lead Exposure Causes Spinal Curvature during Embryonic Development in Zebrafish.

Lead (Pb) is an important raw material for modern industrial production, they enter the aquatic environment in several ways and cause serious harm to aquatic ecosystems. Lead ions (Pb2+) are highly toxic and can accumulate continuously in organisms. In addition to causing biological deaths, it can also cause neurological damage in vertebrates. Our experiment found that Pb2+ caused decreased survival, delayed hatching, decreased frequency of voluntary movements at 24 hpf, increased heart rate at 48 hpf and increased malformation rate in zebrafish embryos. Among them, the morphology of spinal malformations varied, with 0.4 mg/L Pb2+ causing a dorsal bending of the spine of 72 hpf zebrafish and a ventral bending in 120 hpf zebrafish. It was detected that spinal malformations were mainly caused by Pb2+-induced endoplasmic reticulum stress and apoptosis. The genetic changes in somatic segment development which disrupted developmental polarity as well as osteogenesis, resulting in uneven myotomal development. In contrast, calcium ions can rescue the series of responses induced by lead exposure and reduce the occurrence of spinal curvature. This article proposes new findings of lead pollution toxicity in zebrafish.

H2O2/DEM-Promoted Maft Promoter Demethylation Drives Nrf2/ARE Activation in Zebrafish.

The Nrf2/ARE signaling pathway is a cell survival response pathway in response to environmental stresses. The Nrf2/ARE signaling pathway can be activated by stimulating cysteine residues at different positions in the Keap1. However, the epigenetic mechanisms of the Nrf2/ARE pathway under different stimuli are still poorly understood. In this study, we found that both hydrogen peroxide (H2O2) and Diethyl Maleate (DEM) activated the Nrf2/ARE signaling pathway at 120 hpf in zebrafish. H2O2 regulated the demethylation of the maft promoter by inhibiting the expression of methyltransferase. This promotes the mRNA expression of the Nrf2 binding factor maft, thereby promoting the downstream antioxidant genes. The methylation of the Nrf2/ARE signaling pathway was not significantly regulated by DEM. However, under oxidative stress, the methyltransferase inhibitors (decitabine and azacitidine) demethylated the promoter region of maft. It activated the expression of the maft, further improving the Nrf2/ARE signal pathway. At last, antioxidant target genes were activated. It was shown that H2O2 and DEM cooperated with methyltransferase inhibitors, providing an important reference for the treatment of oxidative stress-related diseases and breaking new ground for the study of the mechanism of methyltransferase inhibitors in the process of tumor chemotherapy.

Hydrothermal Corrosion of SiC Coupons Suppressed by Magnetron Sputtered Cr Coatings.

SiC-based components are sometimes susceptible to aqueous dissolution in LWR coolant environments. To address this issue, ~10 µm thick Cr coatings was deposited on reaction-bonded silicon carbide (RBSC) plates by magnetron sputtering. Corrosion behavior of Cr-coated SiC and -uncoated SiC coupons was studied by immersing in autoclave (345°C and 16.5 MPa). The weight loss of the Cr coated SiC coupons (3.02% after the 93-days) in the autoclave tests was effectively reduced due to their Cr-coated surfaces, in contrast to the uncoated ones (20.4% after the 78-days). Moreover, microstructural and compositional evolutions were examined by using scanning electron microscopy (SEM), X-ray diffraction (XRD), and Raman spectroscopy. It was revealed that a continuous and dense Cr2O3 layer formed on the surface after the hydrothermal corrosion, which can suppress the in-diffusion of corrosive medium.

Investigation of Exfoliation Efficiency of 6H-SiC Implanted Sequentially with He+ and H2+ Ions.

Silicon carbide (SiC) is a promising material used in the advanced semiconductor industry. Fabricating SiC-on-insulator via H implantation is a good method. He and H co-implantation into Si can efficiently enhance exfoliation efficiency compared to only H implantation. In this study, 6H-SiC single crystals were implanted with He+ and H2+ dual beams at room temperature, followed by annealing at 1100 °C for 15 min, and irradiations with 60 keV He ions with a fluence of 1.5 × 1016 ions/cm-2 or 5.0 × 1016 ions/cm-2 and 100 keV H2+ ions with a fluence of 5 × 1016 ions/cm-2 were carried out. The lattice disorder was characterized by both Raman spectroscopy and transmission electron microscopy. The intensity of Raman peaks decreased with increasing fluence. No Raman shift or new phases were found. A very high numerical density of bubbles was observed as compared to single H or He implantation. Moreover, stacking faults, Frank loops and tangled dislocations were formed in the damaged layer. Surface exfoliation was inhibited by co-implantation. A possible reason for this is an increase in fracture toughness and a decrease in elastic out-of-plane strain due to dense bubbles and stacking faults.

Double-Sided Nano-ZnO: Superior Antibacterial Properties and Induced Hepatotoxicity in Zebrafish Embryos.

Zinc oxide nanoparticles (Nano-ZnO) have been widely used in the food, cosmetics, and biomedical fields due to their excellent antibacterial and antioxidant properties. However, with the widespread application of Nano-ZnO, Nano-ZnO inevitably enters the environment and living organisms, causing harm to human health and ecosystem safety. Therefore, the biosafety and toxicological issues of Nano-ZnO are gradually being emphasized. Our study found that Nano-ZnO has superior antibacterial properties compared to ofloxacin in the fight against Staphylococcus aureus (S. aureus). Given that ofloxacin can inhibit bacterial-induced inflammation, we constructed a model of bacterial inflammation using S. aureus in zebrafish. We found that Nano-ZnO inhibited the NF-κB-mediated inflammatory signaling pathway. However, in the process, we found that Nano-ZnO caused hepatic steatosis in zebrafish. This suggested that Nano-ZnO had a certain hepatotoxicity, but did not affect liver development. Subsequently, we investigated the mechanism of hepatotoxicity produced by Nano-ZnO. Nano-ZnO triggered oxidative stress in the liver by generating ROS, which then induced endoplasmic reticulum stress to occur. It further activated srebp and its downstream genes fasn and acc1, which promoted the accumulation of fatty acid synthesis and the development of steatosis, leading to the development of nonalcoholic fatty liver disease (NAFLD). To address the hepatotoxicity of Nano-ZnO, we added carbon dots for the treatment of NAFLD. The carbon dots were found to normalize the steatotic liver. This provided a new strategy to address the hepatotoxicity caused by Nano-ZnO. In this work, we systematically analyzed the antibacterial advantages of Nano-ZnO in vivo and in vitro, explored the mechanism of Nano-ZnO hepatotoxicity, and proposed a new method to treat Nano-ZnO hepatotoxicity.

Transabdominal Laparoscopic Ureteroureterostomy With the Intraoperative Retrograde Ureteroscopy-Assisted Technique for Multiple Ureteral Polyps: A Single-Center 10 Years Experiences.

Background: The purpose of this study was to report our experience in treating multiple ureteral polyps with transabdominal laparoscopic ureteroureterostomy (LAP-UU) with intraoperative retrograde ureteroscopy (RU)-assisted technique. Methods: The data of 32 patients who underwent transabdominal LAP-UU with the intraoperative RU-assisted technique due to multiple ureteral polyps between January 2011 and March 2021 were reviewed at our institute. After administration of anesthesia, patients were placed in a passive position and underwent a three-port transabdominal laparoscopy with RU. Detailed data were reviewed, such as demographic characteristics, intraoperative outcomes, postoperative data, complications, and pathology reports. Results: Thirty-two patients were diagnosed with multiple ureteral polyps underwent this surgery method at our institution. The mean duration of symptoms at the time of diagnosis was approximately 7.1 months. The mean age of patients was 42.4 years, with men accounting for 68.8% (22/32), lesion of left for 56.3% (18/32), and the upper ureter for 62.5% (20/32). Furthermore, the median length of the polyps was 3.6 cm, the mean operative time was 174.6 min, and the estimated blood loss (EBL) was about 86.8 ml. The mean time to begin a liquid diet and to be out of bed were 1.7 and 2.3 days, respectively. The average length of hospital stay was 6.3 days. The ureteral stent was removed by cystoscope 2-3 months after surgery. Follow-up duration ranged from 3 to 112 months and none of the patients required another surgery for recurrence. Conclusion: Transabdominal LAP-UU combined with the intraoperative RU-assisted technique is an effective, safe, and reliable surgical option for patients with multiple ureteral polyps. Further long-term follow-up is recommended.

Inhibition of neurogenic contractions in renal arteries and of cholinergic contractions in coronary arteries by the presumed inhibitor of ADP-ribosylation factor 6, NAV2729.

NAV2729 is a presumed inhibitor of the monomeric GTPase ADP ribosylation factor 6 (ARF6) and inhibits smooth muscle contraction outside the cardiovascular system. Its effects on vascular smooth muscle contraction or a possible role of ARF6 in vasocontraction have not yet been examined. Here, we report effects of NAV2729 on neurogenic and agonist-induced contractions in renal interlobar and coronary arteries. Contractions of pig interlobar and coronary arteries were induced in an organ bath by agonists or by electric field stimulation (EFS). Owing to divergent characteristics of both vessel types, EFS-induced contractions were only examined in interlobar arteries, and contractions by agonists acting on muscarinic receptors only in coronary arteries. NAV2729 inhibited frequency-dependent EFS-induced contractions of interlobar arteries. The degree of inhibition was similar using 5 µM and 10 µM NAV2729. Inhibition of EFS-induced contractions was resistant to a nitric oxide synthase inhibitor and to diclofenac. The neurogenic and adrenergic character of EFS-induced contractions was confirmed by inhibition by tetrodotoxin and prazosin. In coronary arteries, NAV2729 (5 µM) inhibited concentration-dependent contractions induced by carbachol and methacholine. Contractions induced by α1-adrenergic agonists, endothelin-1, the thromboxane receptor agonist U46619, or serotonin remained unchanged by NAV2729 in both vessel types. NAV2729 inhibits neurogenic contractions in interlobar arteries and contractions induced by cholinergic agonists in coronary arteries. In both vessel types, NAV2729 does not inhibit contractions induced by receptor agonists other than those acting on muscarinic receptors. Addressing effects in other vessels and in other smooth muscle-rich organs merits further attention.

Inhibition of human prostate smooth muscle contraction by the inhibitors of protein kinase C, GF109203X, and Go6983.

INTRODUCTION: Prostate smooth muscle contraction is promoted by receptor-induced activation of intracellular signaling pathways. The presumed involvement in etiology and medical treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) imparts a high clinical relevance to prostate smooth muscle contraction, which is contrasted by incomplete understanding at the molecular level. Involvement of protein kinase C (PKC) has been commonly assumed, but available studies were limited to nonhuman prostate smooth muscle or cell cultures. Here, we examined the effects of the PKC inhibitors Go6983 and GF109203x on contractions of human prostate tissues. METHODS: Prostate tissues were obtained from radical prostatectomy. Contractions were induced by electric field stimulation (EFS), α1 -adrenergic agonists (noradrenaline, phenylephrine, methoxamine), thromboxane A2 analog U46619, endothelin-1, or calcium chloride in an organ bath. RESULTS: GF109203X (500 nM) and Go6983 (300 nM) reduced EFS-, noradrenaline-, phenylephrine-, methoxamine-, and U46619-induced contractions of human prostate tissues, with maximum inhibitions approaching up to 55%. Using concentrations of 3 µM, GF109203X and Go6983 inhibited EFS- and noradrenaline-induced contractions, with similar effect sizes as 500 and 300 nM, respectively. Endothelin-1-induced contractions were not inhibited by GF109203X, and to neglectable extent by Go6983. After depolarization in calcium-free solution, calcium chloride-induced concentration-dependent contractions, which were inhibited by GF109203X and Go6983. CONCLUSIONS: GF109203X and Go6983 inhibit neurogenic, α1 -adrenergic, and thromboxane A2 -induced smooth muscle contractions in the human prostate, suggesting a role of PKC for human prostate smooth muscle contraction. The inhibition may by be imparted by inhibition of calcium sensitivity.

Phosphoproteomics identifies potential downstream targets of the integrin α2ß1 inhibitor BTT-3033 in prostate stromal cells.

BACKGROUND: Integrin α2ß1 inhibitor BTT-3033 (1-(4-fluorophenyl)-N-methyl-N-[4[[(phenylamino)carbonyl]amino]phenyl]-1H-pyrazole-4-sulfonamide) was recently reported to inhibit neurogenic and thromboxane A2-induced human prostate smooth muscle contraction, and thus represents a target with a different inhibition spectrum than that of α1-blockers in benign prostate hyperplasia (BPH) treatments. Clarifying the underlying mechanisms of the inhibition effects will provide insights into the role of integrin α2ß1 in prostate contraction and enable new intracellular targets for smooth muscle contraction to be explored. METHODS: ProteomeHD was used to predict and enrich the top co-regulated proteins of integrin α2 (ITGA2). A phosphoproteomic analysis was conducted on human prostate stromal cells (WPMY-1) treated with 1 or 10 µM of BTT-3033 or solvent for controls. A clustering analysis was conducted to identify the intracellular targets that were inhibited in a dose-dependent manner. Gene ontology (GO) and annotation enrichments were conducted to examine any functional alterations and identify possible downstream targets. A Kinase-substrate enrichment analysis (KSEA) was conducted to identify kinases-substrate relationships. RESULTS: Enrichments of the actin cytoskeleton and guanosine triphosphatases (GTPases) signaling were predicted from the co-regulated proteins with ITGA2. LIM domain kinases, including LIM domain and actin-binding 1 (LIMA1), zyxin (ZYX), and thyroid receptor-interacting protein 6 (TRIP6), which are functionally associated with focal adhesions and the cytoskeleton, were present in the clusters with dose-dependent phosphorylation inhibition pattern. 15 substrates were dose-dependently inhibited according to the KSEA, including polo-like kinase 1 (PLK1), and GTPases signaling proteins, such as disheveled segment polarity protein 2 (DVL2). CONCLUSIONS: In this study, we proposed that the mechanisms underlying the contractile and proliferative effects of integrin α2ß1 are the LIM domain kinases, including the ZYX family, and substrates, including PLK1 and DVL2.

Fluorescent Egg White-Based Carbon Dots as a High-Sensitivity Iron Chelator for the Therapy of Nonalcoholic Fatty Liver Disease by Iron Overload in Zebrafish.

Iron overload is the direct cause of many ferroptosis diseases, and it is essential to maintain iron homeostasis. In this paper, we report the Fe3+ chelation and therapy of the iron overload nonalcoholic fatty liver disease (NAFLD) by the fluorescent egg white-based carbon dots (EWCDs) obtained through the microwave-assisted pyrolysis method. As a high-sensitivity sensor, EWCDs show a high correlation between fluorescence emission and the concentration of Fe3+ (R2 = 0.993) in low concentration ranges of 0-25 µM. In vivo and in vitro, the EWCDs show characteristics of high biocompatibility and specific binding of Fe3+. As a novel type of the nano-iron-chelator, EWCDs can successfully attenuate the production of lethal reactive oxygen species. EWCDs not only alleviate the endoplasmic reticulum stress response but also regulate the NF-κB signaling pathway downstream of the Nrf2 signaling pathway. EWCDs prevent hepatocyte apoptosis, regulate fatty acid metabolism, and alleviate inflammation. Ultimately, they alleviate NAFLD induced by iron overload in zebrafish. This work may provide a new idea and method for the application of carbon dots in the field of disease detection and treatment.

Leptin Receptor Overlapping Transcript (LEPROT) Is Associated with the Tumor Microenvironment and a Prognostic Predictor in Pan-Cancer.

BACKGROUND: Leptin receptor overlapping transcript (LEPROT) is reported to be involved in metabolism regulation and energy balance as well as molecular signaling of breast cancer and osteosarcoma. LEPROT is expressed in various tissue and is suggested to be involved in cancer developments but with contradictory roles. The comprehensive knowledge of the effects of LEPROT on cancer development and progression across pan-cancer is still missing. METHODS: The expressions of LEPROT in cancers were compared with corresponding normal tissues across pan-cancer types. The relationships between expression and methylation of LEPROT were then demonstrated. The correlations of LEPROT with the tumor microenvironment (TME), including immune checkpoints, tumor immune cells infiltration (TII), and cancer-associated fibroblasts (CAFs), were also investigated. Co-expression analyses and functional enrichments were conducted to suggest the most relevant genes and the mechanisms of the effects in cancers for LEPROT. Finally, the correlations of LEPROT with patient survival and immunotherapy response were explored. RESULTS: LEPROT expression was found to be significantly aberrant in 15/19 (78.9%) cancers compared with corresponding normal tissues; LEPROT was downregulated in 12 cancers and upregulated in three cancers. LEPROT expressions were overall negatively correlated with its methylation alterations. Moreover, LEPROT was profoundly correlated with the TME, including immune checkpoints, TIIs, and CAFs. According to co-expression analyses and functional enrichments, the interactions of LEPROT with the TME may be mediated by the interleukin six signal transducer/the Janus kinase/signal transducers and activators of the transcription signaling pathway. Prognostic values may exist for LEPROT to predict patient survival and immunotherapy response in a context-dependent way. CONCLUSIONS: LEPROT affects cancer development by interfering with the TME and regulating inflammatory or immune signals. LEPROT may also serve as a potential prognostic marker or a target in cancer therapy. This is the first study to investigate the roles of LEPROT across pan-cancer.